THE RESPONSE OF THE ANIMAL ORGANISM TO REPEATED INJECTIONS OF AN ACTIVE DEPOSIT
OF RADIUM EMANATION
INTRAVENOUS INJECTIONS I N DOGS
HALSEY J. BAGG
From the Huntington Fund for Cancer Research, Memorial Hospital,
New York City
Received for publication February 19, 1920
Following intravenous or subcutaneous injections of an “active
deposit” of radium emanation, the writer found (1) in the case
of white rats, that pathological changes had resulted in the liver,
kidneys, spleen, bone marrow, etc., of these animals; and since
the methods employed in these experiments were being used in
the treatment of certain types of human cancer, it was decided
to run a parallel set of experiments on a larger animal, the dog,
and therein to determine the severity of the physiological reactions. To this end a complete urine analysis was made each
day, before and after the treatments; frequent blood counts and
differentials were made; the temperature and weight reactions
were recorded, and finally a histological study was made of the
organs removed at autopsy.
This experiment was undertaken in collaboration with Miss
Ruth Theis of the chemical department of the Memorial Hospital. We will report elsewhere on the detailed findings of the
urine analysis, and mention of them will be made in this paper
only in so far as they aid in the interpretation of what might be
called the general clinical aspects of the problem (2).
APPARATUS AND METHODS
Two female dogs were the subjects of the experiments. Dog
I was a Dalmatian and weighed 3‘44 pounds when first obtained
301
TEE JOURNAL OW CANCER RIDIIEARCH, VOL. V, NO. 4
302
HALSEY J. BAGU
by the laboratory. Dog I1 was a mongrel, with the bull dog
type predominating, and weighed nearly 28 pounds at the beginning of the experiment.
While the dog was being treated it was catheterized at a definite time each day. It was kept in a metal metabolism cage,
in which the urine and feces were collected separately. The catheterized urine completed the twenty-four hour specimen that
was used as a basis of comparison of the urine analysis. Although the dogs were under observation for a comparatively
long time, eighty days in the case of dog I, no bladder infections
were encountered. Each dog was trained to lie quietly on its
back in an ordinary trough shaped animal board, its legs were
loosely tied, and catheterization was effected by means of a silver
chtheter. These arrangements made it possible for one person
to do the work unaided by an assistant. The bladder was emptied and then washed two or three times with sterile warm water,
which was added to the day’s collection of urine, together with
the washings from the floor of the metabolism cage. After the
washing with sterile water, the bladder was again flushed with a
saturated solution of boric acid. Immediately after this operation the dog was fed its daily amount of food previously prepared
and measured according to a definite formula.
The active deposit ” of radium emanation was prepared as
described in the previous article (1). It consisted of a solution
in which radium emanation had been previously deposited upon
common salt, which subsequently was dissolved in sufficient
sterile water to bring the liquid to the strength of a physiological
salt solution. This solution contained all the properties of
radium metal itself.
The intravenous injections were effected as follows: First the
dog was placed on its back on the animal board, and held firmly
in position. Then its ear, previously shaved, was warmed by
several applications of hot cloths until the ear veins became prominent. The ear was washed with alcohol, and by means of a
fine needle and a 2 cc. Luer syringe, the activated solution was
slowly allowed to enter the general circulation. About 2 cc.
of solution were injected at each treatment. The syringe was
,
INJECTIONS OF AN ACTIVE DEPOSIT OF RADIUM
303
covered by a lead shield which acted as a protection for the
fingers of the operator.
The blood samples were also obtained from the ear. Rectal
temperatures were taken each day, and at more frequent intervals
during the period of treatment. The dog was weighed every day
during the time when significant weight changes were occurring.
Throughout the experiment an injection of the active deposit
was not repeated until the examination of the urine showed that
the metabolism of the animal had recovered from the previous
treatment.
A. EXPERIMENTAL RESULTB FOR DOG I
First treatment. In the case of dog I the treatments were
started at the beginning of March and continued until the last
week in the following May. During this period the animal r e
ceived four intravenous injections of the radioactive solution,
the total amount being 231.8 mc. The &st treatment consisted
of an injection of 95.3 mc. This was followed by a period during
which the animal was inactive. The feces were semifluid and
food was eaten only after much persuasion. This condition
lasted for only two days, for on the morning of the third, the
dog’s appetite had completely recovered, and the feces were
again normal. The second treatment was not given until a
month later, and during that time the animal appeared normal,
except for a temporary inexplicable loss of appetite on the thirteenth day of the experiment, and on the twenty-third and
twenty-fourth days.
