SOME USSR RESULTS AND THEORIES PERTAINING TO ACUTE RADIATION SICKNESS

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• Collection: General CIA Records
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• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 17
• Document Creation Date: December 22, 2016
• Document Release Date: July 8, 2011
• Sequence Number: 85
• Publication Date: April 9, 1956
• Content Type: REPORT

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STAT
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SOME USSR RESULTS AND THEORIES PERTAINING TO ACUTE RADIATION SICKNESS
[CCoromrmeespnt:onding The MemberfollowingAcademyreportofwasMpublishedal
tav,
edic by P. D. Gorizon-
Sciences USSR, under
the title The Problem of the Pathogenesis of Acute Radiation Sick-
ness" in Arkhiv Patolo ii, Vol 17, No 4, Oct-Dec 1955, pp 3-14. It
reviews in some detail recent USSR work on the pathogenesis of rad-
iation sickness and compares USSR results in this field with results
obtained abroad.
Author's bibliography, figures, and tables mentioned in text
are appended.]
One of the most urgent problems of contemporary medicine is that pertain-
ing to radiation sickness. Under radiation sickness one understands the path-
rlogical condition brought about by the action of ionizing radiation.
it has been established that for the formation of a single pair of ions
in the air all energy of no less than 32-35 electron volts is needed. The en-
ergy of visible light, infra-red rays, and ultraviolet rays has a magnitude of
2-10 electron volts. It follows that these types of radiant energy cannot as
a rule bring about ionization. The ionizing types of radiant energy that are
of the greatest significance for human pathology comprise gamma rays, X rays,
alpha rays, beta rays, neutrons, and protons.
The energy of these types of radiation may approach millions of electron
volts. We cannot in the present article discuss the characteristic properties
of different types of ionizing radiation. We will only point out that the bi-
ological action produced by these types of radiation depends on the energy and
consequently on the intersity of the processes of ionization. For that reason,
notwithstanding the differences in the clinical syndromes of the pathological
conditions Produced by various types of radiant energy, one may speak of prob-
lem:: of the pathogenesis of radiation sickness which are common to all types
of radiant energy. In the cc:miunications which have been published on the
subject there is no unanimity concerning the essential nature of the radiation
illness. Different theories in regard to the pathogenesis of radiation sick-
ness have been advanced. particularly abroad.
For instance, an article by Jen;;inson and Brown (11,:44) discusses nine
theories which are used to explain the pathogenesis of radiation sickness,
while an article by Shorvon mentions 10 such theories and a manual edited by
Berens in 1952, seven theories.
From our point of view one of the basic shortcomings of the concepts which
are adhered to at the present time is that in order to explain radiation sick-
ness a major significance is ascribed to a single process and that on this ba-
sis attempts are being made to explain the complete pathogenesis of the condi-
tion involved. For instance, enkinson and Brown regard as the principal path-
ogenetic mechanism [which brings about the sickness;] disturbances of the permea-
bility of blood vessels. Warren and Whipple regard changes in the mucous mem-
brane of the intestine and intestinal intoxication as the principal factor,
while Ellinger advances the assumption that the role of histamine is of princi-
pal importance, with the result that some investigators who adhere to his view
regard the pathogenesis of radiation sickness as similar to that occurring
shock. in
A second error is that many investigators do not differentiate between the
problem of pathogenesis and the problem of the biological effect produced by
ionizing radiation.
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One cannot, of course, discuss the theories of pathogenesis without a
knowledge of the action of ionizing radiation on biological substrates. How-
ever, one should not forget that the process of the development of a patho-
logical condition is a more complex phenomenon, which is determined by the
characteristics of the reactions of the organism depending on the development
of its nervous system. In this context, we are of the opinion that in the com-
plex problem of radiation sickness two special problems can be differentiated:
(a) the mechanisms of the primary action of ionizing radiation on biological
substrates in general, and (b) the mechanisms of the pathogenetic action of ion-
izing radiation, i. e., the problem of the harmful effect which is exerted on
higher organisms.
These problems are interdependent and one may speak about their essential
unity. However, this unity extends only to a certain point. As an example of
failure to pay due attention to the qualitative peculiarities of the radiation
affliction depending on the philogenetic and ontogenetic stage of development
of the organisms affected, one may cite a review by Patt (1953), in which the
mechanisms of defense against ionizing radiation are discussed without regard
to the significance of the characteristic., of differently constituted organisms.
