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R O E N T G E N R A Y I N T O X I C A T I O N .I. UNIT DOSE OVER THO RAX NEGATIVE OVER ABDO ME N LETHAL.

EPITHELIITM OF S MALL INTESTINE SENSITIVE TO X rAYS.

BY S. L. WA RR EN AND G. H. WH IPPL E, M.D.From The George Williams Hooper Foundation for Medica l Research, Universityof California Medical School, San Francisco.)

Received for publication, August 16, 1921.)The p apers of th is ser ies form a par t of the general program of s tudyof the non-specific in toxica t ions which is being carr ied forward

in th is laboratory . Th ey are concerned with an inves t igat ion of thesys temic in toxicat ion which develops af ter a sui table exposure to largedoses of hard R oentg en rays . These papers fol low along the logicaldevelo pmen t of th is s tudy, based on the beginnings mad e by Hal l a ndWhipple (3) . Reference to the paper of Hal l and Whipple is necessaryfor a review of some of the rath er extens ive l i terature of th is subjectand for a d iscuss ion of m an y of the funda menta l problems related toRoentgen ray in toxicat ion.

This Roen tgen ray in toxicat ion, we believe, is a t rue non-specificin tox ica t ion and des e rves tho rough s tudy in pa r t fo r th i s ve ryreason. Too l it t le s tud y has been directed toward an under s tandingof the non-specific in toxi cat ion which of ten is a very imp or tan tfactor in many of the so cal led specif ic infections . This R oentge nray in toxicat ion closely resembles the in toxicat ion of in tes t inal ob-s t ruc t ion , ano ther im por ta n t non-specific in toxic at ion. We shal lpoin t out some impo r tan t d if ferences between the in toxicat ion dueto the Roe ntgen rays as contras ted with in tes t inal o bs truct ion, b utthere remain many s t r ik ing s imilar i t ies as emphas ized by Hal l andWhi pple (3).

We bel ieve our exper iments mak e i t c lear tha t th e fundam entalth ing in the s ys tem ic in tox ica t ion due to the Roe n tge n r ays i s aprimary inju ry of the epithelium of the small intestine. This w as sus-

187

Published February 1, 1922

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188 ROENTGEN R Y INTOXICATION I

p e c t e d b y H a l l a n d W h i p p l e b u t n o t c o n c lu s i ve l y p r o v e n . O u re x p e r ime n t s i n n o r ma l d o g s u n d e r c o n t r o l l e d c o n d i t i o n s a p p e a r c o n -v i n c i n g w h e n e x p o su r e s g i v e n o v e r t h e t h o r a x a r e c o n t r a s t ed w i t h t h esa m e e x p o su r e s o v e r t h e a b d o m e n . F o r e x a mp le , a u r d t d o se (3 5 0mi l l i a mp e r e min u t e s ) g iv e n o v e r t h e t h o r a x ( a b d o m e n sh i e ld e d ) c a u se sn o c l i n ic a l d i s t u r b a n c e i n t h e d o g . A su b se q u e . n t e x p o su r e t o t h es a m e u n i t d o s e i n t h e s a m e d o g g i v e n o v e r t h e a b d o m e n ( t h o r a xsh i e ld e d ) w i ll c a u se f a t a l i n to x i c a t i o n a n d d e a th i n 4 d a y s . F o r an o r m a l 3 0 t o 4 0 p o u n d d o g , w e m a y s a y t h a t 3 5 0 m i l l ia m p e r e m i n u t e sg i v e n o v e r th e a b d o m e n is a m i n i m u m l e t h a l d os e .

T h e o u t s t a n d i n g a b n o r m a l i t ie s in t h e a b d o m i n a l e x p o s u re s a re t h er e ma r k a b l e n e c r o se s o b se r v e d i n t h e sma l l i n t e s t i n e . L a r g e a r e a sm a y s h o w c o m p l e t e n e c r o s i s a n d d i s a p p e a r a n c e o f t h e i n t e s t i n a le p i t h e l i u m c o v e r in g t h e v i l li a n d l i n in g t h e c r y p t s . T h e v i l li a r el e f t a s n a k e d p o ly p s ma d e u p o f s t r o ma , v e s se ls , a n d a f e w w a n d e r in gc el ls . T h e i n f l a m m a to r y r e a c t i o n is n o t a s in t e n se a s w o u ld b ee x p e c t ed u n d e r s u c h c o n d i t i o n s w i t h c o m p l e t e r e m o v a l o f t h e c o v er -i n g e p i th e l i u m . T h i s i m p o r t a n t p o i n t w i l l b e d i s c u ss e d i n d e t a i li n a su b se q u e n t p a p e r .

R e g a u d , N o g ie r , a n d L a c a s sa g n e ( 5 ) d e sc r ib e d t h e c h r o n i c g a s t r o -in t e s t i n a l l e s io n s i n d o g s a n d n o t e d e sp e c i a ll y g a s t r i c a t r o p h y a n d i n t e s -t i n a l p e r f o r a t i o n . F r o m m e (2 ) n o t e d e sp e c ia l l y t h e c li n i ca l sy m p to m so f g a s t r o in t e s t i n a l d i s t u r b a n c e i n g u in e a p ig s a n d mic e . D e n i s , M a r -t i n , a n d A ld r i c h ( 1) n o t e d i n r a b b i t s t h e t o x i c e ff e c t o f a b d o m in a lr a d i a t i o n a n d c e r t a i n a b n o r m a l i t i e s i n t h e i n t e s t i n e s w h i c h t h e ys t a t e a r e s e c o n d a r y t o a n u n k n o w n t o x ic f a ct o r .

M ethodT h e p r o c e d u r e i s i d e n t i c a l i n a l l e x p e r ime n t s , u n l e s s o th e r w i se

i n d i c at e d . N o r m a l d o g s a r e u s e d t h r o u g h o u t a n d a r e k e p t i n s t a n d a r dme ta b o l i sm c a g e s w h ic h h a v e sh a r p ly p i t c h e d f l o o r s t o f a c i l i t a t e t h ec o l l e c ti o n o f u r in e . T o i n su r e t h e a c id i t y o f t h e c a g e c o l le c t io n s ,abo ut 1 cc . o f g lac ia l ace t ic ac id is add ed to the cage co l lec t ing bot t lea t t h e b e g in n in g o f e a c h 24 h o u r c o ll e c ti o n . T h e d o g s a re c a th e t e r i z e dd a i ly a t 1 0 o c lo c k . T h e c a g e c ol l ec t io n s , ca g e w a sh in g s , b l a d d e rw a sh in g s , a n d c a th e t e r i z e d u r in e a r e mix e d a n d d i l u t e d t o a u n i tv o l u m e - - u s u a l l y 2 li te r s. T h e t o t a l n i t ro g e n is t h e n d o n e i n d u p li -


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S L W A R R E l ~ A N D G H W H I P P L E 189c a t e b y t h e K j e l d a h l m e t h o d . A b o u t 3 00 c c . o f w a r m w a t e r i s g i v e nd a i l y b y s t o m a c h t u b e a s a r o u t i n e p r o c e d u r e a f t e r t h e d o g is c a t h e -t e r i z e d . W a t e r is a v a i l a b l e a t a l l t i m e s in t h e c ag e .

