ROENTGEN RAY INTOXICATION.

I. UNIT DOSE OVER THORAX NEGATIVE--OVER ABDOMEN LETHAL.

EPITHELIITM OF SMALL INTESTINE SENSITIVE TO X-rAYS.
BY S. L. WARREN AND G. H. WHIPPLE, M.D.
(From The George Williams Hooper Foundation for Medical Research, University
of California Medical School, San Francisco.)
(Received for publication, August 16, 1921.)
The papers of this series form a part of the general program of study
of the "non-specific intoxications" which is being carried forward
in this laboratory. They are concerned with an investigation of the
systemic intoxication which develops after a suitable exposure to large
doses of hard Roentgen rays. These papers follow along the logical
development of this study, based on the beginnings made by Hall and
Whipple (3). Reference to the paper of Hall and Whipple is necessary
for a review of some of the rather extensive literature of this subject
and for a discussion of many of the fundamental problems related to
Roentgen ray intoxication.
This Roentgen ray intoxication, we believe, is a true "non-specific
intoxication" and deserves thorough study in part for this very
reason. Too little study has been directed toward an understanding
of the "non-specific intoxication" which often is a very important
factor in many of the so called specific infections. This Roentgen
ray intoxication closely resembles the intoxication of intestinal ob-
struction, another important "non-specific intoxication." We shall
point out some important differences between the intoxication due
to the Roentgen rays as contrasted with intestinal obstruction, but
there remain many striking similarities as emphasized by Hall and
Whipple (3).
We believe our experiments make it clear that the fundamental
thing in the systemic intoxication due to the Roent gen rays is a
primary injury of the epithelium of the small intestine. This was sus-
187

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Published February 1, 1922
188 ROENTGEN R A Y INTOXICATION. I
pected by Hall and Whipple but not conclusively proven. Our
experiments in normal dogs under controlled conditions appear con-
vincing when exposures given over t he thorax are contrasted wi t h t he
same exposures over t he abdomen. For example, a urdt dose (350
milliampere minutes) given over t he thorax (abdomen shielded) causes
no clinical disturbance in t he dog. A subseque.nt exposure to t he
same uni t dose in t he same dog given over t he abdomen (thorax
shielded) will cause fatal intoxication and deat h in 4 days. For a
normal 30 to 40 pound dog, we may say t hat 350 milliampere mi nut es
given over t he abdomen is a mi ni mum lethal dose.
The out st andi ng abnormalities in t he abdominal exposures are t he
remarkable necroses observed in t he small intestine. Large areas
may show complete necrosis and disappearance of t he intestinal
epithelium covering t he villi and lining t he crypts. The villi are
left as naked polyps made up of stroma, vessels, and a few wandering
cells. The inflammatory reaction is not as intense as would be
expected under such conditions wi t h complete removal of t he cover-
ing epithelium. This i mport ant poi nt will be discussed in detail
in a subsequent paper.
Regaud, Nogier, and Lacassagne (5) described t he chronic gastro-
intestinal lesions in dogs and not ed especially gastric at rophy and intes-
tinal perforation. Fromme (2) not ed especially t he clinical sympt oms
of gastrointestinal disturbance in guinea pigs and mice. Denis, Mar-
tin, and Aldrich (1) not ed in rabbits t he toxic effect of abdominal
radiation and certain abnormalities in t he intestines which t hey
st at e are secondary to an unknown toxic factor.
Method.
The procedure is identical in all experiments, unless otherwise
indicated. Normal dogs are used t hr oughout and are kept in st andard
metabolism cages which have sharply pi t ched floors to facilitate t he
collection of urine. To insure t he acidity of t he cage collections,
about 1 cc. of glacial acetic acid is added to t he cage collecting bottle
at t he beginning of each 24 hour collection. The dogs are catheterized
daily at 10 o'clock. Th e cage collections, cage washings, bl adder
washings, and catheterized urine are mixed and diluted to a uni t
vol ume--usual l y 2 liters. The total nitrogen is t hen done in dupli-

