LD 50 – variations in responses to radiation exposures

The following is taken from Chapter 3 of “Atomic Radiation and Life”, by Peter Alexander,
Pelican Books, London, 1957.

It will take me some time to scan and upload all of the text and diagrams of this chapter. Bear with me and the basis of variation in responses to radiation between species, strains and individuals will be explained.

The variable responses produced by variations in metabolism and other variables will also be explained.

These variations between individuals are additionally affected according to the circumstances involving other variables at the time of exposure. These facts show that simple one response per species – including Humans- is inadequate. This is indeed the situation witnessed in the immediate aftermath
Of Hiroshima. Hiroshima doctors noted that those people at rest at the time of exposure were more likely to survive radiation sickness than those who were experting themselves.

Further, the Hiroshima doctors noted those who suffered thermal burns of a non lethal nature were also more likely to survive radiation sickness than those exposed at the same distance from the bomb blast than those who did not suffer similar thermal burns. (Hersey).

The simplistic study of the responses of special mice in response to external x rays –
Will be seen to be inadequate to explain the full range of human responses to exposures to ionizing radiation of lesser or greater absorbed doses. Both internal and external. The DOE Sykes study -upon which Scott basis his statements regarding the supposed health benefits of not cleaning up contaminated sites etc – must receive critical study by scientists not in the pay of DOE and who do
Not have conflicts of interest determined by their paid roles.

CHAPTER 3
RADIATION SICKNESS

Mammals are exceptionally sensitive to radiation. Table III
on p. 74 shows that there are considerable variations in the
radio-sensitivity of different mammals. None of these figures
are absolute as they depend on the strain of the given
animal: there are mice which have been selectively bred
for high or low radiation resistance, and by successive
brother-sister matings so-called pure strains are obtained
which show more uniform behaviour and have a smaller
f
variation (see Fig. 16). The lethal dose may vary by as
much as 30 per cent between these strains. Other factors also
have a minor influence on the radiation sensitivity; it has
been found that in some cases females are able to sustain a
10 per cent greater dose than males. Body weight appears
to have very little influence; this is surprising, since the
total amount of energy deposited by a given dose of radiation
is proportional to the weight of the animal. More
energy, therefore, will be left in a fat than in a lean animal.

Increase in age substantially lowers resistance to radiation;
the lethal dose for 18-month-old rats was 30 per cent less
than that of young adults (three months) from the same
strain. This is a most important finding since it complements
the observation which is discussed in detail on p. 92
that small doses of radiation produce premature ageing.

As already mentioned, animals in hibernation are remarkably
resistant, and doses of many thousands of roentgen are
necessary, to kill marmots or squirrels while they are dormant.

On warming, the animals will behave as if they had
been irradiated in the non-hibernating state. The bat
appeared to be the one remarkable exception amongst mammals
in that the lethal dose observed was of the order of
15,000 r, i.e. it was twenty to fifty times more resistant than
other mammals. Admittedly it is a hibernating species, but
the experiments were carried out at ordinary temperatures
when the animals should be normal. But these bats did not
eat in captivity and this lowered their metabolic rate to a
state equivalent to hibernation and was responsible for the
apparent radiation resistance. Bats which were eating
succumbed to 700 r.

It is now possible to cool small mammals such as mice
to a temperature only two or three degrees above freezing
point and to return them without harm to ordinary temperature
a few hours later. If they are irradiated at these low
temperatures they are truly radiation-resistant (that is,
even after they have been warmed up) and can tolerate two to
three times the dose which normally would kill them.

The reason for this resistance is that their tissues are deficient in
Oxygen when cold, and this protects against radiation (see p.166).

For obvious reasons no accurate data for man are available,
and a value can only be deduced from the casualties
of the atomic bomb explosions at Hiroshima and Nagasaki.

A fairly good estimate of the radiation intensity at different
distances from the explosion centres can be made, and the
approximate dose received by individuals in different
regions can be calculated. The majority of injuries were due
to blast and the frightful burns produced by the intense heat
given off at the flash of the explosion. From victims who
escaped death from these effects information was obtained
about the effects of gamma radiation. Within 1,ooo metres (five eighths
of a mile) the dose received was more than 1,000 r,
and none who were caught in the open survived for more
than one week. In the zone between 1,000 and 1,250 metres
(dose received about 700 r) those fatally injured died within
two months, but there were a few who appeared to have
recovered. From Table 111 it can be seen that in the order

t

of radiation resistance man ranks between the goat and the
mouse, and is roughly as sensitive as a monkey. In this table
the radiation dose is expressed as the lethal dose required to
kill 50 per cent of the animals in 30 days (abbreviated to LD50/30 days).