D o g s a r e g i v e n a s u b c u t a n e o u s i n j e c t i o n o f m o r p h i n e s h o r t l yb e f o r e e x p o s ur e to r a d i a t io n . A m e d i u m h a r d C o o l id g e t u b e i s u s e dw i t h t h e t a r g e t a n o d e o r a n ti c a t h o d e ) s e t a t a c o n s t a n t d is t a n c eo f 10 i n c h e s f ro m t h e s k i n . A t t h i s d i s t a n c e t h e e f f e c t i v e r a d i a t i o nfo r t h i s m a c h i n e c o v e r s a c i r c l e a p p ro x i m a t e l y 6 i n c h e s i n d i a m e t e r .T h e c u r r e n t s tr e n g t h u s e d is e i t h e r 7.5 o r 8 .0 m i l li a m p e r es . T h eE .M .F. v a r i e s c o n s i d e ra b l y i n d i f f e r e n t e x p e r i m e n t s f ro m 8 5 k i l o -v o l t s t o 1 03 k i l o v o lt s . Th e s p a rk -g a p b a c k i n g u p t h e s e v o l t a g e sv a r i e s a l s o , m e a s u r i n g f ro m 8 t o 1 0 i n c h e s b e t w e e n s h a rp p o i n t s .T h e a m o u n t o f r a d i a t i o n i s c a l c u l a t e d a s t h e p r o d u c t o f t h e c u r r e n ts t r e n g t h i n m i l l ia m p e r e s a n d t h e t i m e o f e x p o s u r e i n m i n u t e s a n d i se x p re s s e d a s m i l l i a m p e re m i n u t e s . I n a l l t h e s e e x p e r i m e n t s t h es t a n d a r d a u t o t r a n s f o r m e r x -r a y e q u i p m e n t o f t h e U n i v e r s i t y o f C a l lfo rn i a H o s p i t a l i s u s e d . A l u m i n u m f il t e rs 2 r a m . ) a r e u s e d t o c u t o u tt h e s o f t e r r a y s . Th e v a r i o u s p a r t s o f t h e d o g w e re e f f e c t i v e l y p ro -t e c t e d f ro m r a d i a t i o n , w h e n i t w a s s o d e s i r e d , b y s h e e t s o f l e a d - fo i la p p r o x i m a t e l y 2 r a m . t h i c k , o r b y l e a d rubber, a p p r o x i m a t e l y 5r a m . i n t h i c k n e s s .

T h e b o d y o f t h e d o g i s m a r k e d o ff r o u g h l y i n to t w o p a r t s b y at r a n s v e r s e l in e a t t h e le v e l o f t h e x i p h i st e r n u m . T h e p a r t b e t w e e nt h i s li n e a n d t h e b a s e o f t h e n e c k is d e s i g n a t e d a s t h e t h o ra x , t h a tb e l o w a s t h e a b d o m e n . E a c h o f t h e s e p a r t s i s t h e n d i v i d e d i n t o a nu p p e r a n d l o w e r h a l f. E a c h u p p e r a n d l o w e r s e g m e n t o f t h e a b d o m e no r t h o r a x i s r a d i a t e d f r o m t h e l a t e r a l a n d m i d v e n t r a l a sp e c t s. T h u st h e v e n t r a l p o r t i o n o f t h e a b d o m e n o r t h o r a x i s e xp o s e d to r a d i a t i o no v e r s i x d i f f e r e n t a r e a s w h o s e c o n t i g u o u s e d g e s o v e r l a p s o m e w h a t .U s u a l l y o n e e x p o s u re i s gi ~c en o v e r t h e m i d d o r s a l r e g i o n o f t h e t h o ra xo r a b d o m e n , c a u s i n g t h e t o t a l d o s a g e t o b e d i v i d e d u p i n t o s e v e np a r t s , w h i c h , h o w e v e r , a r e s p r e a d r a t h e r d i ff u s e ly o v e r t h e p a r t o f t h eb o d y i n v o lv e d . A l l d o g s a r e s a c ri f ic e d u n d e r c h l o ro fo rm o r e t h e ra n e s t h e s i a b y b l e e d in g .


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190 ROENTGEN R Y INTOXICATION. IE X P E R I M E N T A L O B S E R V A T I O N S

S o m e o f o u r t y p i c a l e x p e ri m e n t s a r e t a b u l a t e d b e l o w a n d m a k cs e v e r a l p o i n t s q u i t e c l ea r . H o w e v e r , w e w is h t o r e f e r t o o t h e re x p e r i m e n t s o f s i m i l a r n a t u r e g i v e n i n s u b s e q u e n t p a p e r s o f th i ss e r ie s . T h e s e e x p e r i m e n t s a r e al l i n a g r e e m e n t a n d i n d i c a t e t h a te n o r m o u s d o s e s o f R o e n t g e n r a y s m a y b e g i v e n o v e r t h e t h o r a xw i t h o u t c a u s i n g a n y c li n ic a l r e a c t io n i n a n o r m a l d o g . D o g s h a v eb e e n g i v e n a m o u n t s o f r a d i a t i o n v a r y i n g f r o m 3 0 0 t o 5 1 2 m i l l i a m p e r em i n u t e s o v e r t h e t h o r a x w i t h o u t a n y c l in i ca l s y m p t o m s . O n e d o g

N o . 1 9 -1 1 7) w a s g iv e n 3 5 0 m i U i a m p e r e m i n u t e s o v e r t h e t h o r a x o nt h r e e s e p a r a t e o c c a s i o n s w i t h i n t e r v e n i n g p e r i o d s o f 2 t o 3 w e e k s ; a l lt h i s w i t h o u t a n y a p p a r e n t c u m u l a t i v e e f f e c t s o r c l in i c a l r e a c t i o n .T h e r e i s u s u a l l y a s li g h t t r a n si e n t l e u c o p e n i a a n d t h e r e m a y b e av e r y s l ig h t r is e i n t o t a l n i t r o g e n e x c r e t i o n . A f t e r 2 o r 3 w e e k s , t h es k i n s h o w s l o s s o f h a i r a n d p i g m e n t a t i o n a s a r e s u l t o f t h e e x p o s u r e s .T h e r ib s o f t h e a n i m a l e x a m i n e d a t a u t o p s y s h o w a c o n s i d e ra b l e lo s so f m a r r o w c e l l e l e m e n t s . W e h a v e b e e n a b l e to r e c o g n iz e n o o t h e rr e s u l t s f r o m t h e s e l a r g e d o s e s o f x - r a y s o v e r t h e t h o r a x .

D o g 1 9 - 7 8 T a b l e I ) is a t y p i c a l e x a m p l e o f a c o m p l e t e e x p e r i m e n tt o s h o w t h a t a u n i t d o s e o f x - r a y s i s c l i n ic a l l y i n e r t o v e r t h e t h o r a xb u t l e t h a l w h e n g i v e n o v e r t h e a b d o m e n . T h e t h o r a x d o s e c a u s e s ad e f i n i t e l e u c o p c n i a b u t n o c l in i c a l d i s t u r b a n c e . T h a t t h e s e c o n dd o s c d o e s n o t c a u s e a s m u c h o f a le u c o p c n ia , w e b e l ie v e , m a y b e d u et o t h e t i s s u e i n j u r y i n t h e s m a l l i n t e s t in e .

T h e r a d i a t i o n o v e r t h e a b d o m e n c a u s e s a ty p i c a l c l i n ic a l r e a c t i o na n d t h e r e v i e w o f t h i s c a s e w i l l s u ff ic e f o r a l l s u b s e q u e n t e x p e r i m e n t s .T h i s c l i n i c a l r e a c t i o n i s r e m a r k a b l y c o n s t a n t a n d i s d e s c r i b e d i n d e t a i lb e l o w D o g 1 9 - 7 8 ). T h e l a t e n t p e r i o d o f 2 4 t o 3 6 h o u r s is n o t e d a su s u a l a n d w i l l b e d is c u s s e d l a t e r . T h e r i se i n t o t a l u r i n a r y n i t r o g e ni s n o t g r e a t b u t i s s i g n if i c a n t. T h e f i g ur e f o r t h e l a s t d a y i n c l u d e s ac e r t a in a m o u n t o f f e c a l c o n t a m i n a t i o n .