The fir.;t problem, that of the action of ionizing radiation on biological
substrates, is usually solved within the :;cope of general biological problems
under the application of physicochemical and biochemical methods of investiga-
u or. At present the assumption in regard to the significant role played by
pro?-e:aes of the ionization of the water is most generally recognized. To it-.
lustrate, an energy quantum of gamma radiation knocks an electron out of the
molecule of water, so that a positively charged molecule of water is formed,
while the electron combines with another molecule of water, forming a negatively
charged molecule. In this manner an ion pair is formed:
H2O - e
--'
H
O
H
2
+ HO
H2O 4 e
--
-i20
- -; Ht HO-
In the presence
the formation of new
of oxygen,
different reactions arise which lead either to
ation of the initial
components
substance,;
or as a result of recombination to the restor-
OH
OH
H2 02
I'
H -- I',
c
H
4
02 -P
H 02
OH
A
OH -* i+'0 A 0, etc .
In the process of the ionizacion of water, the neatest significance is
ascribed to the following oxidizing; radios]s: atomic hydrogen (11) [sic), hy_
drox:1. (OH), hydroperoxide (HO,), and hydre(en peroxide (11202).
These radicals represent products of the deccmposition of water arising
under the effect of ionization. They exert an action on the protein molecules,
particularly the most reactive structures of these molecules that contain sulf-
hydryl groups (-SH), and transform these groups into inactive sulfide groups
(S-S).
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in The oxidation of sulfhydryl groups of protein molecules can be represented
the following manner:
2SH+20H -S S +2H20
2 SH a 2 02H ? -S S+ 2 H20
In this manner the functioning of the important cell enzyme systems which
participate in the processes of synthesis is interfered with. This concept is
based on assumptions made by Weiss and Barron.
radiations increases aasethenwatenccontentlofwbiological' structures decreases facts. 1? The resistance to
(for instance, as a result of drying). 2. de-
creases in connection with the reduction of thThe sus e partialipressureoofnoxygen
because a reduction in the number of oxydizing injury de-
brought about in this ma l radicals tht are
injurious action n of
ionizing 3. As is well known, ng radiation is independent of the concentration of nt biological structures
in the solution (this constitutes the so-called dilution effect).
Since the aspects of the biological action of ionizing radiation are dis-
cussed cussed more fully in a monograph by B. N. Tarusov, we will not
However, one must point out that much remains unexplained as far as this lem is concerned. For go into
in what manner the short-lived eradicalss mentionedhabovesbring aboutethesmoreb
remote effects involved in processes that take a long time. B. N. Tarusov's
attempts to fill in this gap by advancing an assumption in regard to the role
played by self-accelerating chemical reactions.
As far as the second problem is concerned, i.e., that of the mechanism of
the development of the pathogenic condition, one may say that injury to cells
or tissues under the action of ionizing radiation is regarded as the
factor in the development of this condition. All theories of pathogenesis that
are ?.no'-,-' to us are based on this assumption (i.e., principal
tin, Ellinger, Jeni:inson and Brown, Cronkhite and Chapman, etc). of A. S. Niki-
According to Nikitin, the scheme of the development of radiation sickness
can be represented in the following manner:
Primary injury to protoplasm
Local disturbance of time
regulation
Disturbance of morphogenesis
Suppression of growth and development
Destruction of irradiated tissue (late
reactions)
Damage to irradiated cells
and their destruction (pri-
rIary destruction of cells)
Humoral reactions
Nervous reactions
General X- ray reaction
According to the concepts which have been outlined, the general reaction
of the organism is brought about exclusively by action along the humoral route
in the sense that various toxic and sensitizing substances enter the blood
from the afflicted tissues.
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r?~~bas~rmisorofthethesensitiury
i vityprodofuceddifferent, tissues and
j
cells garded to radiation on the as sensitivity to radiation the dose of radiation which on
n Holthousen (1920) re-
de-
generation of cells or necrobiosis. Using this criterion, some investigators
arrived at the conclusion that as far as sensitivity to radiation isyconccerned,
the blood cells are on top of the scale, while the tissue of the nervous
is the most resistant to radiation (Ellinger, Blum, de Course
system
y, et al).
As factors which determine the sensitivity of tissues to radiation, the
following are pointed out with a certain measure of justification: (a) the mi-
totic activity of the cells, (b) the degree of differentiation, and
tensity of metabolism. It has been established that the more intensely the
processes of division r (c) the in-
degree of differentiiationtof{thepcells,i andtfinally yuth h me trig less
esses of metabcli;m which take e pronounced the
irtt
proc-
of ese fita of
plone in the tissue , the higher thehe se
i se the nsitivit -
ty
Ionizing radon is found to be.
y
Gimpel'man, Lisko, and Gofman in their monograph point out that there are
two possibilities of injury to the cells: injury to dividing cells and injury
to dormant cells.
in an experiment with a culture of chicken fibroblasts it has seen shown
that in order to bring about degeneration of dormant cells, the application of
2,500 roentgen ;s necessary, whoa dividing cells perish when a dose of 100
roentgen has been applied. The dormant cells do not undergo any after application of the dose of radiation which has seen mentioned until they
begin modifications
ito divide. Then the cell either perishes or produces two daughter cells
incapable of surviving.
