The effects of radiation on hemopoiesis

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Material Information

Title:
The effects of radiation on hemopoiesis
Series Title:
United States. Atomic Energy Commission. MDDC ;
Physical Description:
14 p. : ill. ; 27 cm.
Language:
English
Creator:
Lawrence, John S
Dowdy, Andrew H
Valentine, William N
University of Rochester
U.S. Atomic Energy Commission
Publisher:
Atomic Energy Commission
Place of Publication:
Oak Ridge, Tenn
Publication Date:

Subjects

Subjects / Keywords:
Radiation   ( lcsh )
Radiation Effects   ( lcsh )
Radiation -- Physiological effect   ( lcsh )
Hematopoiesis   ( lcsh )
Genre:
federal government publication   ( marcgt )
technical report   ( marcgt )
non-fiction   ( marcgt )

Notes

Statement of Responsibility:
by John S. Lawrence, Andrew H. Dowdy, and William N. Valentine.
General Note:
Manhattan District Declassified Code
General Note:
"Date of Document: March 1, 1947"

Record Information

Source Institution:
University of Florida
Rights Management:
"Date Declassified: April 18, 1947"
Resource Identifier:
aleph - 005024529
oclc - 288608393
System ID:
AA00012250:00001


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UNITED STATES ATOMIC ENERGY COMMISSION






The Effects of Radiation


by
John S. Lawrence
Andrew H. Dowdy
William N. Valentine


University of Rochester


'I


This document consists of 14 pages.
Date of Document: Mlarch 1, 1947
Date Declassified: April 18, 1947



This document is issued for official use.
Its issuance does not constitute authority
to declassify copies or versions of the
same or similar content and title
and by the same authorss.


Technical Information Division, Oak Ridge Directed Operations
Oak Ridge, Tennessee


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THE EFFECTS OF RADIATION ON HEMIOPOIESIS


By John S. Lawrence, M. D., Andrew H. Dowdy, M. D.,
and William Ni. Valentine, Capt. M. C., A. Ul. S.


A consideration of the effects of radiation on the hematopoietic tissues brings one into a very
controversial field. This is necessarily so since various modes of subjecting the blood and the hem-
atopotetic tissues to radiation have been used. Further, results in one species do not always agree
with those in other species and hence, confusion is caused frequently by an attempt to apply to one
species what hig been found to occur in another. Difficulties of the above type are so commonly found
in the old literature on the subject that it has been decided not to give any review of this literature
in this presentation. Excellent reviews are available for those who want them. One of the most re-
cent reviews is that by Shields Warren in 1942.
The types of radiant energy under consideration in this discussion are either electromagnetic
energy waves such as roentgen and gamma rays or particulate matter having mass such as alpha and
beta particles, protons, and neutrons. While the former are devoid of mass (other than energy mass)
and electrical charge, they may, for convenience, be considered as bullets of energy called quanta.
The alpha particle is the nucleus of the helium atom having a unit positive charge of 2 and a unit mass
of 4. The beta particle (electron) has a negative charge of 1 and a unit mass of 1/1840. The proton
is a component of all atomic nuclei and comprises the entire mass of the hydrogen nucleus. It has a
unit positive charge of 1 and unit mass of 1. The neutron Is a component of all atomic nuclei with
the exception of the hydrogen nucleus. It is neutral in charge and has a unit mass of 1. The positron an
and mesotron are omitted from this discussion for simplification.
An unstable atomic nucleus (one having excess energy) may return to a more stable state by the
release of energy in the form of an alpha particle, an electron, a proton, a neutron (neutron only dur-
ing fission process), a gamma ray, or by a combination of several of these forms of energy. An un-
stable atom may release its excess energy in the form of light, heat, or roentgen rays, or by a com-
bination of two or more of these forms.