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Published February 1, 1922
S. L. W A R R E l ~ A N D G. H . W H I P P L E 189
cat e by t he Kj el dahl met hod. About 300 cc. of war m wat er is given
dai l y by st omach t ube as a rout i ne procedure aft er t he dog is cat he-
terized. Wat er is available at all t i mes in t he cage.
Dogs are given a subcutaneous i nj ect i on of morphi ne short l y
before exposure t o radiation. A medi um har d Coolidge t ube is used
wi t h t he t ar get (anode or ant i cat hode) set at a const ant di st ance
of 10 inches from t he skin. At this di st ance t he effective radi at i on
for this machi ne covers a circle approxi mat el y 6 inches in di amet er.
The cur r ent st rengt h used is ei t her 7.5 or 8.0 milliamperes. The
E.M.F. varies considerably in different experi ment s from 85 kilo-
volts t o 103 kilovolts. The spark-gap backi ng up t hese voltages
varies also, measuri ng from 8 to 10 inches bet ween sharp points.
The amount of radi at i on is calculated as t he pr oduct of t he current
st rengt h in milliamperes and t he t i me of exposure in mi nut es and is
expressed as milliampere mi nut es. I n all t hese experiments t he
st andard aut ot ransformer x-ray equi pment of t he Uni versi t y of Ca l l
fornia Hospital is used. Al umi num filters (2 ram.) are used to cut out
t he softer rays. The various part s of t he dog were effectively pro-
t ect ed from radiation, when i t was so desired, by sheets of lead-foil
approxi mat el y 2 ram. thick, or by lead "rubber," approxi mat el y 5
ram. in thickness.
The body of t he dog is mar ked off roughl y into two part s by a
transverse line at t he level of t he xi phi st ernum. The par t bet ween
this line and t he base of t he neck is designated as t he thorax, t hat
below as t he abdomen. Each of t hese part s is t hen divided into an
upper and lower half. Each upper and lower segment of t he abdomen
or t horax is radi at ed from t he lateral and mi dvent ral aspects. Thus
t he vent ral port i on of t he abdomen or t horax is exposed to radi at i on
over six different areas whose contiguous edges overlap somewhat.
Usually one exposure is gi~cen over t he middorsal region of t he t horax
or abdomen, causing t he t ot al dosage to be divided up into seven
parts, which, however, are spread r at her diffusely over t he par t of t he
body involved. All dogs are sacrificed under chloroform or et her
anest hesi a by bleeding.

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Published February 1, 1922
190 ROENTGEN R A Y INTOXICATION. I
EXPERIMENTAL OBSERVATIONS.
Some of our t ypi cal experiments are t abul at ed below and makc
several poi nt s qui t e clear. However, we wish t o refer t o ot her
experiments of similar nat ure given in subsequent papers of this
series. These experiments are all in agreement and indicate t hat
enormous doses of Roent gen rays ma y be given over t he t horax
wi t hout causing any clinical reaction in a normal dog. Dogs have
been given amount s of radi at i on varyi ng from 300 to 512 milliampere
mi nut es over t he t horax wi t hout any clinical sympt oms. One dog
(No. 19-117) was given 350 miUiampere mi nut es over t he t horax on
t hree separat e occasions wi t h intervening periods of 2 t o 3 weeks; all
this wi t hout any appar ent cumul at i ve effects or clinical reaction.
Ther e is usual l y a slight t ransi ent leucopenia and t here ma y be a
ver y slight rise in t ot al nitrogen excretion. Aft er 2 or 3 weeks, t he
skin shows loss of hai r and pi gment at i on as a resul t of t he exposures.
The ribs of t he animal examined at aut opsy show a considerable loss
of marrow cell elements. We have been able t o recognize no ot her
results from t hese large doses of x-rays over t he thorax.
Dog 19-78 (Table I) is a t ypi cal example of a complete experiment
t o show t hat a uni t dose of x-rays is clinically inert over t he t horax
but lethal when given over t he abdomen. The t horax dose causes a
definite leucopcnia but no clinical disturbance. That t he second
dosc does not cause as much of a leucopcnia, we believe, may be due
t o t he tissue i nj ury in t he small intestine.
The radi at i on over t he abdomen causes a t ypi cal clinical reaction
and t he review of this case will suffice for all subsequent experiments.
Thi s clinical reaction is remarkabl y const ant and is described in detail
below ( Dog 19-78). The l at ent period of 24 t o 36 hours is not ed as
usual and will be discussed later. The rise i n t ot al uri nary nitrogen
is not great but is significant. The figure for t he last day includes a
certain amount of fecal cont ami nat i on.
Dog 19-78. Clinical History and Autopsy (See Table I).
Jan. 27. The dog is isolated on fasting diet. The animal is in good condition
and quite active.
Jan. 29. The abdomen is covered with lead-foil well up to the level of the
diaphragm. The thorax is exposed in seven areas, two midventral, two on each