Figure 1 shows that following the first treatment there was a
considerable drop in the number of white blood-cells, which
reached their lowest point on the eleventh day of the experiment.
The number of cells before treatment was 10,250 and ten days
later their total was only 4200, but from then on there was a
steady recovery until the normal number was again reached just
before the second treatment. Immediately after the injection,
the number of red blood-cells remained practically unaltered,
and, in fact, while the white cells were rapidly decreasing the
reds held their own and slightly increased in number.
804
HALSIY J. BAQQ
As indicated in table 1, on the eleventh day of the experiment
the differential showed that an interesting change had taken
place in the composition of the white blood-cells. The percentage of polynuclear leucocytes had gradually been reduced from
83 to 64, and the relative percentage of lymphocytes correspondingly increased from 16 to 29, while the eosinophiles went from 1
al
Noe#D*y)
I0
a*
w
60
,
7.
a4
FIQ.1. RECORDOB REDAND WHITE BLOOD-CELL
CHANGES
IN DOQI FOLLOWINQ
REPEATEDINTRAVENOU0 INJECTION0 OB THE ACTIVE
RADIUMEMANATION
DEPOBIT OB
The m o w s indicate the time when the injectionswere given, and immediately
above them is indicated the dosage, expressed in millicuries.
to 6 per cent, and 1 per cent of myelocytes was found. There
was also a slight decrease in hemoglobin. Before the next treatment the differential was again normal.
The examination of the urine showed that in response to the
injection there was an increase in the total nitrogen and urea,
and a considerable increase in the uric acid and phosphates, but,
306
INJECTION8 OF AN ACTIVE DJDPOSIT OF RADIUM
as in the case of the blood changes, the metabolism wasalso
back to normal before the next treatment.
Second treatment. The second injectiun occurred on the thirtyfist day of the experiment. A much smaller dose was given,
TABLE 1
Complete record o j the blood counts jor dog I
-
6
a
!
B
Q
b
RADIUM TREATMENTS
:
8
1
1
2
3
7
10
11
-
ra
Bta
ga
8E
-
l o
ir
-
4,4001000
80
16
1
4,112,000
4,2i56,000
4,336,000
80
18
0
4,600,000
85
75
75
76
75
28
20
11
2
6
3
4
f”
13 4,840,000
15
22
31
Second radium treatment, 30 mc. 31
34
41
Third radium treatment, 42 mc. 42
43
4.5
48
Fourth radium treatment, 64.5 mc 65
66
69
80
!2
5
-
E
-
First radium treatment, 95.3 mc.
- 5
b
70
4
85
29
4,440,000
4,500,000
4,664,000
80
16
2
4,136,000
4,690,000
80
80
14
0
4,890,000
4,976,000
80
17
17
25
2
5,544,000
5,4OO1OOO
4,980,000
80
75
80
80
-
7
0
consisting of 30 mc., and save for the fact that the feces were
slightly more fluid than normal, the dog remained well and active. > A s shown in figure 2, the temperature during this period
showed considerable irregularity, with generally low temperatures
for a few days.
306
HALSE1Y J, BAGGI
Three days after the treatment the white blood-cells were
slightly increased in number, but from that point until the third
treatment the cells were decreased about 25 per cent. The red
blood-cells were slightly lowered, but regained their normal number before the next treatment. No significant change was noted
in the differential.
There was a slight rise in the total nitrogen, the urea, and the
total phosphates of the urine, while the uric acid remained at
about the same level.
...................................................
Jo
h..,erIJr
yo
CA
60
x,
m
FIQ.2. TRMPBRATURB
CHARTFOB Doa I
The m o w s indicate the time when the injeations were given. The record WBB
not begun until after the eeaond treatment.