Materials being subjected to these radiations may be considered as being bombarded with quan-
tas of energy without mass and by particulate matter having both mass and energy. All living cells,
whether of man, animal, or plant, are capable of injury from these various types of radiant energy.
The extent, location, and type of injury which may be sustained is dependent upon the kind of radia-
tion under consideration, its physical properties, its mode of application (whether external or inter-
nal), its intensity, duration of exposure, and the character and function of the cells of the species of
animal or plant being subjected to irradiation. In other words, the degree and character of the bio-
logical changes resulting from irradiation are dependent upon many complicating factors and often
subject to difficulties of interpretation.
The conclusions herein reported represent the opinions of the authors at the time of writing.
They are not static and will require changing from time to time as more information becomes avail-
able. Much of the background for these opinions is in the work done by various members of the Man-
hattan Project. It has been our privilege to see many of the reports of this group which have not been
cleared for public presentation. The investigators, in addition to those in this laboratory, whose work
has been used in one way or another in this report are Allen and associates, Bryan and associates,

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Failla and Issociates, Henshaw and associates, Lorenz and associates, Metcalf and associates,
Rekers and associates, and Suter and associates. Their work will be published in scientific journals
in due time. We wish to express ou sincere thanks to them for their willingness to allow us to use
their data.
Much confusion will be avoided in considering radiation effects on hematopoiesis if the following
facts are recognized: First, there is virtually no evidence supporting the concept that the morpholo-
gical con~stues of the peripheral blood are affected directly by radiation except in tremendous
amounts. In other words, the cell that are in the blood are for all intents and purposes relatively
resistant to radiation.

Secon, the peripheral blood picture resulting from radiation is affected markedly at any one
period following irradiation by the length of life of the different morphological elements in the pe-
ripheralblood. (The life span of the red blood cell has been established in man and the dog. The life
spans of the white blood cells and the platelets have been determined in the cat in this laboratory,
but no satisfactory observations have been made on the human.) Thus, since it takes only 10 to 12
hours at the most for complete turnover of all of the white blood cells in the blood at any one time,
changes in the whie blood cell picture should occur within a short interval following irradiation. The
blood platelets in the peripheral blood of the cat require complete replacement every 4 to 5 days.
Hence, changes in their numer in the peripheral blood would not be expected until later than those
of the white blood cells. Finally, the life of the red blood cell in man and the dog is pretty generally
accepted as being approximately 120 days. One would not, therefore, expect reduction in the number
of the red blood cells to become apparent until later than in the white blood cells and the platelets.
Alterations in the numbers of erythrocytes would often be masked by reg, -eration, since the latter
frequently occurs well wihi the life span of this element. To take a concrete example, suppose s8--
ficient parent erythroid cells are destroyed at any one moment by irradiation to reduce the manufae-
ture of red blood cells by 1/10. If we consider that approximately 1.0 per cent of the red blood cells
in the body are mnufatured daily, then, in this situation, we should have 0.9 per cent manufactured
daily, that is, instead of an output of 50,000 red cells daily in the normal male we would have 45,000.
This rate of manufacture wol hav to continue for 60 days before a deficit of 300,000 cells would
develop. Anly change of less tha this amount would be unlikely to be detected in a normal individual
due to the errors inherent in the technique and the physiological variations. By the end of 60 days,
considerable regeneration would be expected to have taken place, and this would most probably result
in complete maskn of any effect of radiation on the erythroid cells.
Third, the effect of radiation on the peripheral blood picture is influenced by the radiosensitivity
of the various parent cells. There is ample reason for considering that the parent cells of the lym-
phocytes are more radiosensitive than the parent cells of the other cellular elements of the blood.
Thus, the total number of lymphocytes diminishes more rapidly following irradiation than that of any
of the other blood cells. Further, an effect of irradiation on the lymphocytes can be demonstrated
with smaller amouns of radiation than is true for the other cells. Additional discussion of these facts
wrill be referred to later.
Fout, the ability of the tissue to regenerate is of great importance. Not too much is known of
this, but there is substantial evidence that this ability is very good in the lymphatic tissue. However,
there is strong evidence that the erythroid, myeloid, and megakaryocytic tissues are capable at very
active regeneration, also. Insuff~icient studies have been made to allow any statement as to the vari-
ations, if any, in the regeneration ability of these various tissues.

The most important consideration from the point of view of the time when changes are to be ex-
pected in the peripheral blood from irradiation is the length of life of the various cellular elements
of the blood. Actually, we shall see that the order of time when these changes do occur in the blood
is the same as their rate of utilization or life span in the blood. In other words, the white blood cells
show changes first. These are followed by changes in the platelets and later in the red blood cells.