On the basis of the concepts outlined above, Cronrhite and Chapman
that the pathogenic condition develops as follows. Having a greater to radiation, the mature cells "uggest
whi you.
perish, le the of the organism that has been irradiatedsdotnote
'43 Propagating cells are affected.
As a result, in vie; of the fact that the natural death of mature cells
is not compensated by the generation of new cells, devastation of a system (e.g.,
blood system) of the organism which is affected takes place and this
ins finally put out of commission. In regard to the ideas which have been out-
iined, one ma system
y say that there is no reason for denying that a direct injurious
effect is exerted on the cells and tissues as a consequence of exposure to ion-
izing radiation. Furthermore, the sensitivity of different tissues of the or-
ganism being irradiate,! is actually different.
However, we regard it as entirely wrong to ascribe the sensitivity of
cells to the structures.' damage inflicted on them because we do not have at our
disposal as yet morphological methods which oa',e it possible to evaluate with
certainty the functional condition of cells, for instance, of cells of the nerv-
ous system. It is precisely this: circumstance which led to the faulty conclu-
sion in regard to the insensitivity of nerve cells to the action of ionizing
radiation' The work done by USSR scientists Tarihanov, Zhukovskiy, Nenenov,
tupal.ov, Raisin, Livanov, and others has demonstrated that the functions of the
central nervous system are disturbed as a result of the action of ionize
diation.
ng ra-
USSR we describedrthenresultstof investigation of the higher nervous activity vitnofs
rats, of the spinal reflexes of dogs, and of electroencepholographic measurements
carried out on rabbits.
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The investigations of the cortical activity of irradiated rats have shown
that in the process of the development of acute radiation sic ness, acute dis-
turbances of the conditioned reflex activities take place (A. Grafov). After
an initial strong reinforcement of conditioned reflexes, a sharp weakening of
conditioned reflex activity develops. Finally, a third period can be differ-
entiated, that of recovery and relative normalization. This period is charac-
terized by the persistent instability of the processes of stimulation and in-
hibition. The length of the individual periods or stages and the time at which
they begin depend on the magnitude of the dose of radiation which has been ap-
plied and the typological characteristics of the organism affected.
The same periodicity of changes in the cortical activity was established
prior to that by M. N. Livanov on rabbits with the use of electroencephalo-
graphic methods of investigation.
These changes are apparently expressed, first of all, in a disturbance of
internal Inhibition, because we established on rats that a breakdown of condi-
tioned inhibition takes place several minutes after irradiation and is associ-
ated with a stoppage of differential inhibition accompanied by disturbances of
extinction.
All these changes are subject to the same regularities which are charac-
teristic for acute pathological processes of diverse etiology. For instance
Jisturtances of internal inhibition were observed after application of anes-
thetics, intoxications, and infections (A. A. Lindberg, V. K. Federov, A. G.
Ivanov-Smolenckiy, and others). We discussed this subject in another article.
Clinical observations have shown that changes in the nervous system ensue
very promptly, i.e., several minutes after the beginning of the application of
therapeutic doses of radiation (Grigor'yev). In other words, these changes oc-
cur at a time when there i.s no reason to assume that injury to cells has taken
place. In this context, we cannot exclude the possibility that tissues are in-
jured by reason of disturbances of the normal reflex regulation.
The cos= bility that there i an indirect injurious effect on tissues pro-
duced by ionizing radiation through the medium of the system midbrain-hypophysis-
euprarenals was shown in experimental investigations by Langendorf and Lorenz
(19'i2i Sc their work on the causes of llsohopenia which develops after irradia-
Ltun- :n the experiments by the investListors mentioned, approximately the
Luse degrees of lymphopenia were outaineu upon local irradiation of the hip,
tae testicle, and the hytophyc?is. Furthermore, the same lymphopenia crigi-
.ated without any exposure to radiation under unfavorable conditions, for in-
stan:'e, when the rat was held motionless on the operating table for several
minutes. In all these experiments the lymphupenia could be eliminated by prior
adreralt?ctemy. These facts testify to the circumstance that one cannot regard
the ly'mphopenla of the irradiated animals only from the standpoint of a specific
sensitivity of lymphocytes to ionizing radiation and of a direct action of ra-
diant energy on lymphocytes.
similarly, one cannot regard the devastation of blood-formic, elements
which follcwa irradiation solely as a result of direct injury inflicted on the
ycung reproductive cells of the organs of hemopoiesis. Booz, Betz, and Firket
(l',;4) have shown that upon general irradiation of guinea pigs with doses rang-
ing from 7CC to 8,000 roentgen, i.e., doses which exceed by several times the
quantities of radiation producing a lethal effect, the tissue of the spleen of
the experimental animals will not lose its capacity to regenerate if it is
transplanted within a day into the healthy, nonirradiated body of another guinea
pig.