Third treatment. A third injection of 42 mc. was given on the
forty-second day of the experiment. It was followed by a slight
amount of diarrhea, loss of appetite which lasted for ten days,
and a decrease in weight amounting to two pounds. There was
also a sharp rise in temperature, with irregular and generally high
temperatures for several days, during which the feces were hard
and dry. There was a further reduction in the number of white
blood-cells to 2900, which number was recorded three days after
the injection. From this point the white cell's rapidly increased,
until at the time of the next treatment they were 12,500 in number.
INJECTIONS OF AN ACTIVE DEPOSIT OF RADIUM
307
The hemoglobin remained at 80 per cent. Th6 number of red
blood-cells increased, so that before the animal was again injected there were approximately a million more red cells present
than there were at the beginning of the experiment. Just after
the third treatment it was noted that the blood tended to clot
with unusual rapidity.
The examination of the urine showed a considerable increase
in the total nitrogen, urea, creatinine, uric acid, and the total
phosphates.
ao ,
FIQ.3. RECORD
OF WEIQBTCHANQES
FOR DOQI AND DOQI1 FOLLOWINQ
REPEATED
INTRAVENOUB
INJECTIONS
OF THE Amvro DEPOSIT
OF
RADIUM
EMANATION
The arrow8 indicate the time when the injection8 were given
Fourth treatment. Sixty-four and a half millicuries were injected on the sixty-fifth day of the experiment. This treatment
was followed by severe vomiting, constipation, the excretion of a
small amount of solid, dry feces, and a sudden rise in temperature to 102". At the end of the following day the temperature
again reached the same high level before finally receding. The
animal refused to eat for two days, and as indicated in figure 3,
there was a steady loss of weight amounting to 31 pounds.
The animal was inactive and obviously seriously ill.
308
HALSEY J. BAGG
The white blood-cells were reduced in number to 5600, but the
red blood-cells were only slightly decreased. The differential
showed a relative inorease in the number of lymphocytes at the
expense of the polynuclear leucocytes. The fact that the animal
refused to eat after the fourth treatment made the chemical
analysis of the urine unreliable. There was, however, a decided
increase in the amount of urine excreted each day.
At this time the dog was killed by means of ether.
Histological report for dog I
The histological study of the organs showed an intensely congested liver, with some capillary varicosities and severe granular
degeneration of most of the parenchyma cells. The kidneys
were also intensely congested, showing a moderate amount of
degeneration of the tubule cells. The malpighian bodies of the
spleen were prominent; the organ was congested, and the pulp
considerably drained of cells. There was marked congestion of
the colon associated with active mucus production. The lymphnodes showed extreme congestion, especially of the pulp. The
lymph-follicles were reduced in size, but the reticulum cells were
generally increased in number. No definite changes were noted
in the lungs, stomach, small intestine, or thyroid.
B. EXPERIMENTAL RESULTS FOR DOG I1
First treatment. The experimental work with dog I1 began in
the first part of June and continued until the end of July. Four
injections were given, the total amount of radium emanation
amounting to 338.4 mc. The initial treatment consisted of 120
mc. injected on the seventh day of the experiment. As indicated
in figure 4, this was followed by irregularly lowered temperature
for several days following the injection. No gastric symptoms
were noted until three days after treatment, when vomiting
occurred; the animal became dull and inactive, and refused most
of its food. Figure 3 shows there was a loss in weight amounting
to 2 pounds, occurring within six days. As shown in figure 5
there was a marked decrease in the number of white blood-cells;
INJECTIONS OF AN ACTIVE DEPOSIT OF RADIUM
309
from 14,400 before treatment to 2150 seven days later. There
was a temporary fall in the hemoglobin from 85 to 75 per cent,
accompanying a decrease of about two million red cells. As
shown in table 2, the differential remained normal, except for a
slight relative increase of lymphocytes. The examination of the
urine showed a large increase in uric acid and the total phosphates.
Second treatment. A small dose, consisting of 17.3 mc., was
injected on the twenty-eighth day of the experiment. After this
treatment there was at fist a temporary drop in the body tem-
1 , .
. . .