WRl~.ggg*pSu









MDDC 85J


It might be mentioned here that the lymphocytes are the first of the white cells to be reduced. This
is considered to be due to the greater radiosensitivity of their parent cells and, possibly, to the fact
that there are less stages between the parent and the adult lymphocyte than is true for the other cells.
Due to this, the marrow may contain appreciably more cells sufficiently differentiated to escape radi-
Sation injury than does lymphoid tissue. These cells might be expected to complete their maturation,
and, until exhausted, to replenish the peripheral blood. In other words, the storage of potential gran-
ulocytes, red blood cells, and platelets may be greater than that of lymphocytes. Of course, the above
statements are based on the assumption that irradiation affects the parent cells; that is, it stops man-
ufacture of cells in their first stage. There is much evidence to justify this assumption.

In this disgassion we shall consider the effects of radiation and/or gamma radiation when admin-
istered in the following ways:
1. Single dose to the body as a whole
2. Repeated small doses to the body as a whole
3. Single or repeated doses to one area
4. Internal radiation (probably beta and gamma. mostly)

SINGLE DOSE OF ROENTGEN RADIATION TO THE BODY AS A WHOLE

First, let us consider the effects of roentgen radiation applied generally in a single dose. Most
of the worthwhile observations with this form of irradiation have been made in animals. How much
these observations apply in the human cannot be stated. Various species (monkeys, rabbits, dogs,
cats, and many others) have been used. In one study (Bryan, Suter et al), a large series of rats was
used. These were divided into groups that received varying amounts of irradiation in a single dose.
The amounts used were 25r, 50r, 100r, 200r, 300r, 400r, 500r, 600r, 700r, 800r, 1000r, 1250r, and
1500r.. The blood findings in these animals were followed closely for 25 days, counts being made at
24 hours after exposure and, following that, at 48-hour intervals intil the 11th day. Additional counts
were made on the 18th and 25th day post radiation. In another study (Metcalf and associates), a large
series of rats was given 550r to the whole body in a single dose. Blood studies were made 15 minutes
after exposure, and, thereafter, at frequent intervals up to 41 days. To avoid hematologic alterations
occasioned by the bleeding procedure itself, no one animal was bled more than a few times. The re-
sults of these experiments may be briefly summarized as follows:

Erythrocytes and Hemoglobin
Little or no detectable alteration of the red blood cells was found in any of the groups receiving
200r or less. In the group receiving 300r to 500r, slight questionable changes occurred during the
first 168 hours after radiation. However, there was a substantial reduction in both erythrocyte and
hemoglobin levels in these groups between 168 and 448 hours. In the groups receiving 600r and above,
the survival time was not long enough for satisfactory observations to be made. However, in the 600r
to 800r groups, significant drops in both the erythrocytes and hemoglobin were present at 168 hours.
After this, rapid declines occurred in erythrocyte and hemoglobin levels.
This period of rapid decline in the red blood cell and the hemoglobin levels demands some con-
sideration. It is of distinct interest that it does not occur in rats receiving less than 500r. It is de-
picted very clearly in Figure 1, which is taken from work reported by Metcalf and associates. In this
experiment, a large series of rats was given a single dose of 550r to the whole body. Studies of the
peripheral blood and various tissues of the animals were made at frequent intervals for 41 days after
exposure. There was a precipitous drop in the red blood cell and the hemoglobin levels comparable
to that seen at the same time interval by Bryan and Suter et al in groups of rats receiving 600r and
above. Metcalf and associates did not feel that abnormal bleeding could explain this rapidly develop-
ing anemia since they noted insufficient evidence to substantiate marked loss of blood. They raised









MDDC 853


the question of the possibility of some alteration in the circulating erythrocytes, since they found ac-
tive phagocytosis of the latter by the reticulo-endothelial cells. There are so many confusing factors
in this reaction, such as lack of knowledge of the life span of the red blood cell in the rat, the possi-
bility of dietary deficiencies secondary to anorexia, the ulceration and sloughing of the intestinal ep-
ithelium, the possible internal bleeding, and some unknown alteration in the red blood cell itself,
that we prefer to offer no explanation for this anemia. We do feel, however, that it probably cannot
entirely be explained by the effect of radiation on the erythroid tissue with consequent failure to man-
ufacture red blood cells, since It occurs at too early a period after radiation. It is, obviously, a re-
sponse that is associated with radiation dosages of LD 50 or above and is nrot, therefore, of great
clinical importance,



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.1 .5 t5 10 50 00 500 10
HOURS


Figure 1.