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Published February 1, 1922
S. L . WARREN A N D G . H. W H I P P L E 191
side, and one over the midscapular region. Each area exposed covered a patch of
skin approximately 5 inches square. Morphia (i gr.) is given to keep the dog
quiet during the exposure. The current strength is 7.5 milliamperes at an ~. ~. IP.
of I00 kilovolts with the spark-gap set at 9 ~ inches. 2 mm. of aluminum filter is
used and the tube is set at a target-skin distance of I0 inches.
TABLE I.
Roentgen Radiation.
Unit Dose Given over Thorax and Subsequently over Abdomen.
Dog 19-78. Adult, female.
D a t ,
~8
Mar. 15
" 17
" 18
Mar. 18
Mar. 19
" 20
" 21
" 22
White Urine.
Weight. blood eor- Diet. Remarks.
puscles
per c. r a m . Volume. T o t a l N.
Ibs. co.
26.0
26.0 7,600
Jan. 29 3 mil]i ere
30 258 1 8 , 0 1 I
31 24. 514, 100 I
Feb. 1 23.8 I 4,600 I
2 23.3 ] 4,600]
" 3 2 3 . 0 I - [
" 8 27.0 5,400 [
" 21 28.3 ] 7,400[
Experiment ended.
Wa t e r . G o o d condition.
X-rays, 350 milliampere minutes, given over thorax. Abdomen shielded.
M
Water.
Mixed.
c
c c
Dog normal.
Dog normal.
Dog normal.
Dog normal.
28.9
27.8
27.3
7,800
7,600
8,000
M
260 2.74
305 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 2.74 "
25.9 7,200 240 3.00 "
25.0 3,900 - - 5.63 "
Chloroform anesthesia and autopsy at once.
Dog normal.
Inactive.
Vomitus and diarrhea.
Moribund.
Jan. 30. Dog remains normal during entire experiment (see Table I). There
was a slight transient leucopenia. Dog was on mixed diet until the second experi-
ment, also given in Table I.
Mar. 15. The dog is active and in good condition.

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Published February 1, 1922
192 ROENTGEN RAY INTOXICATION. I
Mar . 18. Dog given gr. of mor phi a 1 hour before exposure to radi at i on.
The t hor ax and head and neck are t horoughl y screened wi t h lead-foil down to
t he t i p of t he xi phi st ernum. Seven areas are exposed, two mi dvent r al , two on
each l at er al surface, and one mi dl umbar. The current st rengt h is 7.5 mi l l i am-
peres at an E. ~. P. of 95 kilovolts, backed by a 9 inch spark-gap. The r adi a-
tion is filtered by 2 mm. of al umi num. The ski n- t ar get di st ance is 10 inches.
There are no i mmedi at e af t er effects from exposure to 350 mi l l i ampere minutes.
Mar . 19. The dog is br i ght and active.
Mar . 20. Slight evidences of i nt oxi cat i on are mani fest ed by t he dog- - one
soft, yellow, wat er y stool.
Mar . 21. The i nt oxi cat i on becomes mar ked in t he afternoon. The di ar r hea
has progressed from brownish, wat er y mat er i al t o t ar r y, bl ack mucous or bl oody
mucous mat eri al wi t h a ver y foul odor. Vomitus increases in amount and fre-
quency duri ng t he day.
Mar . 22. The ani mal is ver y weak and dull. I n t he afternoon, t he dog is
compl et el y pr ost r at ed. The stools have become ver y frequent and of l arge
volume. The pul se is i rregul ar and t hready. The t emper at ur e has risen t o
40.2C. The respi rat i ons are r api d and i rregul ar. The ani mal is pr act i cal l y
mori bund and is sacrificed under chloroform anesthesia.
Autopsy.--Performed i mmedi at el y aft er deat h by chloroform. The hai r over
t he t horax is thinned. I t is absent over t he st ernum where t he skin is somewhat
pi gment ed from previ ous exposures to radi at i on. Pl eural cavi t y, heart , and lungs
ar e normal. Peri t oneal surfaces are normal. Spleen is somewhat granul ar in ap-
pearance, har d and firm, normal in size. On section, t he trabecul~e st and out .
Mesent eri c gl ands sl i ght l y enl arged and moi s t - - s omewhat pi nki sh in color.
Ki dneys normal in size and appear ance. Bl adder cont r act ed; i t shows a few
ecchymoses in i t s mucosa (cat het er). Li ver is normal. Adrenal s are somewhat
enlarged; appar ent l y normal except for a smal l necrotic mass in t he l eft adrenal .
Stomach contains gas and about 20 cc. of a bi l e-st ai ned fluid. The mucosa is
pal e and normal.
Duodenum is somewhat t hi ck-wal l ed and spast i c. The l umen cont ai ns many
large, round worms and a smal l amount of reddi sh-bl ack mucus. Beginning
shar pl y at a poi nt appr oxi mat el y an inch di st al to t he pyloric valve, t he mucosa of
the duodenum present s a dar k red gl assy appearance. On t hi s background r un
several l ongi t udi nal folds wi t h br i ght r ed hemorrhagi c crests. Number s of small
br i ght r ed petechi~e show up between these plic~e on t he dark, gl assy surface.
The react i on in the jejunum seems less intense, for here t he mucosa is pal er and
t he plic~e are not so conspicuous t hough t hey can be di st i nct l y made out.
Ileum contains a small amount of reddi sh-bl ack mucous mat er i al similar t o
t he stools, and a few r ound worms. The i nt est i nal wal l is t hi n and r at her flaccid
and on close i nspect i on t he i nt ensel y hemorrhagi c mucosa surface seems to have
been denuded of most of t he villi as t he vel vet y appearance is lacking. The
l ongi t udi nal folds wi t h br i ght r ed hemorrhagic crests arc conspicuous. Peyer ' s