Dog 19-78. Clin ical History and Autopsy Se e Tab le I).Jan . 27. The dog is isolated on fasting diet. The anim al is in good conditionand quite active.Jan. 29. The abdomen is covered with lead-foil we ll up to the level of the

diaphragm. The thorax is exposed in seven areas, two midventral , two on each


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S L WARREN A N D G H. W H I P P L E 9side, and one over the midscapular region. Each area exposed covered a patch ofskin approximatel y 5 inches square. Morphia ( i gr.) is given to keep the dogquie t during the exposure. The curr ent stre ngth is 7.5 milliamperes at an ~. ~. IP.of I00 kilovolts with the spark-gap set at 9 ~ inches. 2 mm. of alumi num filter isused and the tube is set at a ta rget-skin distance of I0 inches.

TABLE I.Roentgen Radiation

Uni t Dose Given over Thorax and Subsequently over AbdomenDog 19-78. Adult , female.D a t

~8

Mar. 151718

Mar. 18Mar. 19202122

White Urine.Weight. blood or- Diet. Remarkspusclesper am Volume TotalI bs co

26.026.0 7,600Jan . 29 3 mil]i ere30 2581 8 1 I1 24 . 514 , 100 IFeb. 1 23.8 I 4,600 I2 23.3 ] 4,6 00]

3 2 3 0 I - [8 27.0 5,400 [21 28.3 ] 7,400 [Experiment ended.

W a t e r G o o d c o n di t i on

X-rays, 350 milliampere minutes, given over thorax. Abdomen shielded.

M

Water.

Mixed.ccc

Dog normal.Dog normal.Dog normal.Dog normal.

28.927.827.3

7,8007,6008,000

M260 2.74305 2.68

W a y r . Dog normal.Dog normal.

X-rays, 350 milliampere minutes, given over abdomen. Thorax shielded.26.8 6,400 290 2.83 Water.26.6 7,000 265 2.7425.9 7,200 240 3.0025.0 3,900 - - 5.63Chloroform anesthesia and autopsy a t once.

Dog normal.Inactive.Vomitus and diarrhea.Moribund.

Jan. 30. Dog remains normal during entire experiment (see Table I). Therewas a slight transient leucopenia. Dog was on mixed diet unti l the second experi-ment, also given in Table I.

Mar. 15. The dog is active and in good condition.


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92 ROENTGEN RAY INTOXICATION. IM a r . 1 8. D o g g i v e n g r . o f m o r p h i a 1 h o u r b e f o re e x p o s u r e t o r a d i a t i o n .

T h e t h o r a x a n d h e a d a n d n e c k a r e t h o r o u g h l y s c r e e n ed w i t h l e a d - f o i l d o w n t ot h e t i p o f t h e x i p h i s t e r n u m . S e v e n a r e a s a r e e x p o se d , tw o m i d v e n t r a l , t w o o ne a c h l a t e r a l s u r fa c e , a n d o n e m i d l u m b a r . T h e c u r r e n t s t r e n g t h i s 7.5 m i l l i a m -p e r e s a t a n E. ~ . P . o f 9 5 k i l o v o l t s , b a c k e d b y a 9 i n c h s p a r k - g a p . T h e r a d i a -t i o n i s f i l t e r e d b y 2 m m . o f a l u m i n u m . T h e s k i n - t a r g e t d i s t a n c e i s 1 0 i n c h e s .T h e r e a r e n o i m m e d i a t e a f t e r e f f ec t s f r o m e x p o s u r e t o 3 5 0 m i l l i a m p e r e m i n u t e s.

M a r . 1 9. T h e d o g i s b r i g h t a n d a c ti v e .M a r . 2 0. S l i g h t e v i d e n ce s o f i n t o x i c a t io n a r e m a n i f e s t e d b y t h e d o g - - o n e

s o f t , y e l l o w , w a t e r y s t o o l .M a r . 2 1 . T h e i n t o x i c a ti o n b e c o m e s m a r k e d in t h e a f t e r n o o n. T h e d i a r r h e a

h a s p r o g r e s s e d f r o m b r o w n i s h , w a t e r y m a t e r i a l t o t a r r y , b l a c k m u c o u s o r b l o o d ym u c o u s m a t e r i a l w i t h a v e r y fo u l o d o r . V o m i t u s in c r e a se s i n a m o u n t a n d f r e-q u e n c y d u r i n g t h e d a y .

M a r . 2 2. T h e a n i m a l i s v e r y w e a k a n d d u l l . I n t h e a f te r n o o n , t h e d o g i sc o m p l e t e l y p r o s t r a t e d . T h e s t o o ls h a v e b e c o m e v e r y f r e q u e n t a n d o f l a rg ev o l u m e . T h e p u l s e i s i r r e g u l a r a n d t h r e a d y . T h e t e m p e r a t u r e h a s r i s en t o4 0 .2 C . T h e r e s p i r a t i o n s a r e r a p i d a n d i rr e g u l a r . T h e a n i m a l is p r a c t i c a l l ym o r i b u n d a n d i s s a c r i f ic e d u n d e r c h l o r o f o r m a n e s t h e s i a .Autopsy. - -Performed i m m e d i a t e l y a f t e r d e a t h b y c h l o ro f o r m . T h e h a i r o v e rt h e t h o r a x is t h in n e d . I t i s a b s e n t o v e r th e s t e r n u m w h e r e t h e s k i n i s s o m e w h a tp i g m e n t e d f r o m p r e v i o u s e x p o s u re s t o r a d ia t i o n . P l e u r a l c a v i t y , h e a r t , a n d l u n g sa r e n o r m a l . P e r i t o n e a l s u r f ac e s a r e n o r m a l . S p l e en i s s o m e w h a t g r a n u l a r i n a p -p e a r a n c e , h a r d a n d f i r m , n o r m a l i n s i ze . O n s e c t i o n , t h e t r ab e c u l~ e s t a n d o u t .M e s e n t e r i c g l a n d s s l ig h t l y e n l a r g e d a n d m o i s t - - s o m e w h a t p i n k i s h i n c o l o r .K i d n e y s n o r m a l i n s i ze a n d a p p e a r a n c e . B l a d d e r c o n t r a c t e d ; i t s h o w s a f e we c c h y m o s es i n i t s m u c o s a ( c a t h e te r ) . L i v e r i s n o r m a l . A d r e n a l s a r e s o m e w h a te n l a r g e d ; a p p a r e n t l y n o r m a l e x c e p t f o r a s m a l l n e c r o t i c m a s s i n t h e l e f t a d r e n a l .Stomach c o n t a i n s g a s a n d a b o u t 2 0 c c . o f a b i l e - s t a i n e d f l u i d . T h e m u c o s a i sp a l e a n d n o r m a l .Duodenum i s s o m e w h a t t h i c k - w a l l e d a n d s p a s t i c . T h e l u m e n c o n t a i n s m a n yl a r g e, r o u n d w o r m s a n d a s m a l l a m o u n t o f r e d d i s h - b l a c k m u c u s . B e g i n n i n gs h a r p l y a t a p o i n t a p p r o x i m a t e l y a n i n c h d i s t a l to t h e pyloric valve t h e m u c o s a o fthe duodenum p r e s e n t s a d a r k r e d g l as s y a p p e a r a n c e . O n t h i s b a c k g r o u n d ru ns e v e r a l l o n g i t u d i n a l f o l d s w i t h b r i g h t r e d h e m o r r h a g i c c r e s t s. N u m b e r s o f s m a l lb r i g h t r e d p e te ch i~ e s h o w u p b e t w e e n t h e s e p l ic ~ e o n t h e d a r k , g l a s s y s u r f a c e .