Reticulocytes

Analysis of the data dealing with the reticulocytes has shown that no reductions of: practical mag-
natude could be detected when doses of 100r or less were used. With dosages of 200r to 500r, well-
marked reductions occurred beginning at 72 hours. These persisted up to 120 hours in the 200r group
and up to approximately 280 hours In the 500r group. In groups receiving 600r to 800r, regeneration
of reticulocytes became apparent at 168 to 280 hours, depending on the dosage. In still higher dosage,
the animals died before regeneration could occur. At 72 hours after irradiation (the interval at which
well marked reductions mn reticulocytes were first apparent), successive increments of radiation dos-
age produced, in general, successive reduction in reticulocytes up to the dosage of approximately
500r. Above this point, further increase m the amount of radiation produced no further reduction.
The assumption can thus be made that up to this dosage some erythrocyte precursors capable of dit-
ferentlatlnr ment reticulocytes were still present while, beyond it, virtually none existed.






MDDC 853


Platelets

No significant changes m these elements were detectable in animals receiving less than 200r. In
dosages of 300r to 500r, definite platelet reduction w~as detectable after 120 to 168 hours. Dosages of
500r to 800r resulted in platelet reduction uniformly by thle 5th day. Analysis of Ure data obitained 120
hours after radiation Ithe first point at which substantial platelet reduction occurred) showed that in-
creasing dosage of radiation resulted in increasing reduction In platelets up to, roughly, the neighbor-
hood of 400r to 500r. No further substantial reduction in platelets occurred in dosages of 600r to
1000r.

Figure 2 shows the changes in platelets in rats receiving 550r (Meitcalf and associates). The
statement cp thus be made that platelet production at 120 hours was not maximally decreased until
400r to 500r 5r more were given the animals.


1000


MEAN OF PLATELETS INl PERIPHERAL
2 BLOOD (100,000'5l


















,i *3 11 5 110 50 1100 500
HOURS


Figure 2.


White Blood Cells

It should be noted that since 70 to 90% of the leukocytes
changes in the white blood cell picture of these animals will
than on granulocytes.


in the normal rat are lymphocytes, any
reflect more the effect on lymphocytes


Neutrophils

No unquestionable changes occurred in these cells until dosages greater than 100r were used.
There was a transient early neutrophilic leukocytosis in the rats receiving 550r In the series studied
by Metcalf and associates. The first period at which unquestionable reduction in the total number of
the neutrophils below the pre-irradiation level occurred was 241 to 36 hours after exposure. Following
this, there was a steady decline in the neutrophils up to approximately 72 hours after radiation whhen
they were almost totally absent. Regeneration began at approximately 12 days, normal values for


I?~ll~y~l







MDDC 853


neutrophils being found at 25 days. In the series of Bryan, Suter, and associates, the first unequivo-
cal changes were found at 72 hours but it should be noted that, in this study, counts were made at 24
hours after exposure to radiation,and, following that, at 48-hour intervals. At the 72-hour period, in-
creasing dosage of radiation resulted in increasing reduction of the neutrophil count up to approxi-
mately 400r to 500r, after whih further increments in dosage resulted in no further reduction.
Therefore it can be assumed that at this dosage level no appreciable myeloid tissue capable of fune-
tion remained 72 hous after irradiation. The neutrophil counts returned to approximately normal
levels within 25 days in all suviving animals.
Lymphocytes
In the experiments conducted by Bryan, Suter, and associates, a dosage of 25r wras found to cause
a drop in the lymphocyte level in 24 hours. M~etealf and others found a reduction in the peripheral
blood lymphocytes of rats exposed to. 550r as early as 15 minutes after exposure. In their series, the
lymphocyte level was reduced to almost zero at the end of 15 hours. Experiments in this laboratory
indicate that in cata the output of lymphocytes in the thoracic duct lymph rapidly decreases after ex-
posure to 1500r whle body radiation. Figure 3 shows that low levels are attained within 5 to 6 hours
after irradiation. This sugss that precursor tissues must have ceased production very soon in-
deed after expsure. Bryan, Suter, and others found that the reduction of lymphocytes was still ap-
parent after 25 days in survivors of all groups receiving 50r or more. Progressive reduction in the
lymphocyte coun at the 24-hour period occurred with increasing dosage of radiation up to and includ-
ing 100r, indicating maima cessato of lymphocyte production at this dosage level for this time
interval. Butter et al have show statistically a reduction in lymphocytes following as little as 5r.
Total Leakocytes
TIhe data show close correlation with those given for the lymphocytes since these cells comprise
the vast majority of the cells in the peripheral blood of the rat.
If we return to our discussion of the life span or the rate of utilization of the various cellular ele-
ments in the blood, it is rather remarkable how closely the above results reflect the life span of these
elements. Thus, the first definite diminution noted in the lymphocyte was at 15 minutes, in the gran-
ulocyte at 24 to 36 hours, and in the platelet at 120 hours. The almost immediate reduction in lympho-
cytes is probably due to the greater radiosensitivity of lymphoid tissue and possibly to less storage
of cells as previously mentioned.