The reason why we do not choose the dose
required to kill 1oo per cent is that in any group there is a
natural variation in resistance; some animals succumb more
easily than others and occasionally there are animals which
are very much more hardy. This type of behaviour is shown
in Fig. 16.

If in an experiment one attempts to find the dose at which kills all animals
the value recorded will depend on the chance of having included any
of those that are resistant.

In a series of experiments the values recorded for the 100
per cent lethal dose will vary considerably. The dose
required to kill approximately half the animals can be
determined much more precisely, and this value is then
remarkably constant from experiment to experiment. The
reason for having a definite time limit within which death
occurs will become apparent from the discussion on p. 77.

All the figures given apply when the whole of the animal
has been irradiated. Even if only small parts of the body are
not irradiated, such as the tail of a rat, the lethal dose is
substantially increased. This is brought out clearly in
Table iv, where mice were given 1,025 r, a dose substan-

t
tially greater than that necessary to kill them all; 100 per
cent lethality would probably have been obtained with
700-800 r. Yet after shielding different parts of the animals
there were varying numbers of survivors, showing that the
LD50 had been substantially increased by not exposing a
small part of the animal: protecting the spleen is outstandingly
effective and will be discussed again in another
connexion on p. 175. In the experiments shown in Table iv
the different tissues were shielded by enclosing them in a
sheet of lead through which the X-rays cannot penetrate.

The animal can survive tremendous doses to isolated
parts. It is usual practice to irradiate tumours with many
thousands of roentgen of X-rays without hazarding the
general health of the patient. Yet one-tenth of this dose
given to the whole body would be fatal. Even with localized
irradiation exposure of certain parts is more harmful to the
animal than that of others. Rajewsky working in Germany
used a most ingenious method to detect the critical organs.
He shielded the whole body of the rat with lead except for
a narrow slit, the position of which was progressively
changed. The most sensitive organs were those situated in
the abdomen (the liver, spleen, kidney, and part of the
intestine) but it was not possible to pinpoint any one of
these. To kill the animal it was necessary to give doses of the
order of 8,000 r through this narrow slit even when it
exposed part of the critical area. Shielding of parts of the
body from the radiation not only reduces the lethal effects
but with sub-lethal doses cuts down pathological change
such as induction of leukaemia (see Chapter 5).

THE LETHAL DOSE
The statement can probably be accepted that all exposure
to ionizing radiation is harmful. In view of the general background
of radiation (see p. 122) one must not exaggerate
the importance of small doses. It is probably true that prolonged
exposure to sunlight can lead to skin cancer, and is
the reason for the higher incidence of such tumours among
people who work out of doors, but the remedy is clearly not
a mole-like existence without daylight, any more than the
denial of the enormous benefits of atomic energy is the
answer to the problematical dangers of a small increase in
the radiation background.

We have to distinguish between a dose of radiation given
within a relatively short period and chronic irradiation.
Since the body shows a remarkable capacity for recovery
from radiation it can withstand repeated small doses which
if given over a shorter period or even in one irradiation
would be fatal. Since these recovery processes take many
hours there is no difference between a dose of, for example,
600 r given within one minute at the rate of 600 r/min. or
in one hour at 10 r/rnin. However if the rate is cut down to
1 r/min., the radiation symptoms are very much less, and
the dose required to kill within thirty days will be more
than doubled. If the dose rate is reduced still further, say
to I r/hour, then the animal can tolerate this for very long
periods, and a reduction in the total life-span can be
observed only after receiving in toto a dose approximately
five to six times that necessary to produce death within
thirty days if given at a higher dose rate (see Fig. 17).