T h e r e a c t i o n i n t he j e junum s e e m s l e ss i n te n s e , f o r h e r e t h e m u c o s a i s p a l e r a n dt h e p l ic ~ e a r e n o t s o c o n s p i c u o u s t h o u g h t h e y c a n b e d i s t i n c t l y m a d e o u t .I l eum c o n t a i n s a s m a l l a m o u n t o f r e d d i sh - b l a c k m u c o u s m a t e r i a l s i m i l a r t ot h e s t o o l s , a n d a f e w r o u n d w o r m s . T h e i n t e s t i n a l w a l l i s t h i n a n d r a t h e r f l a c c ida n d o n c l o s e i n s p e c t io n t h e i n t e n s e l y h e m o r r h a g i c m u c o s a s u r f ac e s e e m s t o h a v eb e e n d e n u d e d o f m o s t o f t h e v i l l i a s t h e v e l v e t y a p p e a r a n c e i s la c k i n g . T h el o n g i t u d i n a l f o l ds w i t h b r i g h t r e d h e m o r r h a g i c c r e s ts a r c c o n s p ic u o u s . P e y e r s


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S L W A R R E N A N D G IT W R I P P L E 93

p a t c h e s s e e m t o b e s t r i p p e d o f t h e i r v il l o u s c o v e r i ng s o t h a t t h e y s h o w u p r e a d i l ya s s p e ck l e d o v a l p a t c h e s . T h e i l eo c e c a l v a l v e m a r k s a n a b r u p t e n d o f t h i se x t e n s i v e i n j u r y .Colon m u c o s a i s p a l e , t h o u g h a f e w l o n g i t u d i n a l , h e m o r r h a g i c f o l d s a r e p r e s e n t .T h e w a l l s a r e s p a s t i c a n d t h e l u m e n c o n t a i n s a s m a l l a m o u n t o f r e d d i s h f l u id .

Histological Sections.L u n g s , h e a r t , l i v e r , p a n c r e a s , k i d n e y s , b l a d d e r , u t e ru s , a n d s t o m a c h a r e n e g a -

t i v e. T h e m e s e n t e r i c l y m p h n o d e s a r e sl i g h t l y h e m o r r h a g i c a n d c o n t a i n s o m ep i g m e n t . T h e s p l e e n i s m o d e r a t e l y a t r o p h i c a n d c o n t a i n s p i g m e n t . I n t h eo v a r y t h e o v a a r e a p p a r e n t l y d e a d , t h o u g h n u c l eo l i a n d c h r o m a t i n r e m n a n t s a r es t i l l p r e s e n t w i t h i n t h e n u c l e a r m e m b r a n e .Pyloric duodenum a s e c t i on s ho w s t h e t r a n s i t i o n fr o m n o r m a l i n t a c t p y l o r i cv i l li t o c o l l a p s e d a n d d e n u d e d v i l l i w i t h r e m n a n t s o f d e a d e p i t h e l i u m a n d s o m er e g e n e r a t i n g e p i t h e l i a l c el l s u n d e r g o i n g m i t o s i s . S o m e a r e a s h a v e e s c a p e d in j u r y .Jejunum d e s t r u c t i o n a n d d i s a p p e a r a n c e o f t h e e p i t h e l i u m o f v i l l i a n d c r y p t s ;a f e w c r y p t s r e m a i n , o t h er w i s e t h e n o r m a l s t r u c t u r e i s g o n e . T h e e p i t h e l i u ma r o u n d t h e s e c r y p t s s h o w s m i t o t i c f ig u r e s a n d t h e s e a r e a p p a r e n t l y r e g e n e r a t i o nf o r m s . L a r g e p a l e e p it h e l i a l c e ll s s t i c k o u t i n t o t h e lu m e n o f t h e c r y p t s . T h e i rc y t o p l a s m i s f i ne l y m e s h e d a n d i s d e c i d e d l y e os i n op h i li c . T h e n u c l e i a r e r a t h e rl a r g e a n d p a l e a n d f r e q u e n t l y c o n t a i n m i t o t i c fi g u re s . A l a rg e a m o u n t o f h e m o r -r h a g e h a s o c c u r r e d i n t h e s u b m u c o s a , a n d b l o o d v e s s e ls a r e o c c a s i o n al l y f o u n dp l u g g e d w i t h t h r o m b i o f f i b r in a n d p l a t e l e t s . O n s o m e a r e a s a v e r y t h i n s h e e t o fe p i t h e l i al ce l ls c a n b e s e e n m a k i n g a n a t t e m p t t o r e c o v e r t h e c o l l a p s e d ~ l l i .

T h e ileum s h o w s e x tr e m e i n j u r y , w i t h t h e d i s a p p e a r a n c e o f t h e g r e a t e r p a r t o ft h e c r y p t a n d v i ll o u s e p i t h e l iu m . S t r e n u o u s a t t e m p t s a t r e g e n e r a t i o n a r e b e in gm a d e b y r e m n a n t s o f t h e e p i t h e l i u m w h i c h s h ow s m a n y m i t o t i c f i gu r e s a n d i sf o u n d c l u m p e d i n l i t t l e g r o u p s o r s h e e t s a s i f t h e s e g r o u p s w e r e d e s c e n d a n t s o fo n e o r t w o s u r v i v i n g c e l l s o f t h e o r i g i n a l e p i t h e l i u m .

T h e colon s h o w s s o m e m u c o i d d e g e n e r a t i o n a n d s l i g h t n e c r o si s o f t h e t i p s o f af e w v i l l i , w i t h e v i d e n c e o f r e p a i r .Dog 19-85. Clin ical History and Autop sy See Tables I I and IV .

D o g 1 9 - 85 r e c e iv e d 3 0 0 m i l l i a m p e r e m i n u t e s o v e r t h e a b d o m e n T a b l e I V )w h i c h w a s f o l lo w e d b y d i a r r h e a a n d v o m i t u s a n d p r o s t r a t i o n . S h e r e co v e r e d .1 m o n t h l a t e r s h e w a s g i v e n 35 0 m i l l i a m p e r e m i n u t e s o v e r t h e t h o r a x w i t h n oe f f e c t T a b l e I I . A m o n t h l a t e r 2 m o n t h s a f t e r t h e fi r s t e x p o s u r e) s h e w a sg i v e n 3 5 0 m i l l i a m p e r e m i n u t e s o v e r t h e a b d o m e n w i t h f a t a l r e s u l t T a b l e I I ) .

M a r . 2 . D o g f a s t i n g si n c e F e b . 2 8.M a r . 4 . D o g g i v e n { g r . o f m o r p h i a 1 h o u r b e f o r e e x p o s u r e t o r a d i a t i o n .

L o w e r p a r t o f b o d y s c r e e n e d u p t o x i p h i s t e r n u m b y l e a d - f o i l 2 m m . t h i c k ; 3 50m i l l i a m p e r e m i n u t e s o f r a d i a t i o n d i v i d e d u p i n t o t h e u s u a l s e v e n a r e a s . A c u r -


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194 ROENTGEN RAY INTOXICATION. Irent strength of 7.5 milliamperes is used at 103 kilovolts and backed up by a9~ inch spark-gap. A 2 ram. alumin um filter is used. Skin-target distance10 inches. The tota l time of exposure is 46.6 minutes. There are no appare ntafter effects from the x-ray exposure.

Mar. 5 to 8. The dog remains clinically normal.TABLE II.

Roentgen Radiation.Unit Dose over Tkorax Negative but Subsequent Unit Dose over Abdomen' Lethal.

Dog 19-85. Adul t, female.D a t e .

Mar. 2*c 3cc

W h i t e * h nb l o o d e o r - [ u r e .p u s e l e sW e i g h t . p e r e . m m . V o l u m e . T o t a l N _ _

24.724.4 7,800 ] 355 2.0424.1 6 s 0 o [ 3 1 o [ 1 . 7 1

D i e t .