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STAT
If a leg of a rabbit is exposers to doses amounting to 3,000-5,000 roent-
gen and the body of the rabbit and its other legs are protected from the di-
rect action of the ionizing radiation, one finds that at the expiration of
approximately 3 weeks an ulcer develops on the leg which has been exposed to
radiation. Approximately the same kind of ulcer develops within about the
same time in a symmetrical section of a leg that has not been irradiated (N,. M
Livanov). The possibility that there may be a reflected action of ionizing
radiation has usually seen explained by humoral effects. For instance, P. V.
Sipovskiy, in studying the histology of the bone marrow, found subsequently to
irradiation changes in spots which had not been irradiated. In reference to
this, he states that in order to explain the reflected action of X rays, one
must assume that this action is the result of a secondary effect exerted by
products of protein decomposition (for instance, the products resulting from
the death of cell elements). These products of the decay of cells penetrate
into the blood and subsequently bring about a number of changes in other or-
gans.
It is difficult to explain from this point of view why the ulcer on the
leg which has not been irradiated develops simultaneously and originates in a
symmetrically disposed location.
The ways in which the pathological process is brought about after irradi-
ation is more complex; they cannot be ascribed solely to a direct injury and
to the action of substances that originate in the injured tissues. The changes
in the nervous system, the occurrence of which has been established principally
by USSR scientists, and the facts cited above testify to the possibility that
reactions may develop which are transmitted through the nervous system and the
system of neuro-endocrinic glands (the hypophysis and the suprarenals).
In this context, the problem in regard to the initial ways of the process
and of the location where the principal injury of the nervous system takes
place remains unsolved. One cannot, of course, assume that the nervous system
is affected everywhere in the same measure by some sort of a diffuse process or
that all pathological conditions aru the result of a primary disturbance of
cortical activity. In an investigation dealing with the problem of the appli-
cation of I. P. Pavlov';; teaching to the problems of pathophysiology, we pointed
out that it is necessary to determine in every disease the principal links which
are affected when a disturbance in the functioning of the nervous; system takes
pLa ^e.
The results of experimental investi aticns in which simians were irradi-
ated lead to the conclusion that affliction to a predominant extent of the
higher vegetative centers must be assumed (Clement and Holst). Experiments
which we have carried out on dogs testify to disturbances of the temperature
regulation in irradiated animal:;. This phenomenon may be an expression of the
fact that the activity of the corresponding part of the vegetative system has
been affected. However, the problem in regard to the initial stages and to the
location of the maximum injury to the nervous system cannot be regarded as
solved as far as the role of these effects in the pathology of radiation injury
is concerned.
In trying to clarify the role of the nervous system in the mechanisms of
the pathogenetic action of ionizing radiation, we do not exclude the possibil-
ity that the humoral factor may participate in the pathogenesis.
Notwithstanding the fact that much attention has been paid in the radio-
biological literature to the problem of toxemia, this problem has not been
solved in a unanimous fashion. The most convincing data were obtained in ex-
periments carried out on parabiotic animals in which the blood circulation sys-
tems were merged by establishing a mutual connection between the skin and the
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muscles. This connection was brought about by sewing together two animals and
allowing the tissues to heal. Rats or guinea pigs of the same litter and the
same size were commonly used in these experiments. Under these conditions the
irradiation of one of the animals brings about leukopenia in the other animal,
which has not been irradiated. By using this method, Edwards and Summers did
not obtain any necroblotic changes in the organs of the animal that had not
been irradiated. On the basis of this result, they deny the possibility of
the formation of a toxemic component in the pathogenesis of radiation sickness.
These authors are inclined to explain the leukopenia by a simple mingling of
the blood.
However, Holpakov and Khodos, who carried out experiments on parabiotic
rats, deny this possibility, because in one of the variants of the experiment
they separated the parabionts within several minutes after irradiation, i.e.,
at the time when the irradiated animals were in the stage of leukocytosis which,
as is known, precedes the development of leukopenia. Under these conditions
one cannot explain by mingling of the blood the leukopenia which develops sub-
sequently in the animal that has not been irradiated.
Experiments of this type were also carried out in the USSR on dogs. By
using the method of merging the blood streams, the effects on a healthy dog of
the blood from an irradiated animal and a non'-rradiated animal were investi-
gated. Usually about 50r of the circulating blood was replaced when the method
of merging the blood streams was used. Of course, we did not expect that radi-
ation sickness will develop under the effect of the blood of an irradiated ani-
mal and regard this formulation of the problem as faulty. By using the method
of merged blood streams, one can only detect the accompanying role of the hu-
moral factor in the development of come aspects of radiation sickness.