f
However, there are long-term effects due to genetic changes
which are independent of dose rate. That is to say they
occur to the same extent whether the dose is given rapidly
or slowly. In practice they are more apparent when the
dose is given slowly, since the symptoms of radiation sickness
are then absent or much less severe. These long-term
effects which are transmitted to the progeny of irradiated
animals will be described in the next two chapters.
Radiation sickness, which forms the subject of this
chapter, can be considered in the same way as poisoning;
the consequences may be fatal, or they may give rise to
illness with certain symptoms which disappear in time.
Where a single dose of X-rays of less than 200 r is given
there is no detectable shortening of the life-span in mice or
rats (the animals on which most of the experiments have
f
Figures
f
been carried out), although symptoms of radiation sickness
appear some time after irradiation (see p. 84). However, the
incidence of tumours many months after the irradiation is
greater than in unirradiated animals, and cancer becomes
prominent as a cause of death. In view of the long latent
period between irradiation and the appearance of malignant
growths (see Chapter 5) their effect on the life expectancy
of experimental animals is difficult to determine.
Though almost all of the pioneer doctors using X-rays died
of cancer, most of them lived for twenty to thirty years after
severe over-exposure to radiations. Their lives were shortened,
but not by very much.
With more than 200 r of X-rays death occurs prematurely,
i.e. the lethal action- of the radiation is recognizable.
As the dose is increased beyond this point the time for 50
per cent of the animals to die falls sharply. The complete
dose mortality curve for a strain of white mice irradiated
with X-rays is shown in Figs. 18 and 19. From the first
graph it can be seen that the ~ ~wi5th 3050 r is 100 days.
This is probably less than half the life expectancy of unirradiated
mice, the exact value for which varies somewhat
from laboratory to laboratory. After this the mortality rate
increases rapidly and 500 r gives L D ~ O in thirty days.
Increasing the dose beyond this reduces the time for death
relatively more slowly, and at 1,000 r this reaches three and
a half days.
.The effect of still larger doses is most remarkable, since
these doses do not shorten the time for death any further.
To bring this point out we have to consider the results with
a graph plotted on quite a different scale. In Fig. 18 we were
dealing with deaths in days and hundreds of roentgen, now
we need hours and tens of thousands of roentgen. This is
seen in Fig. 19, which shows that the survival time for
irradiated mice is constant at three and a half days for doses
between 1,000 r and 15,000 r. With very high doses the
time for death falls again, and at IOO,OOO r is only one hour.
We are now approaching the region of instantaneous death;
with 200,000 r the animals die while being irradiated, even
though with exceptio’nally powerful equipment available
this amount of radiation could be given in a few minutes.
This relation between dose and survival time is not confined
to mice, and has been shown to apply to rats and guineapigs
as well, though the numerical values for the different
stages differ. The constant survival period for guinea-pigs
is four and a quarter days and for rats two and a half days.
These variations are small, and there is every reason to
believe that the response of mice is qualitatively representative
of that for mammals in general. It is obvious now
that there is no one value for a lethal dose unless one also
specifies the survival time. The period commonly chosen,
:hirty days, is very informative, since the survival time rises
sharply when doses fall below this value, and after a reducdon
by as little as one third a decrease in survival time
already becomes difficult to establish experimentally.

Different radiations.
So far only the effects of X- and y-rays
have been discussed; that is radiations giving rise to low ion
density tracks or having a low rate of loss of energy (see
p. 23). More densely ionizing radiations are more effective
in producing effects on isolated cells than radiations of low
ion density (see p. 206), and it is not surprising that this also
applies to the death of mammals. Since it is necessary to
irradiate the whole body of the animal it is not possible to
compare the effects of particulate radiations such as
a-particles or protons from an external source since these
radiations would hardly penetrate the skin because their
range in tissues is only a small fraction of an inch. Extremely
large doses of such radiation are therefore necessary to
produce radiation sickness and death within thirty days,
since only part of the body is being irradiated. These radiations
produce intense local skin reactions, but do not kill.
The same applies when animals are irradiated with Beta-rays,
which do not differ in ionization density from X-rays or
gamma-rays but which cannot penetrate deeply; with these a dose
ten times that for X-rays is necessary to kill mammals.
These findings emphasize again the great increase in resist- ,
ance to radiation which results if part of the body is unirradiated
and is able to begin repair processes.
Neutrons have a very great range, for reasons discussed
on p. 34, and can be used in the same way as hard X- and
gamma-rays to produce uniform irradiation of the whole body.
They give rise to protons inside the irradiated tissue, and
these have a much higher ionizing density than the electrons
released by the X- and y-rays used in work of this type.
No single figure can be quoted for the ratio of the effectiveness
of fast neutrons to that of therapy X-rays (e.g. 200 kV)
since different values are obtained depending on the exact
conditions of irradiation. For lethal effects at reasonable
dose rates neutrons are about three times as effective as
X-rays. In other words it is necessary to deposit only one
third of the amount of energy when this is derived from
neutrons as compared with that needed when this is derived
from X-rays.