Water

R e m a r k s .

Good condition.Dog normal.

Mar. 4 X-rays, 350 milllam ~ere minutes, given over thorax. Abdomen shielded.Mar. 5

67

cc 8~c 9

23.8 6,60023.4 8,00023.2 5,40022.9 6,80022.8Experiment ended

290 1.90 Water.325 1.79325 1.96- - - - c c

Mixed.

Dog normal.

Max. 30 25.0 - - - - - - Water. Dog normal.31 24.6 440 2.07Apr. 1 24.1 7,400 325 1.90 Dog normal.Apr. 1 X-rays, 350 milliampere minutes, given over abdomen. Thorax shielded.Apr. 2

3cc 5

23.4 7,300 300 2.1323.1 5,800 290 1.9022.8 7,200 240 2.0722.1 5,400 275 3.16Ether anesthesia and autopsy at once.

W a t c e r .

~c

Dog normal.Diarrhea and vomltus.Severe intoxication.

Mar. 30. Dog has remained normal since the exposure over the thorax. Thereis some depilitation and pigm entatio n of previously exposed areas. Dog fastingfor past 3 days.

Apr. 1. Anim al given J gr. of morphi ne 1 hour before exposure; 350 milliam-pere minut es of radiation spread diffusely over the abdomen in six areas, all ven-tral. Each area averages approximately 25 square inches. The current strength


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S. L . WARREN AND G. I f . WHIPPLE 95i s 7 .5 mi ll i amperes a t an ~ .. ~ . ~ . o f 90 k i lovo lt s , back ed up by a 9 in ch spa rk-ga p .A 2 ram. a luminum f i l t e r i s used . Sk in - ta rge t d i s tance 10 inches . Ther e a reno c l in ica l a f t e r e f fec ts w hich cou ld be a t t r ib u ted to the rad ia t ion .

A p r . 2 a n d 3 . T h e a n i m a l i s a c t iv e a n d l i v e l y .Apr . 4 . There i s qu i te a l a rge vo lum e of ye l low, semif lu id feces and some b i le-

s t a in e d v o r n i tu s t h r o u g h o u t t h e m o r n i n g . I n t o x i c a t i o n b e c o m e s m o r e m a r k e din the a f te rnoon . Th e pu l se i s r egu la r , bu t o f low tens ion .Apr . 5 . Green ish -brown, semif lu id s too l s and b i l e - s tained vom i tus appe ar

r e g u l a r ly t h r o u g h o u t t h e d a y . I n t h e a f te r n o o n , t h e s to o l s a r e t a r r y a n d v i l esmell ing . In genera l , the s too l s appe ar to con ta in d iges ted o r pa r t ly d iges ted redb l o o d c el ls , m i x e d w i t h m u c u s . T h e v o m i t u s a t n o t i m e c o n t a in s a n y b l o o d, b u ti s made up o f a r a the r opa lescen t f lu id con ta in ing th ick , s t r ingy mucus , which a tt imes i s b i l e - sta ined . The an im al is ma rked ly in tox ica ted , e spec ia l ly dur ing thea f t e rn o o n . D o g is a b le t o w a l k b u t q u i t e w e a k a n d c e a se s t o r e s p o n d v o l u n t a r il y .T h e a n i m a l i s n o t m o r i b u n d a n d m i g h t s u r v i v e , b u t i n a l l p r o b a b i l i t y w o u l d d i ed u r i n g th e n ig h t . E t h e r a n e s t h e s ia a n d a u t o p s y a t on c e .Autopsy. Body fa t we l l p rese rved . P leura l cav i t y and thorac ic v i sce ra a renega t ive . Pe r i tonea l ca v i ty con ta ins no f lu id and the pe r i tonea l su r faces a renorm al . L ive r , sp leen , pancreas , ad rena l s , k idneys , and gen i tour in a ry t r ac t a renega t ive .Sto~ck con ta ins abou t 20 cc . o f b i l e - s ta ined , f ro thy mucus , co r respond ing tot h e v o m i t u s o f t h e p a s t 2 d a y s . T h e m u c o s a is p a l e a n d a p p a r e n t l y n e g a t i v e .Small intestine i s somewha t spas t i c and con ta ins a smal l amo unt o f g reen i sh -b r o w n m u c o u s m a t e ri a l .

L o n g i t u d i n a l f o l d s w i th h e m o r r h a g i c c r e s ts a r e c o n s p i c u o u s i n t h e d u o d e n u m .T h e s e f a d e o u t a n d d i s a p p e a r i n th e u p p e r j ej u n u m . I n b o t h t h e d u o d e n u m a n di leum, the re a re pa tc hes o r c lus te r s and s t reaks o f t iny ec chym ot ic specks in themucosa . Th e superf ic ia l nec ros i s i s no t ve r y ex tens ive bu t s t ands o u t in con-t r a s t t o t h e n o r m a l p a t c h e s o f m u c o s a i n t h e j e j u n u m a n d u p p e r i l e u m , w h i c h a r ep a l e a n d v e l v e t y a n d a p p a r e n t l y u n d i s t u r b e d .Colo~ i s nega t ive .

Histological Sections.Lungs , l ive r , pancreas , k idneys , ad rena l s , b ladder , and u te rus a re nega t ive .

O v a r y : t h e o v a a r e d e a d , t h e n u c l e a r m a t e r ia l i s b r o k e n u p , a n d t h e c y t o p l a s m i sf o a m y . S p l e e n: a t r o p h y o f t h e M M p i g h l a n b o d i e s a n d p u l p d e m e n t s ; a f ew f r a g -m e n t e d n u c le i a r e s ee n. S t o m a c h : n o r m a l . D u o d e n u m : ir r e g u la r a n d p a t c h yin ju ry o f v i l lus s t ruc tu res i s appare n t . In in ju red a reas , the re a re ev idences o fmi tos i s and rap id g ro wth o f ep i the l i a l ce ll s and some in f i l tr a t ion o f the a rea byp o l y m o r p h o n u c l e a r l eu c o c y t es . T h e i r r e g u l a r i t y o f t h e in j u r y i s e s pe c i al l y n o t e di n t h e s e c ti o n s f r o m t h e j e j u n u m .Ileum shows ex tens ive in ju r y and des t ruc t ion o f v i l lous ep i the l ium. Th eep i the l ium cover ing the v i l l i and c ryp ts has d i sappeared excep t fo r some rap id ly


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96 R O E N T G E N RAY I N T O X I C A T I O N Igrowing epithelial cells appare ntly regenerating in an effort to cover the denudedareas. Polymorphonuclear and mononuclear leucocytes are rather numerousat the bases of the crypts.

C o l o n shows a certain amount of mucoid degeneration and here and there anoccasional focus of polymorphonuclear infiltration especially under the areaswhere the epithelium is injured.

Dog 19-101. Cl inica l His tory and Autopsy See Tab le I I I ) .Feb. 17. Dog is active and in good condition.Feb. 21. ~ gr. of morphia is given i hour previous to the r adiation; 117 mil-

liampere minutes of radiation are given with a current strength of 7.5 milliamperes,

Dog 19-101.

TABLE HI.Ro e n t g e n Ra d i a t i o n .

3 5 0 M i l l ia m p e r e M ~ u t e s o ve r T h o r a x N e g a t iv e .

D a t e . W e i g h t

l b sFeb. 17 34.020 31.021 30.4

W h i t eb l o o d c o r .p u s c e sp e r C . rn m

8,0007,800

U r i n e . D i e t .V o l u m e . T o t a l_ _ _ _

c o g Water .

R e m a r k s .