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Published February 1, 1922
S. L. W A R R E N A N D G. IT. W R I P P L E 193
pat ches seem to be st r i pped of t hei r villous covering so t hat t hey show up r eadi l y
as speckl ed oval pat ches. The ileocecal val ve mar ks an abr upt end of t hi s
extensive i nj ur y.
Colon mucosa is pal e, t hough a few l ongi t udi nal , hemorrhagi c folds are present .
The walls are spast i c and t he l umen cont ai ns a smal l amount of reddi sh fluid.
Histological Sections.
Lungs, heart , liver, pancreas, ki dneys, bl adder, ut erus, and st omach are nega-
tive. The mes ent er i c l ymph nodes are sl i ght l y hemorrhagi c and cont ai n some
pi gment . The spleen is moder at el y at r ophi c and cont ai ns pi gment . I n t he
ovar y t he ova are appar ent l y dead, t hough nucleoli and chr omat i n r emnant s are
st i l l pr esent wi t hi n t he nucl ear membrane.
Pyloric duodenum: a section shows t he t r ansi t i on from nor mal i nt act pyl ori c
villi to col l apsed and denuded vi l l i wi t h r emnant s of dead epi t hel i um and some
regenerat i ng epi t hel i al cells undergoi ng mitosis. Some areas have escaped i nj ur y.
Jejunum: dest ruct i on and di sappearance of t he epi t hel i um of vi l l i and cr ypt s;
a few cr ypt s remai n, otherwise t he nor mal st r uct ur e is gone. The epi t hel i um
ar ound these cr ypt s shows mi t ot i c figures and these are appar ent l y regenerat i on
forms. Lar ge pal e epi t hel i al cells st i ck out i nt o t he l umen of t he crypt s. Thei r
cyt opl asm is finely meshed and is deci dedl y eosinophilic. The nuclei are r at her
large and pal e and frequent l y cont ai n mi t ot i c figures. A l arge amount of hemor-
rhage has occurred i n t he submucosa, and bl ood vessels are occasi onal l y found
pl ugged wi t h t hr ombi of fibrin and pl at el et s. On some areas a ver y t hi n sheet of
epi t hel i al cells can be seen maki ng an a t t e mpt to recover t he col l apsed ~l l i .
The ileum shows ext reme i nj ur y, wi t h t he di sappearance of t he great er pa r t of
t he cr ypt and villous epi t hel i um. St renuous at t empt s at regenerat i on are bei ng
made by r emnant s of t he epi t hel i um which shows many mi t ot i c figures and is
found cl umped i n l i t t l e groups or sheets as if t hese groups were descendant s of
one or two survi vi ng cells of t he ori gi nal epi t hel i um.
The colon shows some mucoi d degenerat i on and slight necrosis of t he t i ps of a
few villi, wi t h evidence of repai r.
Dog 19-85. Clinical History and Autopsy (See Tables I I and IV).
Dog 19-85 received 300 mi l l i ampere mi nut es over t he abdomen ( Tabl e IV)
which was followed by di ar r hea and vomi t us and pr ost r at i on. She recovered.
1 mont h l at er she was gi ven 350 mi l l i ampere mi nut es over t he t hor ax wi t h no
effect ( Tabl e I I ) . A mont h l at er (2 mont hs af t er t he first exposure) she was
given 350 mi l l i ampere mi nut es over t he abdomen wi t h f at al resul t (Tabl e I I ) .
Mar . 2. Dog fast i ng since Feb. 28.
Mar . 4. Dog gi ven { gr. of mor phi a 1 hour before exposure t o r adi at i on.
Lower pa r t of body screened up to xi phi st ernum by lead-foil 2 mm. t hi ck; 350
mi l l i ampere mi nut es of r adi at i on di vi ded up i nt o t he usual seven areas. A cur-