Something approximating to a whole body irradiation
with a-rays can be achieved by causing the animal to inhale
the gas radon which emits a-particles and distributes itself
fairly uniformly through the body. In this way it was found
that this radiation was about twice as effective as neutrons
e. five to six times as effective as X-rays) in producing
acute death, illustrating the danger of densely ionizing
radiations. The body is able to recover less from the radiation
of higher specific ionization than it does after exposure
to X-rays and y-rays, and the relative effectiveness of
neutrons becomes even greater when chronic effects at low
dose rates are studied. This can be seen by comparing the
recovery in an organ with frequently dividing cells, such as
the spleen, after irradiation with X-rays and with neutrons,
with a dose which produces in each case a high proportion
of cell death. The appearance of the organ a day or so after
irradiation will be the Same, but after about a week regener-
ation and new cell colonies will be seen only in the animal
irradiated with X-rays. Consequently the destructive action
of neutrons does not fall off nearly so rapidly as that of
X-rays on decreasing the dose rate. Thus chronic effects can
be produced by repeated exposure to fast neutrons at one -tenth
or even less of the dose necessary with X- or gamma irradiation.
This applies particularly to theincidence of opacities
in the lens of the eye, eventually leading to cataract, so
safety precautions when working with fast neutrons must
be much more stringent than those for X- or y-rays. Besides
being more effective the effects of densely ionizing radiations
are sometimes qualitatively different. The symptoms
after irradiation with neutrons are not the same as those
observed after exposure to X- and y-rays, and the cause of
death would appear to be different.
Although exposure to alpha- and beta-ray-emitting isotopes is
much less hazardous than exposure to isotopes emitting
gamma-rays, because of the lack of penetration, the former
become dangerous if they are inhaled, since they may
become widely distributed and thereby give rise to a whole body
dose or become fixed in certain organs, when they
often induce cancer (see p.149). For this reason strict safety
precautions must be observed in handling radioactive
materials, even if the radiation dose received from them by
external irradiation is very small. The Beta-ray emitting radioactive
dust which contaminates enormous areas after
nuclear explosion is likely to produce more casualties than
the momentary flash of neutrons and gamma-rays released during
the explosion.

-
THE CAUSE OF DEATH
The symptoms of acute radiation sickness are summarized
in Table v, but these tell us little about the cause of death.
If a pathologist carries out a post-mortem examination on
a mammal which has succumbed after a radiation dose of
a few hundred roentgen he would find it very difficult to
pinpoint death to failure of a particular organ. He would
find internal haemorrhages of varying severities, and in
some cases, though by no means all, they would be considered
to be the cause of death; haemorrhage can kill either
by destroying the function of a vital organ or by producing
severe anaemia. But the site at which haemorrhage is found
varies in different animals; in rats and mice it is confined
almost entirely to the intestine, where it would not be lethal;
whereas, in the pig, haemorrhages are also found near the
heart where they could kill. Now anaemia is observed in all
animals after irradiation, though death often occurs before
this is really severe. If anaemia causes death, then blood
transfusions ought to prevent it, but in practice no increase
in survival or even significant increase in the time between
irradiation and death is found by giving extensive
transfusions.