Dog normal

Feb. 21 X-rays, 350 milliampere minutes, over thorax. Abdomen shielded.Feb. 222324

25262728

30.130.029.128.828.128.127.8

7,3007,9005,6007,3007,6007,4006,900

415605565605408370335

3.022.862.692.522.492.242.21Experiment ended.

Apr. 11 31.3 I 7,6001 - - - -Ether anesthesia and autopsy at once.

W a t c e r .

~c

Dog normal.

Dog normal.

at an E. xf. ~-. of 103 kilovolts. It was then found necessary to give the rema inin g233 milliampere minutes a t a c urr ent s tren gth of 10 miJliamperes with an E. ~r. ~-.of 90 kilovolts. 2 mm. of alum inu m filter used, spark-gap of 9 inches betweensharp points. The skin-targe t distance is 10 inches.

Apr. 7. Dog is exposed to 450 milliampere minu tes of rad iati on over the abdomen and sacrificed under ether anesthesia on Apr. 11.


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S . L . W A R I P , I q A N D G . ] ~. q { I P P L E 1 9 7A ~ o p s y . T h e pleura l and pe r ica rd ia / su r faces a re mois t and sh iny . Th e

h e a r t a n d l u n g s a r e n e g a t iv e . T h e o t h e r c h a n g e s d o n o t c o n c e rn th e e x p e r i m e n tg i v e n i n T a b l e I I L

D o g 1 9 5 0 . C l i n i c a l H i s t o r y a n d A u t o p s y .T o b e c o n t r a s t e d w i t h T a b l e I I I ; a c o n t r o l e x p e r i m e n t o v e r t h e a b d o m e n .F e b . I0 . D o g a c t i v e a n d n o r m a l ; f a s ti n g .Feb . 11. i g r . o f mo rph ia 1 hour p rev ious to rad ia t ion ; 340 mi l l i ampere min-

u t e s a r e s p r e a d o v e r t h e a b d o m e n i n t h e u s u a l s e v e n a r e a s; s c r e e n in g o f t h e t h o r a xand low er pe lv i s wi th l ead- fo il . A cu r ren t s t r eng th o f 7 .5 mi l li amperes a t 97k i lovo l t s i s back ed up b y a 9 inch sp ark-gap ; 2 ram. o f a luminum f i l te r therad ia t ion . Th e sk in - ta rge t d i s tance i s I0 inches .

F e b . 1 2 . T h e d o g is l i v e ly a n d a c t i v e. A s m a l l a m o u n t o f w h i t e f r o t h yv o m i t u s a n d s o m e f lu i d b r o w n f e c es a p p e a r o n t h i s d a y .

Feb . 13 . The re is ev idence o f s l igh t in tox ica t ion . The pu l se t ens ion is low.h e v o m i t u s i s o f l a r g e v o l u m e a s m u c h a s a p i n t i n a n h o u r a n d i s d e e p l y b i le -

s t a in e d . T h e d i a r r h e a is f r e q u e n t b u t s c a n t y i n a m o u n t a n d c o n s i s ts m o s t l y o fb l o o d . A t t i m e s i t i s b l a c k t h i c k a n d t a r r y . T h e d o g i s q u i t e w e a k .

Feb . 14 . Th e in tox ica t ion i s qu i te severe . Th e an imal i s weak . The pu l sei s o f l o w t en s i o n a n d q u i t e ir r e g ul a r. T h e v o m i t u s is l a r g e i n a m o u n t a n d d e e p l yb i le -s ta ined . Th e d ia r rhea is p ro fuse and f requen t . A t t imes the feca l ma te r ia ls e e m s t o b e m a d e u p p r a c t i c a l ly o f p u r e b l o o d a n d c o n t a i n s m a n y c l ot s . A g a i ni t may be t a r ry and v i l e smel ling. Th e dog is comatose and i s sac r if i ced und ere the r anes thes ia . Au top sy a t once .Autopsy. Thoracic visce ra and se rous su r faces a re nega t ive . The l ive rsp leen adrena l s k idneys lym ph nodes and gen i tour ina ry t r ac t a re nega t ive .The pancreas shows a few smal l f a t nec roses .Stomach: f il led wi th a b lood y muc ous mate r ia l ; mu cosa pa le and norm al .

Small intestine i s sp a s t i c a n d c o n t a i n s a s m a ll a m o u n t o f b l o o d y fl u id . T h emuc osa i s a du l l r ed da rker in the duodenum l igh te r in the i l eum. Long i tud ina lf o ld s w i t h h e m o r r h a g i c c r e s ts a r e e v i d e n t i n s o m e s e ct io n s e s p e ci a ll y t h e p a l e rs e c ti o n s o f t h e l o w e r j e j u n u m b u t t h e y a r e m a s k e d i n t h e d u o d e n u m b y t h e i n t e n sedark du l l r ed o f the muco sa the re . The in tes t ina l wa l l i s th in appar en t ly dueto much loss o f subs tan ce in the mucosa . Th is i s e spec ia l ly ma rked in the i leum.Colon a n d cecum con ta in a b loody flu id . The i r muc osa i s in genera l pa le .

His to lo g i ca l S ec t i o n s .L i v e r k i d n e y s a d r e n al s u t e r u s a re n o r m a l . S p l ee n s h o w s s o m e p u l p a t r o p h y

a n d p r o m i n e n c e o f t h e r e t i c u l u m P a n c r e a s c o n t a i n s a f e w f a t n ec r o s es i n o n es e c ti o n o t h e r w is e i t is n o r m a l . I n t h e o v a r y t h e c h r o m a t i n n e t w o r k o f t h e o v ai s b roke n up thou gh the nuc leo l i a re s ti l l p resen t . Th e ova in genera l appe ara b n o r m a l a n d s e e m t o b e d e g e n e r a t i n g .


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98 R O E N T G E N RAY I N T O X I C A T I O N . IS tomach and cdon a r e n o r m a l .Sma ll intestine p r e s e n t s t h e u s u a l p i c t u r e o f n e c ro s i s a n d d e s t r u c t i o n o f v i l l o us

a n d c r y p t e p i t h e l i u m , r e g e n e r a t io n o f e p i t h e l i u m w i t h m i t o t i c f i g u r es , a n d i n fi l-t r a t i o n o f p o l y m o r p h o n u c l e a r s i n t o t h e b a s e s o f t h e c r y p t s .

I n t h e i leum t h e ~ l l i s h o w o n l y a n a k e d r e t i e n l u m w i t h a f e w g r o u p s o f r e g e n -e r a t i n g e p i t h e l i a l c e l l s a n d t h e l y m p h f o l l ic l e s . T h e b l o o d v e s s e ls i n t h e m u c o s aa r e f r e q u e n t l y t h r o m b o s e d .

T h e mesenteric lymph nodes a r e f i l le d w i t h r e d b l o o d c e ll s a n d p o l y m o r p h o n u -c l e a rs a n d p h a g o c y t i c c e l l s c o n ta i n i n g c e l l d e b r is a n d p i g m e n t .

D o g 1 9 - 8 5 .

T A B L E I V .Roentgen Radiation.

Sublethal Dose over Abdomen.

D a t e .White

blood corWeight. pu~:les erlbs.

25.0 8 000

D i e t . R e m a r k s

Feb . 4 Wate r . Dog normal .Feb . 4 X-rays , 300 mi l ~mpere minu tes , over abdomen . Thorax sh ie lded .Feb . 5

678910" 1120

24 .5 6 ,00024.0 8,00023 .5 3 ,40023 .3 8 ,40023 .0 5 ,80023.0 7,80022 .5 5 ,40025.0 7,400

W a t e r .c

c~gc

Mixed .

D o g normal.Inac t ive .Vomitus and diarrhea.No d ia r rhea o r vomitus .Clinical improvement.G o o d c o n d i t i on .