N o q D r ~ S 10
ao
30
w
50
' R
FIG.4. TEMPERATURE
CHARTFOR DOQI1
The arrows indicate the time when the injections were given
perature, followed by a rapid increase at the end of the following
day, at which time 102.5' was reached. No other change was
noted in the animal's general condition. It remained active, and
ate with its usual good appetite. There was a steady decrease in
the number of white blood-cells, the hemoglobin remained normal, but the red blood-cells continued to increase slowly. The
weight remained stationary, as indicated in figure 3. The analysis of the urine showed only a slight increase in the total nitrogen, the creatinine, the urio acid, and the total phosphates.
310
HALSEY J. BAGG
Third treatment. On the thirty-seventh day of the experiment the animal received an injection of 54.7 mc. Following
this there was a slight temporary increase in temperature, during
which time the animal was somewhat inactive for three successive
days, but showed no signs of digestive disturbances, except for
a temporary refusal of food on the fourth day. During this
TABLE 2
Complete record f the blood counts for dog I I
m
RADIUM TRXUTMENTB
d
8
B
1
6
B
”
2,
-
First radium treatment, 120 mc.
3
4
7
8
9
11
14
28
6,400,000
5,924,000
--
-
85 1i
J
8
14
la
‘&
!z
I
I
ii
ir
-
-
PQ
iE
13,800 85
14,400 85
0
5,600,000
5,280,000
4,880,000
4,680,000
4,978,000
8,900
4,550
2,815
2,150
5,700
85
80
75
80
0
0
0
85
0
29 5,260,000
Third radium treatment, 54.7 mc. 37
4,450
85
Second radium treatment, 17.3
ma.
28
38 5,800,000
49 5,814,000
3,m 85
4,100 80
0
0
85
0
Fourth radium treatment, 146.4
52
mc .
53 5,200,000
57 4,520,000
2,600
1,400 85
-
period the animal lost 13 pounds in weight. The number of red
and white blood-cells remained fairly constant, and yet the differential showed a relative decrease in the percentage of lymphocytes, with a corresponding relative increase in the polynuclear
leucocytes and the formation of a few eosinophilic cells. The
urine showed an increase in the total nitrogen and the phosphates,
while the creatinine stayed at about the same level.
311
INJECTIONB O F AN ACTIVE DEPOSIT OF RADIUM
Fourth treatment. The final injection was a large one, and
consisted of 146.4 mc. administered on the fifty-second day of
the experiment. Just before the treatment the temperature
went as high as 102.3", and after the treatment it reached 102.7'
No.08 Whits Bfooa Ccll~
IY64rnr.
. . . . . . . . . . . . . . . . . .............................
No.O.$DA.rS
rb
0
1 . . . . . . . ia" . . . ' . . . , ' . . ' " . .
i
~0.05~13s
a0
YO
30
._
.,... . . . . . ,.........,.....
30
40
...
50
,
60
FIG.6. RECORD
OF REDAND WHITEBLOOD-CELL
CHANQES
IN DOQI1 FOLLOWINQ
OF THB~ACTIVBDEPOSIT
OF
REPEATED
INTRAVENOUS
INJECTIONS
RADIUM
EMANATION
The arrows indicate the time when the injections were given
and then as suddenly receded. A few hours after the treatment
a considerable amount of mucus covered vomitus was found in
the cage, as well as a large quantity of fecal matter, semi-solid
and odorless, and also covered with mucus. The animal refused to eat during the rest of the experiment except for an occa-
312
HALSEY J. BAGG
sional small amount of food. It lost 2 pounds in weight within
five days, and remained seriously ill and inactive. The white
blood-cells decreased still further in number until at the end of
the experiment they were as low as 1400 cells, The differential
showed a very decided reduction in the percentage of lymphocytes.
These cells were reduced to 3 per cent, while a corresponding
relative increase in the polynuclear leucocytes was recorded,
amounting to 95 per cent. The hemoglobin remained normal
and the red blood-cells were but slightly decreased in number.
The urine analysis was unreliable, because the animal refused to
eat. The animal was killed by ether anesthesia.
Histological report for dog I1
The histological study of the organs showed a general fatty
and granular degeneration of the liver, associated with capillary
congestion. The kidneys showed a slight granular degeneration
of the tubule cells, with general venous congestion. There was
a marked old thickening of the trabeculae of the spleen, a heavy
pigmentation of the parenchyma cells, associated with small
and scanty follicles. The splenic pulp showed considerable
congestion and fibrosis. The bone marrow from the head of the
femur was devoid of lymphoid cells, which were largely replaced
by fat. The lungs were congested, and showed a slight degree
of emphysema. There was a small amount of catarrhal exfoliation of the sinus cells of the lymph-nodes. The pancreas, the
thyroid and parathyroid, the stomach, and the small intestine
showed no structural changes.