t

After irradiation the body loses some of its ability to
produce antibodies which combat invasion by bacteria
against which it is normally immune (see p. 100) and
following an atomic explosion the surgeon finds that even
minor wounds become septic, in spite of the most rigorous
precautions. As a result, infection is almost invariably seen
after a whole body dose of a few hundred roentgen. Because
of the haemorrhages in the intestines the body is invaded by
bacteria from this source, and such infections of course are
extremely dangerous, but if they were the ultimate cause
of death, treatment with antibiotics should decrease mor-
tality. The effect of these modern drugs is dramatic wheresease
ever a disease is brought about by bacterial infection,
especially since a number of different types, capable
between them of destroying most kinds of bacteria, are now
available. Yet the effect of these drugs in radiation sickness
is from spectacular; there is some evidence that a
combination of antibiotics can produce a slight increase in
the time between the lethal dose and death, but the mortality
tality rate is not decreased; in other words treatment with
antibiotics does not increase the resistance of the animals
to a lethal dose. This proves that infection alone is not the
cause of death, but it does not mean that for people who
have been irradiated these infections need not be treated.
With marginal doses effective treatment of the infection
with antibiotics may make all the difference and it can also
change the course of the sickness; for example, after
irradiation rats suffer from severe diarrhoea, which contributes
to death because the loss of water and salts disturbs
the normal metabolism; if treated with the antibiotic,
aureomycin, the diarrhoea disappears, but the animal dies
none the less, although a few days later than it would have
done so without treatment. When newly hatched chicks are
irradiated their kidneys fail to act, and in this case it is
possible to attribute death to damage in one specific organ,
but this is very unusual. In view of these variations it may
appear that radiation sickness is an ill-defined condition
and that it should not be considered as a whole. Indeed,
some have held the view that since the symptoms and apparent
causes of death are different for different animals, the
fundamental mechanism leading to death is different, too.

No complete explanation can be given the paradox
that although the pathological changes from whole body
irradiation are diffuse and ill-defined, yet death occurs
with remarkable regularity. The problem must be different
from poisoning with chemical substances, which have to
penetrate through the body and eventually become localized
in certain organs. Initially radiation acts equally on all
cells, since it does not have to rely for its dissemination on
transport by the circulating fluids, such as the blood stream,
As a result damage is very widespread; for example, every
part of the bone-marrow is affected and no parts are available
to undertake repair; this is clearly shown by the
increase in survival which occurs when very small parts of
the body are shielded against the radiation (see p. 75),
The whole of radiation sickness is a complex interplay
between cellular damage and impaired recovery processes;
this introduces the great diversity and apparent lack of
specificity. After whole body irradiation mitosis is stopped,
blood production ceases in the bone-marrow, and the
walls of the intestine are no longer replaced by new cells as
they get worn away. Microscopic examination of these
organs will show them to be completely devoid of new cells
a day after a whole body irradiation of several hundred
roentgen. Yet this same effect is produced with doses which
do not kill, and no difference can be seen one or two days
after irradiation between animals which have received a
lethal dose and those which have been given a slightly
smaller dose which does not kill. The inhibition of cell
division is only temporary, and the bone-marrow and the
walls of the intestine begin to fill up with cells again, three
or four days after irradiation, so that at the time of death
these organs do not appear to have been severely damaged;
yet there can be no doubt that the act of putting them
temporarily out of commission contributed to death.
Presumably by the time these radiosensitive organs are
producing cells again the opportunity for repair and
recovery of other irradiated cells has been lost.
The great interdependence of the different organs and
cells in the body may be the reason why mammals are so
much more susceptible to radiations than most unicellular
organisms. The effect of irradiating one organ is often to
impair the function of another, which need not even have
been exposed to radiation. By irradiating the whole body
the balance between organs is disturbed, and a vicious
circle is set up: a disturbed condition persists for several
days, brought about largely by the fall in blood cells, which
in turn are not being replaced by the bone-marrow. By the
time the individual cells have recovered, it is too late for
delicate interplay between the different organs to be
re-established, and the complex machine comes to a standstill.
One might almost say that it is the diversity and the
absence of any specific response which is the cause of death.

Ionizing radiations hit mammals at their weakest point:
the co-ordination of function at the level where it is beyond
the control of the brain. The brain and central nervous
system are remarkably radiation-resistant, and there is no
indication that impairment of these plays any part in
radiation sickness.

EFFECTS FOLLOWING NON-LETHAL DOSES *
When considering the injuries following doses of radiation
which are not lethal, it is necessary to differentiate between
long- and short-term effects. The long-term effects are those
which become noticeable only a considerable time after
the radiation is given, and when all the immediate signs of
radiation have disappeared and are probably forgotten.
* The discussion is confined to X- and gamma-rays. Irradiation with
densely ionizing radiations produces the same symptoms but at very
much lower doses. The relative importance of the different injuries and
the time at which they appear are different for different radiations. The
densely ionizing rays such as neutrons are more effective than X- and
gamma-rays, but the magnitude of this difference – the relative biological
effectiveness (RBE) see p. 206 – is not the same for different effects produced.
As already mentioned (see p. 81) the RBE of densely ionizing
particles is greater when the comparison is made at low as opposed to
high dose rates.