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Published February 1, 1922
194 ROENTGEN RAY INTOXICATION. I
rent strength of 7.5 milliamperes is used at 103 kilovolts and backed up by a
9~ inch spark-gap. A 2 ram. aluminum filter is used. Skin-target distance
10 inches. The total time of exposure is 46.6 minutes. There are no apparent
after 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. Adult, female.
D a t e .
Mar. 2
* c 3
cc 4
W h i t e * " hn
b l o o d e o r - [ u r e .
p u s e l e s
W e i g h t . p e r e . m m . V o l u m e . T o t a l N _ _
24.7
24.4 7,800 ] 355 2.04
24.1 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
" 6
" 7
c c 8
~c 9
23.8 6,600
23.4 8,000
23.2 5,400
22.9 6,800
22.8
Experiment ended
290 1.90 Water.
325 1.79
325 1.96 "
- - - - cc
Mixed.
Dog normal.
Max. 30 25.0 - - - - - - Water. Dog normal.
" 31 24.6 440 2.07 "
Apr. 1 24.1 7,400 325 1.90 " Dog normal.
Apr. 1 X-rays, 350 milliampere minutes, given over abdomen. Thorax shielded.
Apr. 2
" 3
" 4
cc 5
23.4 7,300 300 2.13
23.1 5,800 290 1.90
22.8 7,200 240 2.07
22.1 5,400 275 3.16
Ether 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. There
is some depilitation and pigmentation of previously exposed areas. Dog fasting
for past 3 days.
Apr. 1. Animal given J gr. of morphine 1 hour before exposure; 350 milliam-
pere minutes 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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Published February 1, 1922
S. L. WARREN AND G. If. WHIPPLE 195
is 7.5 milliamperes at an ~.. ~. ~'. of 90 kilovolts, backed up by a 9 inch spark-gap.
A 2 ram. aluminum filter is used. Skin-target distance 10 inches. There are
no clinical after effects which could be at t ri but ed to the radiation.
Apr. 2 and 3 . The animal is active and lively.
Apr. 4. There is quite a large volume of yellow, semifluid feces and some bile-
stained vornitus throughout the morning. Intoxication becomes more marked
in the afternoon. The pulse is regular, but of low tension.
Apr. 5. Greenish-brown, semifluid stools and bile-stained vomitus appear
regularly t hroughout the day. I n the afternoon, the stools are t ar r y and vile
smelling. I n general, the stools appear to contain digested or par t l y digested red
blood cells, mixed with mucus. The vomitus at no time contains any blood, but
is made up of a rather opalescent fluid containing thick, stringy mucus, which at
times is bile-stained. The animal is markedly intoxicated, especially during the
afternoon. Dog is able to walk but quite weak and ceases to respond voluntarily.
The animal is not mori bund and mi ght survive, but in all probability would die
during the night. Et her anesthesia and aut opsy at once.
Autopsy.--Body fat well preserved. Pleural cavi t y and thoracic viscera are
negative. Peritoneal cavi t y contains no fluid and the peritoneal surfaces are
normal. Liver, spleen, pancreas, adrenals, kidneys, and genitourinary t ract are
negative.
Sto~ck contains about 20 cc. of bile-stained, frot hy mucus, corresponding t o
the vomitus of the past 2 days. The mucosa is pale and apparent l y negative.
Small intestine is somewhat spastic and contains a small amount of greenish-
brown mucous material.
Longitudinal folds with hemorrhagic crests are conspicuous in the duodenum.
These fade out and disappear in t he upper jejunum. I n bot h the duodenum and
ileum, there are patches or clusters and streaks of t i ny ecchymotic specks in the
mucosa. The superficial necrosis is not ver y extensive but stands out in con-
trast to the normal patches of mucosa in the jejunum and upper ileum, which are
pale and vel vet y and apparent l y undisturbed.
Colo~ is negative.
Histological Sections.
Lungs, liver, pancreas, kidneys, adrenals, bladder, and uterus are negative.
Ovar y: the ova are dead, the nuclear material is broken up, and the cytoplasm is
foamy. Spleen: at r ophy of the MMpighlan bodies and pul p dement s; a few frag-
mented nuclei are seen. Stomach: normal. Duodenum: irregular and pat chy
i nj ury of villus structures is apparent. I n injured areas, there are evidences of
mitosis and rapi d growth 'of epithelial cells and some infiltration of the area by
polymorphonuclear leucocytes. The irregularity of the i nj ury is especially noted
in the sections from the jejunum.
Ileum shows extensive i nj ury and destruction of villous epithelium. The
epithelium covering the villi and crypt s has disappeared except for some rapidly