Experiments with the use of the method of merged blood streams have actu-
ally shown that the blood of irradiated animals brings about leukopenia (V. D.
F.ogozhin).
One must note that under the experimental conditions in question the non-
irradiated recipient of the blood develcps not only changes in the composition
of the peripheral blood but also mouifications of hemopoiesis in the bone marrow.
When punctates of the bone marrow of the nonirradiated recipients were taken in
cases when the donor was all irradiated animal, it could be established that
changes in the cell composition of the i,one narrow had taken place. Although
these changes were lea:; sharply pronounced, they were analogous to those ob-
served in animals which suffer from radiation sickness (N. K. Yevseyeva).
Normally, the number of myeloid elements of the bone marrow is higher than
tee quantity of erythroblastic elements. For that reason the ratio of erythro-
blastic cells to myeloid cells is always less than unity. This ratio in dogs
is most often within the range 0.3-0.6.
According to the experimental results, this ratio in healthy dogs remains
within normal limits after merging of the blood streams. When a mutual blood
exchange between a healthy dog and an irradiated dog has been carried out, this
ratio changes in a healthy animal in the same direction as in an irradiated ani-
mal.
It has been established that upon irradiation with a dose of 500 roentgen,
unless complete devastation of the bone marrow takes place, the content of ery-
throblastic and myeloid elements changes in such a manner that the relative
quantity of erythroblastic cells increases. As a result of this the ratio in-
creases up to unity and may become higher than unity. The same increase of the
ratio, although less pronounced, takes place in dogs which have received blood
from an irradiated animal in the course of an exchange transfusion. The dynamics
of the modifications of the ratio in three dogs are shown in Table 1.
STAT
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Still more convincing were the data obtained by including in the system
of merged circulation individual parts of the body of irradiated animals (G. P.
Gruzdev). By joining the circulation of various tissues of the head, extremi-
ties, intestine, and spleen of irradiated animals to the general circulation
of nonirradiated animals, the physiological indexes (blood pressure and respi-
ration) and the composition of the blood of the nonirradiated animal serving
as recipients were modified. The changes produced in this manner were then
studied.
As a result of the experiments which have been carried out, it was estab-
lished that blood which has pronounced hypotensive properties flows from the
head of an irradiated animal while blood flowing from a leg has the property
of producing sharply expressed and persistent leukopenia, or more correctly
neutropenia. A lymphopenic effect was produced by the blood flowing from the
spleen. Effects of this type have never been found to result from the blood
of the same organs of nonirradiated animals. Figure 1 [not reproduced in this
report; see page 9 of the source) represents a kymogram of changes in the blood
pressure produced by blood flowing from the head of an irradiated dog. In Fig-
ure 2, curves are given which describe the changes in the number of leukocytes
produced by blood derived from the leg of an irradiated animal (the dose of to-
tal irradiation of the dog amounted to 800 roentgen).
At present we have the task of determining the nature of the active sub-
stances found in the blood and of studying the dynamics of their development,
because our experiments were carried out as late as the 3d day after irradia-
tion.
The literature contains a great number of communications dealing with the
role of histamine in the development of radiation sickness. However, data on
the manner in which the histamine content changes in the blood of large labora-
tory animals were not available.
For that reason, T. M. Mel?gunova investigated the problem by carrying
out experiments on irradiated dogs. This investigator, by using basically the
determination of histamine-like substances on the atrophinized cat as an ex-
perimental method, showed that as the development of the radiation sickness ad-
vances, the number of dogs which contain histamine-like substances in the blood
increases; the maximum is observed on the fifth day of the disease (see Table
2).
The data cited cannot be regarded as proof of the decisive role of hista-
mine, particularly during the initial periods of the development of the sick-
ness. However, they demonstrate that histamine-like substances are actually
formed in the irradiated body when the effect produced by the radiation is in-
tense (i.e., when a dose of 600 roentgen has been applied).
On the basis of the results discussed above, we may draw up a scheme of
the routes along which the pathogenetic action of ionizing radiation is ex-
erted. This scheme, in addition to comprising the direct injurious effect on
tissues, includes routes which are activated through the medium of the nervous
system and also humoral routes along which the pathogenetic action is exerted
(see Figure 3). In the scheme represented in Figure 3, the routes along which
normalization and restoration of the disturbed equilibrium take place are also
shown. These rcutes proceed along the nervous system.