These delayed effects may also arise after periods of continued
exposure to radiation at a low intensity, so that no
immediate symptoms become apparent. Besides the time
factor there is another characteristic difference; the damage
giving rise to immediate effects – radiation sickness – is
quickly repaired by the body and the severity of the symptoms
is therefore very dependent on the rate at which the
radiation is received. The injuries which become apparent
as late changes seem to be irreparable, or at best only
incompletely reparable, and are therefore much less dependent
on dose rate. This is the reason why radiation at very
low intensity may fail to produce any symptoms typical of
radiation sickness, while still bringing about long-term
injuries, some of which will be dealt with in the next two
chapters.
Radiation sickness can be of two types: the one follows a
single large dose and the other small doses repeated over
long periods. The so-called critical dose in a single irradiation
is about 100 r, and below this no unpleasant symptoms,
such as vomiting and general lethargy, are observed. Blood
tests (see below) can reveal a single exposure between 25
and 50 r, but below this dose no pathological changes can
be found. Symptoms of radiation sickness also occur after
repeated radiation with low intensities, although the appearance
of long-delayed effects complicates the picture. From a
study in Britain, Sweden, and the U.S.A. of hospital personnel
connected with radiation therapy, it would appear
that a dose of less than I r per week produces definite,
though slight, symptoms after several years. However, the
effect is small and in animals any harmful effects can only
be recognized following continual irradiations with more
than 5 r per week. If this dose is given throughout life a shortening in
life-span in mice can just be detected, although much
higher doses are necessary for this to become marked (see
Fig. 17).

The safety or tolerance doses are not dictated by
considerations of radiation sickness, but rather by the
dangers from long-term effects (see Chap. 4). This is the
reason why the internationally accepted level of X- and
gamma-radiation to which research and industrial workers and
hospital staff can be exposed without harm is set as low as
0.3 r in any one week, and it has been suggested that the
tolerance dose should be reduced to 0.1 r/week. If a
particularly hazardous operation results in the worker
getting, for example, 0.2 r/hour, then he can only do
this work for fifteen hours in the week and for the rest of
the time must stay away from all radiations. In Britain
only a very small proportion of those engaged on work
involving substances or machines which give off atomic
radiations receive the full tolerance dose, and the majority
of the staff at Harwell, for example, receive less than one
tenth of this dose.

For densely ionizing radiations, such as neutrons or
X-rays, no definite safe level has been proposed, since the
data on which a recommendation could be based have not
yet been obtained. We do know that they are much more
effective in producing many types of injury than the sparsely
ionizing radiations, and at present one prefers to err on the
side of safety and set a tolerance equivalent to 0.01 r per
week for these radiations.

Course of illness. When a single heavy dose is received, as it
was at Hiroshima and Nagasaki, the victims can be divided
into three groups,* and the course of the sickness for these
* The same sequence of events was also found with the Japanese
fishermen who accidentally received lethal doses from the radioactive
fall-out following the test explosion of the first hydrogen bomb, the force
of which greatly exceeded expectations. Very much has been learned
about the details of severe radiation sickness from the clinical history of
eight physicists who received large doses of radiation in an accident
which occurred at the American atomic research laboratories at Los
Alomos. In an experiment to demonstrate that an explosive chain reaction
sets in when two pieces of polonium exceeding a critical size are
brought together, the hands of Dr Louis Slotin slipped, and he and his
colleague received whole body doses exceeding 600 r which ended in
death on the ninth and twenty-fourth day. Bystanders who received a
smaller dose recovered. In spite of the most intense efforts made to save
them nothing could be done to stave off the total collapse of the two
scientists who died. The progress of the disease could not be influenced
by any treatment.