DISCUSSION AND SUMMARY OF RESULTB
The results of these experiments are interesting in that they
show that very decided physiological reactions follow repeated
intravenous injections of an active deposit of radium emanation.
Clinical data have established the fact that external applications
of radium or $-rays will produce decided changes in the composition and number of blood cells, and the results of this investigation show that the same changes may be obtained by injecting
intravenously the active deposit of radium emanation.
INJECTIONS OF AN ACTIVE DEPOSIT O F RADIUM
S
313
In the case of external applications of filtered radium the physiological changes are produced mainly by gamma ray activity,
while in the case of the radioactive solution used in the present
experiments, the effect is largely due to alpha ray activity. The
results show that following such intravenous injections there is a
prompt reduction in the number of white blood-cells, which was
especially well illustrated in the case of dog 11, whose white
cells were reduced from 14,400before the treatments to 1400 at
the end of the experiment. The terminal dose for the same animal also produced a remarkable reduction in the relative percentage of lymphocytes. As shown in table 2, after repeated
doses of the radioactive solutions, the percentage of lymphocytes
was reduced from 19 before treatment to 3 after the fourth injection. In this case, dog 11, the four injections totaled 338.4
mc., and the last dose that preceded the sudden drop in lymphocytes, was a very large one, 146.4 mc. In both animals, however,
after an initial moderate dose of the active deposit there was a
gradual increase in the relative percentage of circulating lymphocytes in the blood. Dog I, that received 231.8 mc. in four injections (the total dose was 106.6 mc. less than the amount given
to dog 11),showed a terminal increase in the relative percentage
of lymphocytes after moderate doses, which however were sufficient to reduce considerably the total white blood-cell count.
If it is true that following the instances where moderate doses
of the active desposit of radium emanation were given to these
animals there was an increase in, or a tendency to an increase in,
the actual number of lymphocytes in the body, not merely those
in the circulation, then these results may be considered similar
to those of Murphy (3), of Murphy and Morton (4),and, more
recently, of Murphy and Nakahara (5 and 6), in their experimental work concerning lymphoid destruction and the stimulation of the lymphoid elements in animals after exposure to x-rays.
It is possible that such was the case, but the histological data at
hand are not sufficient to settle the point.'
1
In order to determine the presence of lymphoid stimulation it will be neces-
sary to kill the treated animal after a single moderate dose, and not to continue
with larger doses as was done in these experiments. Further experiments are
planned to elucidate this subject.
314
HALSEY J. BAGG
The present experiments show that the apparent red bloodcell destruction was slight in comparison with the white bloodcell changes. I n the case of dog I, see figure 1, an initial injection of 96.3 mc. of radioaotive solution was promptly followed
by a constant increase in the number of red blood-cells, which
remained above normal until the second injection was given.
This increase, however, may not have exceeded the limits of
variability normal to the changes in the number of red bloodcells. After the second treatment, there was a sudden return
to the normal number, followed by gradual increases in the red
blood-cells, which continued to remain above normal from then on
until the end of the experiment. Dog I1 lost about 25 per cent
of its red blood-cells after an initial dose of 120 mc. This was no
doubt a significant response. This loss was followed by a gradual
increase after the injection of the two succeeding moderate doses
of 17.3 mc. and 54.7 mc. respectively. The large terminal dose
of 146.4 mc. again reduced the number of red cells to their previously low figure.
Comment on the subject of these red blood-cell changes brings
up a point similar to one discussed in regard to the possibility of
the stimulation of lymphoid production following intravenous
injections of the active deposit solutions. Again the histological
data are not sufficient to show the presence of increased red bloodcell production in the bone marrow, etc. How much of the apparent increase in the circulating red blood-cells was due to the
attending diarrhea, or other undetermined conditions, is still
unknown.