D o g 1 9 - 8 5 . C l i n i c a l H i s t o r y ( S e e T a b l e I V ) .F e b . 3 . D o g a c t i v e a n d i n g o o d c o n d i t i o n ; f a s t i n g .F e b . 4 . g r . o f m o r p h i a g i v e n 1 h o u r b ef o r e r a d i a t i o n . T h e u p p e r p a r t o f

t h e b o d y a b o v e t h e l e v e l o f t h e x i p h i s t e r n u m i s s cr e e n ed b y 2 r a m . o f s h e e t l e a d -f o il . E x p o s u r e s m a d e o v e r t h e a b d o m e n a n d p e lv i s i n s e v e n p a r t s . T h e c u r r e n ts t r e n g t h i s 7. 5 m i l l i a m p e r e s a t a n E . M . . o f 1 0 0 k i l o v o l t s , b a c k e d u p b y a 9i n c h s p a rk - g a p . T h e r a d i a t i o n i s f i l te r e d b y 2 m a n. o f a l u m i n u m . T h e s k i n -t a r g e t d i s t a n c e i s 1 0 i n c h es . T h e t o t a l e x p o s u re t i m e i s 4 0 m i n u t e s - - 3 0 0 m i l l i am -p e r e m i n u t e s . T h e d o g i s c l i n ic a l l y u n a f f e ct e d b y t h e e x p o s u r e t o r a d i a t i o n .

F e b . 5 t o 7 . D o g n o r m a l .


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S L W R R E N A N D G If W H I P P L E 199Feb. 8. The animal shows a slight degree of intoxication. The vomitus whichappears is mostly a clear frothy mucus. Diarrhea is brownish and scanty.Feb. 9. Mild intoxication; no diarrhea or vomitus.Feb. 10. From this date, recovery to normal is rapid.

D I S C U S S I O N

A t t h e v e r y s t a r t o f t hi s d i sc u s si o n, w e w i sh t o p o i n t o u t t h e f a c tt h a t t h e s e e x p e r im e n t s c o n c e r n n o r m a l d o g s a n d n o t h u m a n b e i ng ss u f f e r i n g f ro m d i s ea s e , f o r e x a m p l e l e u c e m i a , c a n c e r , a n d s o fo r t h . W efe e l t h a t t h e s e e x p e r i m e n t s a r e l e s s c o m p l i c a t e d fo r t h i s v e ry r e a s o na n d m a y g i v e u s t h e o p p o r t u n i t y t o c o r r e c t m i s t a k e n i m p r e s s i o nsg o t t e n f r o m t h e c o m p l e x r e a c t i o n s w h i c h m a y r e s u l t f r o m R o e n t g e nra d i a t i o n o f a d i s e a s e d h u m a n b e i n g .

O u r n e g a t i v e r e s u l t s o f t h o ra x r a d i a t i o n (u p t o 5 1 2 m i l l i a m p e rem i n u t e s ) a r e o f i n t e r e s t in r u l in g o u t c o n v i n c i n g ly c e r ta i n o f t h e b o d yc e l l s w h i c h h a v e b e e n s u s p e c t e d a s c a u s a t i v e f a c t o r s i n t h e g e n e ra lR o e n t g e n r a y i n t o x i ca t i on . F o r e x a m p l e , t h e s e e n o rm o u s d o s esg i v e n o v e r t h e n o r m a l t h o r a x m u s t i n j u r e m o r e b o n e m a r r o w c e l l st h a n d o t h e a b d o m e n e x p os u re s . T h e r i b s a n d t h o r a c i c v e r t e b n es u r e l y c o n t a i n m o r e u n i t s o f r e d m a r r o w t h a n d o t h e l u m b a r v e r t e -b ra e. E x a m i n a t i o n o f t h e r i b m a r r o w s o m e d a y s a f t e r a n e x p o s u r es h o w s a l m o s t c o m p l e t e d i s a p p e a ra n c e o f r e d m a r r o w c e l ls , so w e k n o wt h a t t h is r e a c t i o n h a s t a k e n p l a c e, y e t t h e r e is n o t a t r a c e o f a n yc l in i c a l d i s t u rb a n c e . Th i s r u l e s o u t t h e r e d m a r r o w a s a f a c t o r int h e c h a r a c t e r is t i c s y s te m i c d i s t u r b a n c e n o t e d i n o u r e x p e r i m e n t s .

T h e s e s a m e a r g u m e n t s a p p l y t o l y m p h a t i c ti ss u e . T h e l y m p hg l a n d s i n t h o ra x a n d a b d o m e n u s u a l l y s h o w s o m e l os s o f c e il s b u t n o tt o a n y v e r y g r e a t e x t e n t. I t i s s ig n i fi c an t t h a t P e y e r s p a t c h e s i n t h ei n t e s t in e m a y s h o w o n l y m o d e r a t e i n j u r y w h e n t h e e p i t h e l i u m c o v e r in gt h e l y m p h fo l li c le s a n d l i n i n g t h e c ry p t s h a s c o m p l e t e l y v a n i s h e d d u et o t h e x - r a y i n j u r y . I n o u r e x p er i m e n ts , th e r e f o re , t h e i n t e s t i n a le p i t h e li u m i s m u c h m o r e s e n s i t iv e t o i n j u r y t h a n a r e t h e c e ll e l e m e n t so f t h e l y m p h g l a n d a n d P e y e r s p a t c h .

T h e s p le e n o f th e d o g i s n o t p r o f o u n d l y a f f e c te d b y t h e R o e n t g e nra d i a t i o n . F o r o n e th i n g , i t i s n o t a s c e l lu l a r a s t h e h u m a n s p l e e n ,b u t w e f e e l t h a t t h e n o rm a l s p l e e n c e il s a r e n o t e a s i l y d e s t ro y e d b y t h ex - r a ys . A f t e r l a r g e e x p o su r e s w e n o t e a m o d e r a t e a t r o p h y o f t h e


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2 0 0 ROENTGEN R Y I N T O X I C A T I O N I

s p l e e n w i t h s h r i n k a g e o f t h e M a l p i g h i a n c o rp u s c l e s , b u t p l e n t y o fl y m p h o c y t e s r e m a i n e v e n a f t e r i n t e n s iv e r a d i a t i on .Th e t h o ra x e x p o s u re s , o f c o u r se , c o v e r t h e h e a r t a n d l u n g s , w h i c hm a y b e d is m i s se d w i t h o u t c o m m e n t . T h i s a r e a a ls o i n c lu d e s a l a rg ep a r t o f t h e circulat ing blood W e c o n c l u d e , t h e r e fo re , t h a t t h e x - r a y sh a v e n o i n j u r i o u s e f f e c t u p o n t h e c i r c u l a t i n g b l o o d c e ll s.

Th e t h o ra x e x p o s u re s t h e r e fo re ru l e o u t s e v e ra l f a c t o r s w h i c ha t o n e t i m e o r a n o t h e r h a v e b e e n t h o u g h t t o b e r e s p o n s i b l e f o r t h eg e n e r a l s y s t e m i c i n t o x i c a t i o n - - r e d b o n e m a r r o w , l y m p h a t i c t i s s u e ,a n d c i r c u l a t i n g b l o o d . W e m a y n o w c o n s i d e r t h e v a r i o u s t is s u e s i nt h e a b d o m e n w h i c h m a y b e r e s p o n si b le f o r t h e f a t a l r e a c t i o n f o ll o w in gl a rg e d o s e s o f t h e x - r a y s .