Pavlov's teaching extends the possibilities of understanding the patho-
genetic effect of etiological factors. Specifically, in the pathology of ra-
diation, concepts based on Pavlov's teaching make it possible to interpret with
facility the otherwise inexplicable circumstance that there is no correspondence
between the amount of energy absorbed and the 'biological effect produced. Cal-
culations show that upon general irradiation of the organism acute pathological
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changes are produced by doses which are many times smal necessary
for inflicting injury on the cells. ler than those In order that visible
be observed, one must s
h
b
c
a
u
ject t rage il
o radiochemical action 1/10 number of molecules of the cell prosn cels may
has been irradiated with 1,000 rtoenasm (Dessauer) 1/100 of the total
standing the fact that When a duvedg organism
laces o
produced,
changes take injury to
intoonly -
one out of 100,000,000 molecules of cell protoplasm.
if approximately f the calculation is This figure
f tion on the cells is obtained
carried out on the basis of direct ation of ionizing a-
(Gampei'man, Lisko, Gofman, and Zirkle).
This significant discrepancy in the biological effect is explained by fact that in the total organism the action of ionizing radiation may be exerted
not only as a noclceptive irritation the
about only as
of the tissues , i.e., an irritation which directl
Lion of j rye elements of , but also, I,. an irritation which x y in brings
the body. produces ecita-
This postulate is of fundamental significance, inasmuch as the energy lev-
els at which the irritations indicated above exert their effect are entirely
different: the level is much lower in cases when the environment exerts its
effect through the nervous system of the organism. This is the reason why cal-
culations based on data pertaining to models represents
isms or to isolated tissues are not always plex and h1 hl c applicable whenttheseffects ongc m-
? Y developed organisms are considered.
If one envisages the Possibility that pathological
processes take place
as a result of disturbances of the regulatory function exerted by system, the dependence of general symptoms not only on the dose of absorbed
energy, but also on the magnitude of the area which has been irradiated be-
comes understandable. For instance, although local irradiation of rather ex-
tensive surfaces (i.e., the whole head or the surface of the abdomen) can be
carried out [without a lethal effect] by means of doses of the order of 1,000
or more roentgen, the death of a dog may ensue subsequently to
ation with a dose of Only 300 roentgen or even less.
difference depends on the n y general irradi-
dntee aceide of umber of afferent Iicseemv to
e us i tnvo this
ionizing radiation. From thisJnoiat wof'vie, becomes clear
why irradiation of the abdomen (a section which is particularly brings about most readily general change;ntthelorganism that saory y
typical of radiation sic re
kness.
Tams, in discussing the pathogenetic action of ionizi
but also the n? radiation, one
must consider not only its role as a factor which directly injure. tissues,
nervous system. part played by it as an irritant which exerts an effect on the
Irritation of the Peripheral afferent
systems takes place, as D1. N. Livanov:., :nves tigat ions have demonstrated.
After irradiation there is a disturbance of normal impule formation r[Thnpu.on
tion"] and development of spontaneous biological currents in
eous nerves. 'ilnpulsa-
peripheral cutan-
However, the understandi
sic}He ng of the problem of the pthoenesio
ss is no, complete if only the of
At the hei ht U radiation
mechanisms mentioned above are considered.
active g of the pathological condition, other etiological factors
and ma involve autoinfoction of the organism as one of the contributing
effects (P. N. Kiselev).
Disturbances of Permeability which arise under the effect of ionizing ra-
diation may turn out to be the decisive factor responsible for the penetration
of bacteria into the tissues of the organism from inhabit (for instance, the intestine These al lledds exith acteria,"tontly
penetrating into the tissues, may produce phenomena ofautosensitizationyon
follows from work by Sanarelli, Shvartsman, and particularly P. F. Zdrodovskiy
It
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that hyperergic inflammation processes may arise which are characteristic for
the development of so-called anaphylactoid reactions. The sensitization of
tissues which is necessary for the occurrence of these reactions develops within
several hours. Under these conditions the introduction into the blood stream
of products derived from bacterial bodies leads to acute hemorrhages. The in-
creased permeability of the intestinal walls of irradiated animals was demon-
strated in experiments carried out by P. N. Kiselev in which foreign serum,
thorotrast, or bacteriophage had been introduced. Modification of the permea-
bility of blood vessels was noted by D. N. Mogil'nitskiy and his collaborators.
The dynamics of changes in the permeability and strength of the walls of blood
vessels during the development of acute radiation sickness were studied in the
USSR by V. A. Razorenova on different species of animals. M. V. Gradova, using
A. D. Ado's method, demonstrated in our laboratory the possibility of increased
accumulation of antigens in the tissues of the irradiated body.
Without considering the special problem in regard to increased permeabil-
ity, we will only point out that this process is of great significance for sen-
sitization and for the development of a modified reactivity of the irradiated
organism.
The ways along which sensitization may take place are shown in Figure 4,
which depicts the second stage, or according to our terminology the polyetio-
logical stage, of the development of radiation sickness. The fact that sen-
sitization of an irradiated organism by bacterial cells and the products of
their decay takes place has been pointed out long ago by A. Yugenburg, L. G.