During the period in which the white blood-cells were being
materially reduced there was a decidedly noticeable tendency for
the blood to clot with considerable rapidity. This condition
may have been brought about by the possible liberation of enzymes set free as a result of the destruction of large numbers of
blood-cells.
In a previous work of the writer in which white rats were used
as subjects, it was found that following lethal injections of the
active deposit of radium emanation, the animals died after showing symptoms of marked enteritis. This subject was discussed,
INJECTIONB O F AN ACTIVE DEPOSIT O F RADIUM
315
and the phenomenon attributed to the fact that experimental
data tend to show that a considerable amount of the radioactive
substance was deposited in the intestinal tract. In the hase of
the dogs of the present investigation similar digestive disturbances
were noted. After the first injection of 95.3 mc. dog I became
inactive, diarrhea was present, and the dog refused to eat; but this condition lasted for only two days. ' The second injection
was smaller, 30 mc., but following it the animal remained well
and active, and showed no signs of digestive disturbances. The
third injection consisted of 42 mc., and was followed by a slight
amount of diarrhea, loss of appetite, and a reduction in weight.
The fourth treatment, consisting of 64.5 mc., resulted in the animal refusing its food altogether, severe vomiting, and a further
loss in weight.
The reaction of dog I1 to an initial dose of 120 mc. wa8
interesting in that no digestive disturbances were noted until
three days after the treatment, when vomiting occurred, and the
animal became dull and inactive and would eat only a part of
its food. The following injection consisted of 17.3 mc., and, as
in the case of the small injection for dog I, it produced no digestive disturbances. Even with a dose of 54.7 mc., the third for
dog 11, no physical changes were noted, except that the animal
was somewhat inactive for three days, andrefused to eat on the
fourth. The terminal large dose, however, 146.4 mc., produced
a prompt reaction in the case of dog 11. Vomiting was severe,
a large amount of mucus covered feces was extruded, the animal
refused to eat altogether, and lost two pounds in weight within
five days.
Similar, but not as severe, intestinal disturbances were noted
by Berg and Welker (7) in their work on the metabolism of
dogs in nitrogenous equilibrium. They found, however, that no
gross symptoms, except diarrhea, resulted from the administration by mouth of a preparation of 240 activity of radium bromid.
As shown in figure 2 and figure 4 the limits of the temperature
changes indicate a considerable daily variation. It is thus dif€icult to make any definite statements concerning temperature reactions in response to this type of radium treatment. The sharp
316
HALSEY J. BAOQ
rise in temperature in response to the terminal dose that was
given to dog I is no doubt beyond the limits of the probable
error of the variability for that case, and indicates a definite
attempt on the part of the organism to adjust itself to the toxic
disturbances brought about by the radium treatment. This
toxemia probably resulted from the relatively sudden destruction of a large amount of cellular material which had to be eliminated by excretory organs, already damaged by previous radium
treatments and passing through processes of degeneration. A
similar temperature reaction probably holds good in the case of
the second treatment for dog 11, although the dose in this case
was a small one, and again in the terminal reaction for the same
animal, although why the treatment should be immediately
preceded by a high temperature as well as followed by one, is
still unanswerable.
The effect of repeated injections of an active deposit of radium
emanation upon the weight of the animal is clearly shown in the
case of dog 11,see figure 3. There was a gradual almost constant
decrease, amounting to about 25 per cent of the original weight.
The metabolic changes showed in the main that the total nitrogen content of the urine, the urea, the creatinine, the uric acid,
and the total phosphates were markedly increased, probably as a
result of active tissue destruction, and also to some extent due
to the interference of the proper functioning of the excretory
organs, as a direct result of the injections of the active deposit.
That active degenerative changes had occurred as a result of
the radioactive injections is shown by an examination of the
microscopical sections of the organs. These results resemble
those obtained by the writer after similar injections in white
rats. In both experiments there was considerable congestion
in the principal organs, but the more pronounced degenerative
changes in the white rats were far more severe than those that
occurred in the dogs.
As previously stated in detail, a considerable amount of degeneration was found in the liver and kidneys of the animals.