categories is summarized in Table v, which applies when
there are no complicating factors due to burns or other
injuries. The most remarkable feature of the whole illness
is that, apart from attacks of severe vomiting which set in
within an hour or so after irradiation, the victim has no
indication that he has received a fatal or near-fatal dose.
If a dose in excess of 600 r has been received death is almost
certain, and a few days after the dose the patient is obviously
very ill. His temperature rises and he loses weight very
rapidly because he can take no nourishment. The linings of
the stomach have been so severely damaged that food can
no longer be absorbed. Within two weeks or a month at
most death occurs, and so far there is no treatment which
can be given to human beings which alters the progress of
these events. The methods of assisting recovery, described in
Chapter 7, are not sufficiently advanced to be used clinically.
If the vomiting stops after a day or two the dose received
is in the lethal range; that is, a considerable proportion, but
not all, of those affected will die (dose about 300 to 500 r),
but the outcome is not necessarily fatal. For one or two
weeks there are no well-defined or distressing symptoms,
and even the general feeling of lassitude which sets in a day
or so after the irradiation may wear off. But quite suddenly
a variety of signs due to infection and anaemia are observed,
as well as loss of hair and-diarrhoea. From then on the
patient may go steadily downhill or may recover, although
he will not feel completely fit for some months. Prompt
treatment of infections probably increases the chance of
survival, but on the whole the outcome is almost entirely
dependent on the make-up of the individual, and apart from
rather obvious medical measures there is little scope for the
physician to influence the course of the illness.

Doses of the order of 200 r produce no immediate symptoms,
and if uncomplicated by other factors should not
prove fatal. After two or three weeks a general feeling of
ill-heath becomes apparent, followed by other symptoms of
a more definite type. Anaemia will take longest to disappear,
and it may be several months before complete recovery

has been achieved; 100 r or less does not bring about any
obvious symptoms of illness and only a blood count shows
that the irradiation has occurred. A single dose of the order
of 25 r produces no observable effects, and can probably be
accepted as a calculated risk, under certain conditions.
Fortunately no data are available for man of continued
relatively high dose levels, and human
experience of protracted exposure is limited to doses which
give rise at the most to changes in the blood picture, but
none that cause death by radiation. Experience with experimental
animals indicates that with continuous irradiation with more than 50 r
per day the symptoms are the same as for a single large dose, except that
they will set in after many weeks when the total dose received is several times
the lethal dose for a single irradiation.

Smaller daily doses right down to 2 or 3 r per day can still be considered
lethal, since they definitely shorten life, but the illness now has a quite
different character. None of the typical symptoms such as
diarrhoea, severe anaemia, or loss of appetite and weight,
are observed, and the changes seen can best be summarized
as being akin to those normally associated with old age.

Continuous irradiation with doses which do not exceed 25 r
per day may be said to age the animals prematurely. The
data in Fig. 17 can be taken to show that the lethal
dose (LD50) of X-rays given at the rate of 10 r per day is
6,500 r. A more useful way of looking at the results is that
continued irradiation of 10 r/day lowers the life-span
(expressed as the period in which half the animals have
died) of the rat from ninety-five weeks to sixty-five weeks.

In the same series of experiments I r per day lowered the
time necessary for half the animals to die to seventy-eight
weeks. Even as little as 0.1 r per day may have produced
some reduction in life-span.

A large single dose which does not kill also leaves a permanent
mark which is revealed as premature ageing. There
is an increase in the incidence of cancer a long time after
irradiation (see Chapter 5) and this will contribute to a
decrease in life expectancy. But even when allowance
has been made for such deaths, irradiated animals
still die sooner than normal ones (see Fig. 20). No
specific cause for these earlier deaths can be given and they
follow the same pattern as those of ordinary animals dying
f
of old age. Some investigators believe that atomic radiations
hasten the onset of typical senile alteration and can be
considered to accelerate ageing.
Efect on the blood. There are two circulating fluids in
mammals which are responsible for supplying every part
of the body with food derived from the digestive organs and
with oxygen from the lungs. In addition they have to dispose
of waste products, which are eventually eliminated by the
excretory organs; and of carbon dioxide which is exhaled.