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196 R O E N T G E N RAY I N T O X I C A T I O N . I
growing epithelial cells apparently regenerating in an effort to cover the denuded
areas. Polymorphonuclear and mononuclear leucocytes are rather numerous
at the bases of the crypts.
Colon shows a certain amount of mucoid degeneration and here and there an
occasional focus of polymorphonuclear infiltration especially under the areas
where the epithelium is injured.
Dog 19-101. Clinical History and Autopsy (See Table I I I ) .
Feb. 17. Dog is active and in good condition.
Feb. 21. ~ gr. of morphia is given i hour previous to the radiation; 117 mil-
liampere minutes of radiation are given with a current strength of 7.5 milliamperes,
Dog 19-101.
TABLE HI.
Roentgen Radiation.
350 Mi l l i ampere M~ u t e s over Thorax Negative.
Dat e. Wei ght
l b s .
Feb. 17 34.0
" 20 31.0
" 21 30.4
Whi t e
bl ood cor.
pusc!es
per C. rnm
8,000
7,800
Uri ne.
Di et .
Vo l u me . Tot al N _ _ _ _
c o . g .
- - Wat e r .
I I
Remar ks.
Dog normal
Feb. 21 X-rays, 350 milliampere minutes, over thorax. Abdomen shielded.
Feb. 22
" 23
" 24
" 25
" 26
" 27
" 28
30.1
30.0
29.1
28.8
28.1
28.1
27.8
7,300
7,900
5,600
7,300
7,600
7,400
6,900
415
605
565
605
408
370
335
3.02
2.86
2.69
2.52
2.49
2.24
2.21
Experiment ended.
Apr. 11 31.3 I 7,6001 - - - -
Ether anesthesia and autopsy at once.
Wa t c e r .
~c
Dog normal.
Dog normal.
at an E. xf. ~-. of 103 kilovolts. I t was then found necessary to give the remaining
233 milliampere minutes at a current strength of 10 miJliamperes with an E. ~r. ~-.
of 90 kilovolts. 2 mm. of aluminum filter used, spark-gap of 9 inches between
sharp points. The skin-target distance is 10 inches.
Apr. 7. Dog is exposed to 450 milliampere minutes of radiation over the abdo
men and sacrificed under ether anesthesia on Apr. 11.

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Published February 1, 1922
S. L. WARIP, EIq A N D G. ]~. %%q{IPPLE 197
A~opsy. --The pleural and pericardia/ surfaces are moist and shiny. The
heart and lungs are negative. The other changes do not concern the experiment
given in Table I I L
Dog 19- 50. Cl i ni cal Hi st ory and Aut ops y.
To be contrasted with Table I I I ; a control experiment over the abdomen.
Feb. I0. Dog active and normal; fasting.
Feb. 11. i gr. of morphia 1 hour previous to radiation; 340 milliampere min-
utes are spread over the abdomen in the usual seven areas; screening of the thorax
and lower pelvis with lead-foil. A current strength of 7.5 milliamperes at 97
kilovolts is backed up by a 9 inch spark-gap; 2 ram. of aluminum filter the
radiation. The skin-target distance is I 0 inches.
Feb. 12. The dog is lively and active. A small amount of white f r ot hy
vomitus and some fluid brown feces appear on this day.
Feb. 13. There is evidence of slight intoxication. The pulse tension is low.
The vomi t us is of large volume, as much as a pi nt in an hour, and is deeply bile-
stained. The diarrhea is frequent but scant y in amount and consists most l y of
blood. At times, it is black, thick, and tarry. The dog is quite weak.
Feb. 14. The intoxication is quite severe. The animal is weak. The pulse
is of low tension and quite irregular. The vomi t us is large in amount and deeply
bile-stained. The diarrhea is profuse and frequent. At times, the fecal material
seems t o be made up practically of pure blood and contains many clots. Again
it may be t ar r y and vile smelling. The dog is comatose and is sacrificed under
ether anesthesia. Aut opsy at once.
Autopsy.--Thoracic viscera and serous surfaces are negative. The liver,
spleen, adrenals, kidneys, l ymph nodes, and genitourinary t ract are negative.
The pancreas shows a few small fat necroses.
Stomach: filled with a bl oody mucous material; mucosa pale and normal.
Small intestine is spastic and contains a small amount of bloody fluid. The
mucosa is a dull red, darker in the duodenum, lighter in the ileum. Longitudinal
folds wi t hhemor r hagi c crests are evident in some sections, especially the paler
sections of the lower jejunum, but t hey are masked in the duodenum by the intense
dark dull red of the mucosa there. The intestinal wall is thin, apparently due
t o much loss of substance in the mucosa. This is especially marked in the ileum.
Colon and cecum contain a bl oody fluid. Their mucosa is in general pale.
Histological Sections.
Liver, kidneys, adrenals, uterus are normal. Spleen shows some pul p at rophy
and prominence of t he r et i cul um Pancreas contains a few fat necroses in one
section, otherwise it is normal. I n the ovary, the chromatin network of the ova
is broken up, t hough the nucleoli are still present. The ova in general appear
abnormal and seem to be degenerating.