Perets, and R. S. tdostova. They also pointed out the role which the effects
that have been mentioned play in the development of the decisive reaction.
Subsequently, the increased permeability of the vascular endothelium leads
othef
to nunderstand, these
if s the rsharp
lowering of the nhagocytic activity of the elements of connective tissue is
tai:^n into consideration and it is realized that this phenomenon is accompanied
by a thorough-going leukopenia and a sharply lowered capacity to form anti-
bodies; as well as changes in the activity of these antibodies.
The possibility that the irradiated organism may become infected has been
established by many investigators and cannot be doubted. Much remains to be
done before the pathogenesis of radiation sickness can be completely understood.
Future in.,estibations will show which processes play a decisive role in differ-
ent sta;;es of' the sickness.
Conclusions
Within the scope of the complex problem involved in the pathogenetic ac-
tion of ionizing radiation, one must distinguish between (a) the mechanisms of
o6ical
more imaryomplactiexoMeen
conditions affecting hid;hernorganisms
that develop on the basis of tine primacy effect.
As far as the action of ionizimd radiation on biological substrates is
concerned, the most generally accepted theory is one which regards the observed
changes from the standpoint of the assunnpticn that water is ionized and oxidiz-
ing radicals develop as a result of the action of radiation.
To understand the pathogenetic action of ionizing radiation, we cannot
limit ourselves to a consideration of the direct action of ionizing radiation
on the tissues of the organism. It iz possible that other effects are exerted
through the medium of the nervous system. This assumption is supported by nu-
merous facts which testify to the occurrence of changes in the functioning of
various divisions of the nervous system.
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The problem in regard to the initial stages of the development of the path-
ogenic process and to the localization of the predominant affliction of the nerv-
ous system in the course of radiation sickness remains unsolved.
The toxemic factor undoubtedly plays a role in the development of the ra-
diation affliction. At present one may regard as established that substances
which exert a hypotensive effect appear in the blood of the irradiated organ-
ism and bring about changes in the cell composition of the blood.
Different tissues play different roles in contributing to changes of bio-
logical functions produced in the organism under the effect of radiation, By
merging the blood streams of two animals it could be shown that the head of an
irradiated animal (dog) evolves substances which have a hypotensive activity
while the organs of hemopoiesis evolve substances the principal activity of
which leads to changes in the composition of the blood.
Histamine-like substances appear in the blood of irradiated animals. The
maximum of the development of these substances takes place on the 5th day after
irradiation.
The processes of autoinfection and autosensitization play a considerable
role in the development of acute radiation sickness.
The routes along which the pathogenetic activity of ionizing radiation is
exerted have been schematically outlined on the basis of published data and ex-
perimental results.
(Figures are appended.]
Ye. I, Bakin, Vestnil: Rent(,;enologii i Rndiologii, No 4, 1945, pp 63-60,
72-74
Ch. Berens, Radioaktivnyy Raspad i Medi_tsina (Radioactive Decay and Medi-
cine), Moscow, 1951 enpcl'mar dromeLofvRadiat on Sickness), i1oscow ai,',SGstryy Luchevoy Sindrom (The Acute Syn-
P. D. Gorizontov, Voprosy Patologicheskoy Fiziologii v Trudakh I. P. Pav-
lova (Problems of Pathological Physiology in I. P. Pavlov's Works), Moscow,
1952; article in book Biologichesi;oye Deystviye Izlucheniy i Klinika Luchevoy
Bolezni (The Biological Effects of Radiation and the Clinical Aspects of Radi-
ation Sickness), Moscow, 1954; Processes of Inhibition in Experimental Radia-
tion Pathology, Zhurnal Vysshey Nervnoy De atel'nosti imeni I. P. Pavlova, Vol
5, No 3, 1955, PP 318-328 Y
Yu. G. Grigor'yev, Vestnik Radiologii i Rentgenologii, No 5, 1954, pp 3-10
M. Zhukovskiy, Ubzor Psikhiatrii, Nevrolcgii, i Eksperimental'noy Psikhol-
ogii, No 11, 1903, pp 801-814
P. F. Zdrodovslciy, Problema Reaktivnosti v Uchenii ob Infektsii i Immunitete