The spleen was also considerably altered, while it is to be noted
that the bone marrow from the head of the femur in dog I1 was
INJECTIONS OF AN ACTIVE DEPOSIT OF RADIUM
317
devoid of lymphoid cells. The lymph-nodes as well as the lungs
showed pathological changes in the case of dog 11. The intestinal tract of dog IT apparently showed no definite changes,
while in the case of dog I, the only pathological changes that
were noted were found in the colon, which was markedly congested, and showed signs of active mucus production. The
stomach, thyroid, pancreas, and musculature presented no
definite changes.
From a consideration of the results of the investigation as a
whole, one may say that in the intravenous use of the solution
form of the active deposit of radium emanation, as a therapeutic
agent in cancer or other diseases, it is necessary to keep in mind
the fact that after an initial dose of such radioactive substance
the animal organism is irretrievably altered, and from then on
will not give the same reaction to a repetition of the initial dose.
The organism, as seen in the dogs of this experiment, is able to
compensate for a severe initial dose of the radioactive substance,
but after a certain point has been reached the natural protective
adaptations on the part of the organs affected become inadequate
to meet the demands of the organism as a whole, and the
effects of the intoxication are greatly aggravated.
CONCLUSIONS
1. Large intravenous doses of an active deposit of radium emanation produce a considerable reduction in the number of white
blood-cells, but while the white cells may be reduced by as much
as 80 per cent of their total number, from the effects of an
initial dose, the simultaneous reduction in the number of red
blood-cells is less, and amounts to a reduction of about 25 per
cent;.
2. Repeated doses, amounting to a total of 338.4 mc. distributed in four intravenous injections, apparently produce a very
marked decrease in the number of circulating lymphocytes of the
blood.
3. Digestive disturbances, such as severe vomiting and diarrhea, followed large doses of the radioactive solutions, and were
associated with a considerable reduction in the body weight.
T E E JOURNAL OF CANCER RESEARCH, VOL. V, NO.
4
318
HALSHY J. BAGG
4. In several cases, a rise in body temperature followed the
treatments, suggesting an adaptive reaction on the part of the
animal organism to meet the toxic condition produced by the
relatively sudden destruction of a considerable amount of cellular
material.
5. The metabolic changes, as determined by the daily urine
analysis showed that the larger injections of the radioactive solutions were followed by very decided increases in the total nitrogen content of the urine, the urea, creatinine, uric acid, and the
total phosphates.
6. Relatively small or moderate doses of the radioactive solution, if administered after the organism has already been injured
by a previous injection, even when the metabolism is again back
at normal, produce definite changes in the chemical content of
the urine, indicative of destructive changes within the organism. These injections may or may not be followed by gross
symptoms of digestive disturbance.
7. The histological study of the organs showed considerable
congestion in the principal viscera. The liver showed a general
fatty and granular degeneration, the kidneys showed a granular
degeneration of the tubule cells, and the spleen presented considerable congestion, while the splenic pulp was largely drained
of cells. The bone marrow was devoid of lymphoid tissue,
which was largely replaced by fat. There was extreme congestion in the pulp of the lymph-nodes in one animal, associated with a reduction in size of the lymph-follicles. The lungs
in one animal were normal, while in the other, which received
the larger total of the radioactive solution, they were congested
and showed slight signs of emphysema. The colon in one of
the animals was markedly congested, and showed signs of active
mucus production. The other organs showed no definite changes.
8. When the active deposit of radium emanation is used intravenously as a therapeutic agent, great care should be taken to
grade the dose in accordance with the general physical condition
of the patient, which should be determined by frequent urine and
blood analyses; and if more than one dose is given during the
treatment, the second dose should be made smaller in accordance
with the strength of the original dose.
INJECTIONS O F AN ACTIVE DEPOSIT O F RADIUM
319
ACKNOWLEDGMENT
The writer wishes t o express his indebtedness to Dr. James.
Ewing for his aid in the interpretation of the pathological results,
and to Miss Ruth Theis and Dr. Stanley Benedict, who planned
the chemical scope of the experiment.
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(3) MURPHY:
Jour. Am. Med. Assn., 1914, lxii, 1469.
Jour. Exper. Med., 1915, xxii, 800.
(4) MURPHYAND MORTON:
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Jour. Exper. Med., 1920, xxxi, 1.
(6) NAEAHARA
AND MURPHY:
Jour. Exper. Med., 1920, xxxi, 13.
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