Figure 4 show the actual changes that occurred in the total number of the white blood cells, the
number of the lymphoeytes an the number of the neutrophils in the peripheral blood of the rat at var-
ious intervals of time after exposure to 550r (Metcalf and associates).
The data which have just been presented can be reviewed by means of the next two figures. In
Figure 5 we have shown by means of heavy lines the known rate of utilization of the lymphocyte, the
granulocyte, the platelet, an the red blood cell. Since we did not have these data for the rat, we have
used the valus obtained in the cat for the white cells and platelets and those obtained in the dog and
man for the red blood cell. The other lines on the chart show the actual rate of disappearance of these
peripheral blood elements at various periods of time after exposure to 500r. It is readily seen that
the dimnution of lymphocyites was very precipitous, almost all of them being absent 12 hours after
radiation. The line of descent parallels that of the rate of utilization of the lymphocytes. The granu-
]locytes did not show any appreciable diminution until 24 to 36 hours but, following that, their line of
descent closely approximated that of the line showing their rate of utilization. The platelets did not
begin to disappear until between 72 and 120 hours. The line from 72 hours to 168 hours is roughly
parallel with that showing their actual rate of utilization.
The rate of disappeared of the red blood cells was very slow, and from the 120th to the 168th
hour it paralleled the lne showing the rate of utilization of the red cell.







MDDC 853


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Mo CAT NUMBER 381


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---ABSOLUTE NEUTROPHIL COUNT
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24
TIME IN HOURS


Figure 4.


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MDDC 853


120

110

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TIME INHOURS ATER 500R WHOL BODY RDIATIONIN RAT

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at 24 hour for the lyphcye at4 72husfrtegaulct n h eiuoctada 2 o




mark edandpsibly maxima thrfreduchtio thate thi peiod because there waros onlymt one doae expsre a
that timge (550r-My tetal rands aocuilates) Al ot theirlf dataon t hr eeotandfo h td
ies of Bryan, uer hand asciartes. The factsmetion aed pnroteviosl wginthreeneo the ee en ffpect of
various doages of rdaino the different periphercal blood elements. castten bh egnwevisalied son thiscat


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MDDC 853


were present at 1 hour after irradiation. (Bryan, Suter, et al.) At 6 hours after irradiation, cytolysis
of the cells in the lymph follicles had reached its maximum, and the cellular debris was rapidly be-
ing removed by macrophages. At 24 hours after Irradiation, regeneration and repair of the lymph
nodes was actively progressing, and by the 20th post-irradiation day regeneration was complete
(Metcalf and associates). It should be noted that these findings in the lymph nlodes did not show good
correlation with the peripheral blood picture, since the total number of the lymphocytes in the periph-
eral blood at the end of 25 days was still appreciably below normal.

The changes mn the spleen after irradiation followed closely those observed in the lymph nodes
except that the whole process was somewhat more prolonged. Regeneration was first observed be-
tween the 30th and the 35th hours after irradiation and was not completed until 40 days after exposure.













150

to 120
g KEY
m (10 LYMPHOCYTES 24 HOURS POST RADIATION
RETICULOGYTES 72 HOURS POST RADIATION
2 M GRANULOCYTES 72 HOURS POST RADIATION
co 100 II0 PLATELETS 120 HOURS POST RADIATION
~ o

<80

170

S60

S50
a 40

a. 30

20

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Son, 100 200 300 400 500 600 700 800
IRRADIATION DOSAGE IN ROENTGENS









Figure 6.