T h e k i d n e y s a r e v e r y s l i g h t l y d i s t u r b e d , a s i s s h o w n i n a p a p e ro f t h i s s e r i es M c Q u a r r i e a n d W h i p p l e 4 ) ) .T h e l iv e r is n o t c o n c e r n e d a n d w e b e li e v e c a n b e r u l e d o u t w i t h o u tq u e s t i o n . Th e re i s n o h i s t ol o g i c a l e v i d e n c e o f i n j u ry , b u t m o re t h a nt h a t , t h e r e i s n o e v i d e n c e o f f u n c t i o n a l d i s t u rb a n c e . D o g s w i t h b i l ef i s t u l m s h o w n o d i s t u rb a n c e i n fu n c t i o n a n d n o c h a n g e i n t h e l e v e l o fb i le a c i d a n d b i le p i g m e n t o u t p u t . 1

Th e p a n c re a s a n d a d re n a l s s h o w n o h i s t o lo g i c a l e v i d e n c e o f i n -j u r y b y t h e x - r a ys . W e k n o w o f n o f u n c ti o n a l d i s t u r b a n c e w h i c h m a yb e a t t r i b u t e d t o t h e s e s t ru c t u r e s .

T h e g a s t r o i n t e s t i n a l t r a c t i s r e m a r k a b l y s e n s i t i v e t o t h e R o e n t g e nr a y s . I n s u b s e q u e n t e xp e r i m e n t s, w e s ha l l r e v i e w t h e r e m a r k a b l eu l c er s w h i c h c a n b e p r o d u c e d i n t h e s t o m a c h , b u t a s a w h o l e, t h es t o m a c h a n d c o l o n a r e c o n s i d er a b l y m o r e r e s i s t a n t t h a n t h e s m a l li n t e s t i n e .

The epithel ium of the small in test ine f ro m t h e p y l o ru s t o t h e i l eo c e c a lv a l v e i s r e m a r k a b l y s e n si t iv e t o t h e R o e n t g e n r a y s . T h e s e d o s e su s e d w i l l c a u s e n e c ro s i s o f t h i s e p i t h e l i u m w i t h p r a c t i c a l l y c o m p l e t ed i s a p p e a r an c e . W e b e l i e v e t h e s y m p t o m s o f i n t o x i c a t io n a n d t h ef i n a l l e t h a l p o i s o n i n g a r e d u e t o t h i s i n j u ry o f t h e i n t e s t i n a l e p i t h e l i u m .W e n e e d n o t r e f e r t o t h e s e v e re i n t o x i c a t i o n w h i c h d e v e l o p s fo ll o w i n ga fu n c t i o n a l d i s t u rb a n c e o f t h i s s a m e e p i t h e l i u m i n t e s t i n a l o b s t ru c -t i o n) . W e m a y in f e r t h a t t h e x -r a y s m a y p r o d u c e s u b l e th a l i n j u r y

Experiments to be published elsewhere.


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S L WARREN A~D G H WHIPPLE 201to t h i s i n t e s t i n a l e p i t h e l i u m w h ic h ma y b e r e s p o n s ib l e f o r a v a r i e tyo f d i s t u r b a n c e s a s s o c i a t e d w i th g a s t r o in t e s t i n a l s y mp to ms .

SLrMMARY

R o e n t g e n r a d i a t i o n o f th e t h o r a x a b d o m e n s h ie l de d ) i n d o g s ,e v e n w i th l a r g e d o s e s u p t o 5 1 2 mi l l i a mp e r e min u t e s ) , g iv e s n oc l in i c a l e v id e n c e o f i n to x i c a t i o n . T h e r e ma y b e a t r a n s i e n t l e u co -p e n i a a n d a s l i g h t r i s e i n u r i n a r y n i t r o g e n .

R o e n t g e n r a d i a ti o n o f t h e a b d o m e n t h o r ax s h i el d ed ) in d o g s ,w i th a d o s e o f 3 5 0 mi l l i a mp e r e min u t e s , w i l l a lmo s t c e r t a in ly c a u s e af a t a l i n to x i c a t i o n . S ma l l e r d o s e s m a y b e s u r v iv e d b u t u s u a l l y w i ths ig n s o f g a s t r o in t e s t i n a l i n to x i c a t i o n .

T h i s l e t h al i n t o x i c a t io n d u e t o a b d o m i n a l r a d i at i o n p r e s e n t s ar e ma r k a b ly u n i f o r m c l i n ic a l a n d a n a to m ic a l p i c tu r e . T h e r e is al a t e n t p e r i o d o f 2 4 t o 3 6 h o u r s , d u r in g w h ic h t h e d o g i s p e r f e c t l yn o r m a l c l i n ic a l ly . T h e 2 n d d a y u s u a l l y s h o w s t h e b e g in n in g o fd i a r r h e a a n d p e r h a p s s o m e v o m i t u s . T h e 3 r d a n d 4 t h d a y s s h o wp r o g r e s s iv e i n to x i c a t i o n w i th i n c r e a s in g v o m i t i n g a n d b lo o d y d i a r r h e au n t i l t h e d o g b e c o m e s s t u p o r o u s . D e a t h i s a l m o s t al w a y s o n t h e4 t h d a y .

A n a to mic a l l y t h e o n ly l e s io n s o f si g n i fi c a nc e a r e t o b e f o u n d i n t h es m a l l i n t e s ti n e . T h e e p i t h e l i u m o f t h e c r y p t s a n d v i l li sh o w s m o r eo r l e ss c o m p le t e n e c r o s is , a n d t h i s c o n d i t i o n ma y i n v o lv e a lmo s t a l l o ft h e s m a l l i n t e s ti n e . T h e e p i t h e l i u m m a y v a n i s h c o m p l e t e l y e x c e p tf o r a f e w ce l ls h e r e a n d t h e r e w h ic h h a v e e s c a p e d a n d a r e o f t e n f o u n din mi to s i s , p r o b a b ly a n e f f o r t a t r e p a i r a n d r e g e n e r a t i o n .

W e a r e f o r c e d t o t h e c o n c lu s io n t h a t t h i s r e ma r k a b l e i n ju r y o ft h e e p i t h e l i u m o f t h e s ma l l i n t e s t i n e i s r e s p o n s ib l e f o r t h e v a r i o u sa b n o r ma l r e a c t i o n s a n d f i n a l l e t h a l i n to x i c a t i o n w h ic h f o l l o w a u n i td o s e o f R o e n t g e n ra d i a t i o n o v e r t h e a b d o m e n o f a n o r m a l d o g . T h i ss e n s i t i v e n e s s o f t h e i n t e s t i n a l e p i t h e l i u m to x - r a y s i s n o t a p p r e c i a t e da n d s h o u ld b e g iv e n p r o p e r c o n s id e r a t i o n i n c l i n ic a l w o r k .

I n c o n c lu s io n w e w i s h t o e x p r e ss o u r s i n c e r e a p p r e c i a t i o n f o r t h ea s s i s ta n c e a n d a d v i c e g i v e n u s b y m e m b e r s o f t h e D e p a r t m e n t o fR o e n t g e n o l o g y o f t h e U n i v e r s i t y o f C a l if o rn i a H o s p i t a l - - D r s . H o w a r dE . R u g g le s , L lo y d B r y a n , O r r i n S . C o o k , a n d E l i z a b e th S c h u l z e .


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2 2 I OEINTG]~Iq RAY I N T O X I C A T I O N . IBIBLIOGRAPHY.

1. Denis W . Ma r t in C. L. and Aldrich M . A m . J . M ed . S c . 1920 clx 555.2. Fromme G. Z. Geburtsh. u . G yn~k. 1916--17 lxxix 579.3. Hall C. C. and Whipple G. H. A m . J . M ed . S c . 1919 clvii 453.4. McQuarrie I . an d Whipple G . H . J . E xp . M ed . 1922 xxxv 225.5. Reg aud C. Nogier T . and Lacassagne A. Arch. aectric m~d . 1912 xx 321.


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