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198 R O E N T G E N RAY I N T O X I C A T I O N . I
Stomach and cdon are normal.
Small intestine present s t he usual pi ct ur e of necrosis and dest ruct i on of villous
and cr ypt epi t hel i um, regenerat i on of epi t hel i um wi t h mi t ot i c figures, and infil-
t r at i on of pol ymorphonucl ears i nt o t he bases of t he cr ypt s.
I n t he ileum t he ~l l i show onl y a naked ret i enl um wi t h a few groups of regen-
erat i ng epi t hel i al cells and t he l ymph follicles. The bl ood vessels in t he mucosa
are frequent l y thrombosed.
The mesenteric lymph nodes are filled wi t h r ed bl ood cells and pol ymor phonu-
clears and phagocyt i c cells cont ai ni ng cell debri s and pi gment .
Dog 19-85.
TABLE IV.
Roentgen Radiation.
Sublethal Dose over Abdomen.
D a t e .
White
blood cor-
Weight. pu~:les per
lbs.
25.0 8,000
D i e t . R e m a r k s .
Feb. 4 Water. Dog normal.
Feb. 4 X-rays, 300 mil!~mpere minutes, over abdomen. Thorax shielded.
Feb. 5
" 6
" 7
cc 8
" 9
" 10
" 11
" 20
24.5 6,000
24.0 8,000
23.5 3,400
23.3 8,400
23.0 5,800
23.0 7,800
22.5 5,400
25.0 7,400
Water.
c
c~
gc
Mixed.
Dog normal.
Inactive.
Vomitus and diarrhea.
No diarrhea or vomitus.
Clinical improvement.
G o o d condition.
Dog 19- 85. Cl i ni cal Hi st ory (See Table I V) .
Feb. 3. Dog act i ve and in good condi t i on; fasting.
Feb. 4. gr. of mor phi a gi ven 1 hour before radi at i on. The upper par t of
t he body above t he level of t he xi phi st ernum is screened by 2 ram. of sheet l ead-
foil. Exposures made over t he abdomen and pelvis in seven par t s. The cur r ent
st rengt h is 7.5 mi l l i amperes at an E. M. . of 100 kilovolts, backed up by a 9
inch spark-gap. The r adi at i on is fi l t ered by 2 man. of al umi num. The skin-
t ar get di st ance is 10 inches. The t ot al exposure t i me is 40 mi nut es- - 300 mi l l i am-
per e minutes. The dog is clinically unaffected by t he exposure to radi at i on.
Feb. 5 to 7. Dog normal .

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S. L. WARREN A N D G. If. W H I P P L E 199
Feb. 8. The animal shows a slight degree of intoxication. The vomitus which
appears 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 .
At t he ver y st ar t of this discussion, we wish t o poi nt out t he fact
t hat these experiments concern normal dogs and not human beings
suffering from disease, for example leucemia, cancer, and so forth. We
feel t hat these experiments are less complicated for this ver y reason
and ma y give us t he opport uni t y to correct mi st aken impressions
got t en from t he complex reactions which ma y result from Roent gen
radi at i on of a diseased human being.
Our negat i ve results of t horax radi at i on (up to 512 milliampere
mi nut es) are of i nt erest in ruling out convincingly certain of t he body
cells which have been suspected as causative factors in t he general
Roent gen r ay intoxication. For example, t hese enormous doses
given over t he normal t horax mus t injure more bone marrow cells
t han do t he abdomen exposures. The ribs and thoracic ver t ebne
surel y cont ai n more units of red marrow t han do t he l umbar vert e-
brae. Exami nat i on of t he rib marrow some days aft er an exposure
shows al most complete disappearance of red marrow cells, so we know
t hat this reaction has t aken place, yet t here is not a trace of any
clinical disturbance. This rules out t he red marrow as a fact or in
t he characteristic syst emi c disturbance not ed in our experiments.
These same argument s appl y t o l ymphat i c tissue. The l ymph
glands in t horax and abdomen usually show some loss of ceils but not
to any ver y great extent. I t is significant t hat Peyer' s patches in t he
i nt est i ne ma y show onl y moder at e i nj ur y when t he epithelium covering
t he l ymph follicles and lining t he crypt s has completely vanished due
t o t h e x-ray injury. I n our experiments, therefore, t he i nt est i nal
epithelium is much more sensitive to i nj ur y t han are t he cell elements
of t he l ymph gland and Peyer' s pat ch.
The spleen of t he dog is not pr of oundl y affected by t he Roent gen
radiation. For one thing, i t is not as cellular as t he human spleen,
but we feel t hat t he normal spleen ceils are not easily dest royed by t he
x-rays. Aft er large exposures we not e a moder at e at r ophy of t he