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MDDC 853


Cellular destruction in the bone marrow reached its maximum between 2 1/2 and 5 hours after
:irradiation. Most of the accumulated cellular debris was removed by the 30th1 post-exposure hour.
By the 8th day, hypoplasia was very severe, but, at no time, was complete aplasia observed. Active
regeneration began at approximately 12 days after irradiation and was completed on the 40th day.
The greatest reduction in the megakaryocytes occurred between the 4th and 12th days, after
which regeneration began. This was complete at approximately the 41st day. Figure 7 shows the
changes actually foun in the number of the megakaryocytes of the bone marrow at different intervals
of time after exposure. Figure 8 shows time at which regeneration began in the various cellular ele-
ments in the peripheral blood.

REPEATED SMALL DOSAGES OF RADIATION TO BODY AS A WHOLE

Several studies of animals exposed repeatedly to small doses of roentgen and gamma radiahon
have been made. It is even more difficult to summarize these findings than those of the studies in
which a single dose was used. Again, various animals were used -mice, guinea pigs, rats, rabbits,
and others. Marked differences on the basis of species sensitivity have been found. The rabbit has
the greatest natural resistance, no rabbit having died as a result of hemopotetic changes even though
the total dosage of gamma radiation reached 9000r (Lorenz and associates). The mouse occupies an
intermediate position and the guinea pig has the least resistance. These differences are largely quan-
titative rather than qualitative.

In exposures of this sort, the total dosage is the most important single factor. Within imis, the
effect of roentgen radiation given in this way is cumulative.

In one study (Lorenz and associates), the only significant change in the peripheral blood of mice
chronically exposed to roentgen radiation was a reduction in the lymphocytes. This occurred early
in the animals getting 4.4r and 8.8r daily and the effect persisted. Less significant reductions in
hemoglobin, erythrocytes, and platelet levels were obtained.
As regards guinea pigs in this same study, the leukocytes were found to be reduced a few weeks
after exposure was begun. This depression of leukocytes was evident in animals receiving 0.11r or
more daily and the degree was, within limits, dependent upon the amount of the exposure. The reduc-
tion in the level of the leukocytes was due largely to reduction in the heterophites although there was,
also, some lymphocytic reduction. Anemia of significant degree did not develop in guinea pigs ex-
posed to 0.11r and 1.1r daily, but did occur at higher daily dosage, the onset depending mainly upon
the amount of the dosage (19 to 79 weeks).

Reduction of platelets did not occur in the animals in the 0.11r group. Animals receiving larger
daily doses did sho reduction in the number of their platelets, the degree of reduction depending to
a good extent upon the dosage. These changes did not become apparent until about 1 year after expo-
sure was begun.
The bone marrow of these guinea pigs showed moderate to severe atrophy. No changes were
found in the bone marrow of the mice. There was evidence of radiation injury in the lymphoid Lissue
of both the mice and the guinea pigs, but there was no correlation with the total dose or dose rate.

RADIATION TO A LOCAL AREA

The effect oft the hematopoietic tissue of radiation applied locally to non-hematopoietic tissues
has been a source of considerable argument and speculation for a number of years. The occurrence
of leukopenia in individuals receiving local radiation in areas where little or no hematopoietic tissue
was located has made it seem to some that local radiation produced a generalized effect on the hem-
atopoletic tissues. Wle have recently reported observations made in this laboratory on this problem
in the cat. W~e were unable to find any evidence of an effect of radiation on the blood picture of nor-
mal cats connected for long intervals of time by carotid anastomoses with irradiated cats at various






MDDC 853


1000


HOURS

Figure 7.


KEY
a~ERYTHROGYTES
PLATELETS
NEUTROPHILS
SLYMPHOGYTES


6 9 12 (5 18 21 24 27
TIME IN DAYS AFTER 500 R WHOLE BODY RADIATION IN RATS

Figure 8.








MDDC 853


periods following Irradiation. The blood picture of the non-irradiated cat following discontinuation of
the carotid anastomosis was the same as in normal animals under these conditions.

Rekers anld his associates have made observations on dogs which are in agreement with our find-
ings. Thus, they found that when the whole body was radiated with the exception of one extremity, the
hematopoletic tissues in the non-irradiated extremity suffered little change other than a slight possi-
ble temporary compensatory hyperplasia. Furthermore, the clinical course of the animal and the
magnitude of the deflection of the peripheral blood elements was altered less, suggesting that non-
radiated marrow exerts a sparmng or maintenance action. Contrariwise, when the body was spared and
the two lower extremities were heavily radiated (2500r), there was neglible deflection of the elements
of the peripheral blood despite the extreme radiation changes to the marrow, skin, and vascular
structure of the radiated areas.