(The Problem of Reactivity in the Theory of Infection and Immunity), Moscow 1950
STAT
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skikh Rabot Akademii MeditsinskikhcNauknSSSRk(AbstractsNofcScientificoResearch
Work Done at the Academy of Medical Sciences USSR), Moscow, 1949, PP 103-105
P. N. Kisselev, article in book Biologicheskoye Deystviye Ioniziruyushchego
Islucheniya (Biological Effects of Ionizing Radiation), Moscow, 1554
I. V. Kolpakov, V. I. Khodos, Arkhiv Patologii, No 1, 1949) PP 25-31
A. A. Lindberg, Doklady Akademii Nauk SSSR, Vol 1, No 4, 1935, pp 249-256
B. N. Mogil'nitskiy, article in book Trudy Nauchnoy Sessii Institute Rent-
genologii i Radiologii imeni V. M. Molotova (Works of the Scientific Session of
the Institute of Roentgenology and Radiology imeni V. M. Molotov), Moscow, 1949,
p 131
M. I. Nemenov, Rentgenoterapiya Cherez Vozdeystviye Na Nervnuyu Sistemu
(X-Ray Therapy By Exerting Action on the Nervous System), Moscow, 1950
289 S. A. Nikitin, Uspekhi Sovremennoy Biologii, Vol 22, No 2, 1946, pp 277-
L. G. Perets, R. S. Mostova, Vestnik Rentgenologii i Radiologii, Vol 12,
No 3, 1933, Pp 115-126
P. V. Sipovskiy, Vestnik Rentgenologii i Radiologii, Vol 13, No 4, 1934,
PP 263-269
(Fundamentalsrof theOBiologicaloActionkof Radioactive R diaation), Moscow, yosIcooww, , 1 19554
4
I. R. Tarkhanov, Gazeta Botkiiui, 1896, Pp 753-758
I. Ye. nl'piner, Uspekhi Sovremennoy Biologii, Vol 34, No 2, 1952, p 219
A. Yugenburg, L. G. Peretts, Vestnik Radiologii i Rentgenologii, Vol 12,
No 3, 1933, pp 1.27-143 Non-USSR
Guzman, E. S., Barron Symposium on Radiobiology, New York, 1950
Bloom W., Histopathology of Irradiation from External and Internal Sources,
New York, 1948
Booz, Betz and Firket, Compt. Rend. Soc, Blol, 1954, No 5-6, pp 627-628
Clement, C. D. and Hoist, E. A., Arch. Neurol. and Psych., 1954. Vol 71,
No 1, pp 68-79
Cronkite, E. P. and Chapman W. H., The Military Surgeon, 1949, Vol 104,
No 1, PP 7-29
Edwards, J. L. and Sommers, Journ. Lab. Clin. Med., 1952, Vol 40, No 3,
PP 342-354
Jenkinson, E. L. and Brown, W. A., Amer. Journ. of Roentg. and Radium
Therap., 1944, Vol 51, No 4, pp 496-503
Langendorff, H. and Lorenz W., Strahlentherapy (Radiation Therapy), Vol 88,
No 2, PP 177-189
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Lyman R., Kupalow B. and Sholz, N., Archives of Neurology and Psychology,
1933, Vol 29, No 1, PP 56-87
Patt ff., article in book: Eeystvie Izlucheniy and Primenenie Izotopov in
Biologic, (The Effects of Radiation and the Application of Isotopes in Biology),
No 4, 1954, Moscow
55 Shorvon, L. M. British Journal of Radiology, 1949, Vol 22, No 253, pp 49-
Zirkle R., Radiology, Vol 52, No 6, p 846
p 187 Warren and Whipple, Journal Experimedical Medicine, 1922, Vol 35, No 2,
De Coursey E., Journal American Medical Association,
PP 904-905 1953, Vol 151, No 11,
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4. A
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Table 2. The Development of Histamine-Like Substances in the Blood
of Irradiated Dogs
Number of Dogs
Exhibiting
Total Number of
Dogs Subjected
Activity of the
iinstheiBlood Type
Time Since
In absolute Ex
os
to ~n
figures
In
p
ure to
Radiation
44
3
6
27
12
44
Within the first
few hours
15
5
30
1 day
43
31
72
5 days
30
6
20
7 days
31
6
20
10 days
41
8
20
Periods in ex-
FIGURES
[Figure 1 of source not reproduced here.]
cess of 10 days
J J J 7 I2 17 22 days
Fig 2. Changes in the Number of Leukocytes (in Percent of the Initial Quantity)
in Recipient Dogs Which Received Blood From the Leg of a Healthy Dog
(Controls a', b', and c') or From the Leg of Irradiated Dog (Experi-
ments a, b, and c)
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Routes along which injury takes place
Routes along which adaptation develops
Fig 3. Scheme Showing Routes Along Which the Pathogenetic Action of
Radiant Energy Is Exerted
Radiant energy Lncreaselof
i, permeability
The taking up of bacterial proteins
by the blood circulation system The taking up of "exit bacterial'
d their eir penetration into
Increase in the permeability of s sues
blood vessels Sensitization of tissues
Bacteriemia and septic phenomena Hyperergic inflammation
(hemorrhagic phenomena pro-
duced by the anaphylectoid
reaction of tissues)
Fig b. Scheme That Describes the Second (Polyetiological)
Stage of the Development of Radiation Sickness
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