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200 ROENTGEN RAY INTOXICATION. I
spleen wi t h shrinkage of t he Malpighian corpuscles, but pl ent y of
l ymphocyt es remai n even aft er intensive radiation.
The t horax exposures, of course, cover t he hear t and lungs, which
ma y be dismissed wi t hout comment . This area also includes a large
par t of t he circulating blood. We conclude, therefore, t hat t he x-rays
have no injurious effect upon t he circulating blood cells.
The t horax exposures therefore rule out several factors which
at one t i me or anot her have been t hought t o be responsible for t he
general systemic i nt oxi cat i on--red bone marrow, l ymphat i c tissue,
and circulating blood. We ma y now consider t he various tissues in
t he abdomen which ma y be responsible for t he fat al react i on following
large doses of t he x-rays.
The ki dneys are ver y slightly disturbed, as is shown in a paper
of this series (McQuarrie and Whipple (4)).
The liver is not concerned and we believe can be ruled out wi t hout
question. There is no histological evidence of i nj ury, but more t han
t hat , t here is no evidence of functional disturbance. Dogs wi t h bile
fistulm show no di st urbance in funct i on and no change in t he level of
bile acid and bile pi gment out put . 1
The pancreas and adrenals show no histological evidence of in-
j ur y by t he x-rays. We know of no functional di st urbance whi ch ma y
be at t r i but ed t o t hese structures.
The gast roi nt est i nal t r act is remarkabl y sensitive t o t he Roent gen
rays. I n subsequent experiments, we shall review t he remarkabl e
ulcers whi ch can be produced in t he stomach, but as a whole, t he
st omach and colon are considerably mor e resi st ant t han t he small
intestine.
The epithelium of the small intestine from t he pylorus to t he ileocecal
valve is remarkabl y sensitive to t he Roent gen rays. These doses
used will cause necrosis of this epithelium wi t h pract i cal l y complete
disappearance. We believe t he sympt oms of i nt oxi cat i on and t he
final lethal poisoning are due to this i nj ury of t he intestinal epithelium.
We need not refer to t he severe intoxication which develops following
a functional di st urbance of this same epithelium (intestinal obstruc-
tion). We ma y infer t hat t he x-rays ma y produce sublethal i nj ury
Experiments to be published elsewhere.

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Published February 1, 1922
S. L. WARREN A~D G. H. WHIPPLE 201
to this intestinal epithelium which may be responsible for a vari et y
of disturbances associated with gastrointestinal sympt oms.
SLrMMARY.
Roent gen radiation of t he thorax (abdomen shielded) in dogs,
even wi t h large doses (up to 512 milliampere minutes), gives no
clinical evidence of intoxication. There may be a t ransi ent leuco-
penia and a slight rise in uri nary nitrogen.
Roent gen radiation of t he abdomen (thorax shielded) in dogs,
wi t h a dose of 350 milliampere minutes, will almost certainly cause a
fatal intoxication. Smaller doses may be survived but usually wi t h
signs of gastrointestinal intoxication.
This lethal intoxication due to abdominal radiation presents a
remarkably uniform clinical and anatomical picture. There is a
l at ent period of 24 to 36 hours, during which t he dog is perfectly
normal clinically. The 2nd day usually shows t he beginning of
diarrhea and perhaps some vomitus. The 3rd and 4t h days show
progressive intoxication with increasing vomi t i ng and bloody diarrhea
unt i l t he dog becomes stuporous. Deat h is almost always on t he
4t h day.
Anatomically t he only lesions of significance are to be found in t he
small intestine. The epithelium of t he crypts and villi shows more
or less complete necrosis, and this condition may involve almost all of
t he small intestine. The epithelium ma y vanish completely except
for a few cells here and there which have escaped and are often found
in mitosis, probably an effort at repair and regeneration.
We are forced to t he conclusion t hat this remarkable i nj ury of
t he epithelium of t he small intestine is responsible for t he various
abnormal reactions and final lethal intoxication which follow a uni t
dose of Roent gen radiation over t he abdomen of a normal dog. Thi s
sensitiveness of t he intestinal epithelium to x-rays is not appreciated
and should be given proper consideration in clinical work.
I n conclusion we wish to express our sincere appreciation for t he
assistance and advice given us by members of t he Depar t ment of
Roentgenology of t he University of California Hospi t al --Drs. Howard
E. Ruggles, Ll oyd Bryan, Orrin S. Cook, and Elizabeth Schulze.

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202 I%OEINTG]~Iq RAY I N T O X I C A T I O N . I
BIBLIOGRAPHY.
1. Denis, W., Martin, C. L., and Aldrich, M., Am. J. Med. Sc., 1920, clx, 555.
2. Fromme, G., Z. Geburtsh. u. Gyn~k., 1916--17, lxxix, 579.
3. Hall, C. C., and Whipple, G. H., Am. J. Med. Sc., 1919, clvii, 453.
4. McQuarrie, I., and Whipple, G. H., J. Exp. Med., 1922, xxxv, 225.
5. Regaud, C., Nogier, T., and Lacassagne, A., Arch. aectric, m~d., 1912, xx, 321.

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