These observations point strongly to the absence of any direct effect of radiation on hematopoi-
etic tissue not directly in the exposed area. The possibility of some indirect non-specific effect ex-
Ists but It does not seem very likely that this could explain the chronic low-grade leukopenia that is
encountered at times in humans who have received local roentgen radiation over presumptively insuf-
ficient amounts of hematopoietic tissue to result in leukopenia. There is much need for very critical
study of such individuals. In particular, 1t is extremely important to determine the amount of hem-
atopoletic tissue which has been ir~radlated in such patients. It may be greater than suspected.

INTERNAL RADIATION

The use of radioactive Isotopes makes it necessary to consider this form of radiation more thor-
oughly than previously. The main difference in use of radiation of this type is that alpha and beta ra-
diations can, with the use of suitable isotopes, produce changes in tissues that would not ordinarily be
reached by these radiations. The possibility of giving radiation to special cells and tissues without
affecting other tissues is a very interestmg and important consideration. If radioactive isotopes can
be found with high specificity for different tissues, it should be possible to accomplish much by such
agents. Work on the thyroid gland represents only one important clinical application of this form of
radiation therapy. Insofar as the blood is concerned, little more seems to have been accomplished by
the use of radioactive phosphorus than by roentgen radiation. It is not the purpose of this presenta-
tion to discuss in any detail the use of radioactive isotopes. It is intended merely to call attention to
this type of radiation and to mention how it differs from roentgen radiation.

THE EFFECT OF NEUTRONS

There is not a great deal to be said on this subject. Henshaw and his group have reported on the
effect of neutrons on the hematopoietic tissue of CF, mice. They gave small doses on repeated occa-
sions. 4.3 n per day for 6 days a week produced, in their opinion, a steady downward drop in the total
white blood cell count, involving both lymphocytes and heterophiles. They interpreted their data as
showing no changes in the peripheral blood of animals receiving 1.15 n daily. They felt that the
threshold responses of the peripheral blood were at least a factor of 10 less sensitive than survival
responses m CF, mice. The r/n ratio varied between 8 to 1 and 35 to 1.
The late pathological effects of neutron radiation were general atrophy and neoplasia of the hem-
atopoietic organs. The degree of acute damage varied with the dose and with the intensity of the radi-
ation, that is, the effect was less with an increase in the exposure time.

Failla and Evans have made observations on the effect of fast neutrons on mice, also. They found
that 8r gave almost the same effect as I n when the percentage of survival, the median lethal time,
and the hematological effects were used as indices of comparison.






MDDC 853


EFFECT OF TOTAL BODY RADIATION ON COAGULATION OF BLOOD
AND HEMORRHAGIC MANIFESTATION

Considerable important work on this problem has been done by Allen and his associates. In short,
they have shown that in the dog hemorrhagic manifestations could not be explained by platelet reduc-
tion, per se. They have presented strong evidence for the assumption that the hemorrhagic manifes-
tations are due in these animals to the liberation of heparin in Large amounts as the result of radia-
tion. Various anti-heparin substances -toluidine blue, certain thionin dyes and protamine--have
been shown to have a very salutary effect on the coagulation defect in radiation sicknless of the dog.
They have further been able to isolate from the blood of such dogs a substance which they consider
to probably'6e heparin. This is a most important observation and changes our concept about hemor-
rhagic manifestations in radiation sickness a great deal. Further work in this connection will be ob-
served with great interest.

EFFECT OF RADIATION ON MiAN

The purpose of all of the studies which have been reviewed is to get a better idea of the effect of
radiation on the human. Acute experiments dealing with the effect of radiation on the whole body are
not of tremendous practical importance as it seldom happens that human beings are so exposed. How-
ever, such exposures do occur and do, within limits, result in changes of much the same nature as
reported in the rat. Thus, leukopenia, thrombopenia, and anemia were found in some of the Japanese
who were within the area where radioactivity developed immediately following detonation of the atomic
bombs. These individuals received essentially single doses of whole body radiation, since it has been
shown that residual radiation in these areas was unimportant. The order of the development of the
blood changes in these individuals was (1) leukopenia, (2) thrombopenia, and (3) anemia.
Most human exposures, however, are more likely to be in the nature of small amounts received
repeatedly. Results of such experiments are not as clear cut as are those with single exp~osures.
Nevertheless, certain general deductions can be reached from the animal experiments. It is most im-
portant in this connection to understand that there is much work indicating that exposure to radiation
is cumulative. In other words, the total amount of radiation to which an individual has been exposed
is a very important factor in the lesions which he may develop, regardless of the time elapsing dur-
ing the period of exposure. This should not be construed as meaning that the rate at which radiation
is given has nothing to do with the final effect on the individual, for there is considerable evidence in-
dicating that toxic reactions are not the same in acute radiation exposure of large amounts as in chron-
'ic repeated exposure. However, it does mean that the total amount of radiation exposure is a very im-
poritant determinant as regards the pathological changes occurring in any individual. Minimal expo-
sure becomes very important if repeated often enough to produce a total amount of radiation of any
significant amount. Furthermore, the possibility of the development of leukemia and allied disorders
must be considered in every instance when there is exposure to radiation of any appreciable amount.
The incidence of leukemia has been found to be higher in susceptible animals exposed to radiation
than inr those not so exposed in repeated instances. This does not need to be interpreted as meaning
that chronic radiation will produce leukemia. It may be that radiation merely causes the more rapid
development of a process that would develop in time anyway. Be that as it may, leukemia is certainly
found more commonly in humans and in animals exposed to chronic radiation than in normal animals
or humans. Another important consideration is brought up by a recent report of Lorenz and Jacobsen
of the development of anemia and thrombopenia in two male guinea pigs approximately 6 months after
they were removed from exposure and within 3 weeks after their erythrocyte and platelet counts had
recovered to 4.0 million and 150,000 per cu mm, respectively. Such observations naturally raise the
question of long term results of radiation. One can very properly wonder whether anemia, leukopenia,
thrombopenia, leukemia, or other hematopoletic disorders will develop in a higher percentage of in-
dividuals who have been exposed to radiation, even though in very small amounts, than in unexposed
individuals. Time will be required to answer this. Until we have the answer it will be very important
to go slowly in our interpretation of the end results of radiation of either animals or humans.






MDDC -853


From a practical standpoint it has seemed to us very important to consider any change from
normal inR the blood of a human with possible exposure to radiation as due to radiation until proved
not to be. Thus, polycythemia as well as anemia, leukocytosis as well as leukopenia, and thrombocy-
tosis as wel as thrombopenia must all be considered as being possibly due to radiation in those who
have been exposed. Also, changes in the differential formula must be so interpreted. In the human,
it has been our experience over a number of years, that leukopenia is the most common finding with
chronic exposure of small amounts. This leukopenia is associated with diminution in both neutrophils
and lymphocytes. The degree of the leukopenia, however, is more closely associated with the neu-
trophils since these cells are normally much more abundant in the blood of the human than are the
lymphocytes. Other changes than leukopenia do occur, of course, but they are not so common.
This discussion should not be closed without calling attention to the close similarity between
hematopoietic changes in chronic radiation exposure and chronic benzol intoxication. Thus, in both
conditions the same changes may occur in the peripheral blood and the bone marrow, the incidence
of leukemia is increased, and finally, apparent recovery may be followed by the sudden development
of marked anemia or other blood abnormalities.

In conclusion, it may be said that we are just beginning to see some of the results of chronic ra-
diation exposure. As pointed out, the cumulative effect is established, the incidence of leukemia is
increased, and finally, changes may develop after apparent recovery. What additional effects of
chroni radiation will be fond we are unable to say.

ACKNOWLEDGMENTS

The reports of the work of the following investigators have been used in the preparation of this
paper and are gratefully acknowledged.
Allen and associates, University of Chicago, Chicago, Illinois
Bryan and associates, University of Rochester, Rochester, New York
Failla and associates, Columbia University, New York City, New York
Henshaw and associates, Clinton Laboratories, Oak Ridge, Tennessee
Lawrence and associates, University of Rochester, Rochester, New York
Lorenz and associates, Metallurgical Laboratory, University of Chicago, Chicago, Illinois
Metcalf and associates, University of Rochester, Rochester, New York
Rekers and associates, University of Rochester, Rochester, New York
Suter and associates, University of Rochester, Rochester, New York


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