The blood circulates through a closed system of tubes and
is pumped very efficiently by the heart. The whole round
trip through the body and lung and back to its startingpoint
only takes about two minutes. All tissue is bathed in
fluid which exudes from the finest capillaries carrying the
blood and is collected again and returned to the veins by
lymph vessels which ensure the forward flow of the liquid.
To fulfil its purpose the blood contains cells which originate
in the blood-producing organs from which they are discharged
into the blood stream where they perform different
specific functions. After a certain time the blood cells
deteriorate and are then disposed of by the spleen or alimentary
canal. Under normal circumstances the blood cells are
replaced as required by the blood-forming organs which
carry, however, a reserve supply for release in emergency .
such as a haemorrhage. The volume of tissue fluid is kept in
balance by the intake of drink and its distribution between
the blood and tissue is complex, involving a number of
factors and organs.
The red cells are by far the most common, and there are
about 500 of these t; every one of the others, which are
known as white cells and consist of many different types.
The main division is into lymphocytes, which are made in
the lymph glands, and granulocytes, which are produced in
the bone-marrow: the latter can be divided into a number
of sub-groups, the most common of which are the neutrophils.
Since lymph tissue is spread throughout the body,
nothing short of total body irradiation will influence all the
sites at which they are produced, but for the same reason it
is almost impossible to irradiate any part of the body without
exposing some lymphoid tissue. Lymphocyte counts
are therefore a very sensitive biological indicator for detecting
irradiation. The red cells and the various types of
granulocytes are formed in the bone-marrow and a few other
organs, from one and the same basic cell, the reticulocytes.
This is the precursor of a number of cell types and environmental
conditions determine the kind of differentiation they
undergo to become a particular type of mature blood cell.

Once they have acquired their full degree o f specializa~io~\
they are ko longer cipable of division,&d new cells neecletl
for replacement are produced by division of the retic~tlocytes.
The lifetime of the cells varies greatly; lymphocytes SUP
vive for less than a day; granulocytes live for about thrw
days; while the same red cells carry on for three or four
months before they break up and have to be replaced. A
short-lived blood component of the greatest importance is
the platelets, which are related to the granulocytes and
carry enzymes that are necessary if blood clotting is to occur.
Platelets are therefore vital for the control of haemorrhages
and if there are too few present, small injuries – particularly
internal ones – which would normally be quite harmless,
may prove fatal.
Radiation to the whole body affects a11 the different cells
of the blood, but as with all radiation injuries these changes
f
only become noticeable some time after irradiation. The
general pattern for a dose which does not kill is shown in
Fig. 21. A reduction in the number of lymphocytes can be
recognized less than one hour after irradiation. In addition
to giving a very early indication, a significant drop in
lymphocytes is found in man and animals after as little as
one dose of 25 r of total body irradiation. This great sensitivity
is due to the fact that the circulating lymphocytes have
such a very short life, and any intederence with cell division
in the lymph-forming tissue is bound to be reflected very
quickly in the blood picture. In addition the lymphocytes
themselves are very radio-sensitive and radiation may
shorten their life and thereby aggravate the shortage resulting
from the hold-up in mitosis. With less than lethal doses
a gradual upward trend in the lymphocyte count can be
observed after three days, but the subsequent rate of recovery
is rather slow. For doses in the lethal range where some
of the animals survive, the lymphocyte count does not begin
to recover for about two weeks and in the early stages gives
no indication whether an animal will survive or not. The
low number of lymphocytes is not thought to be critical to
the animal and does not contribute to the more serious
aspect of radiation sickness, but it is diagnostically most
useful.
The fall in granulocytes can be observed only a day after
the irradiation and the lowest value is reached after about
seven days. The dose required to give a significant depression
lies between 50 and 75 r and it is therefore less radiosensitive
than a lymphocyte count, but it provides a much
more important indication of the seriousness of the radiation
injury. The number of granulocytes does not return to
normal for at least two to three weeks, and it is during
this period that death from acute fadiation sickness occurs.
An increase in the number of blood cells is a very good
sign, and suggests that recovery will occur. With chronic
exposure the fall in granulocytes occurs very slowly, but
there is also much less power of recovery than with Iymphocytes,
and the count may stay permanently low after all
exposure to radiation had come to an end.

The restoration of the granulocyte count following single
irradiation is brought about by the release of cells held in
reserve in the spleen, and in addition reticulocytes are
released from the bone-marrow before these have had a
chance to develop into the fully differentiated cells. Tlir
presence of the so-called immature cells is very typical 01′
radiation damage and about two to four weeks after a sevcrr
exposure (depending on the animal used) the number ol’
these cells is greatly in excess of those normally present
(Fig. 22). The presence of these immature cells is not neces-
f
sarily beneficial, since they cannot exercise all the functions
of the fully differentiated cells and can be harmful to some
important organs. This is a typical case of how radiation
can upset the fine balance of the whole body and interfere
with organs which are themselves radiation-resistant.
The fall in platelets can be observed at about the IOO r
level and in general follows that of the granulocytes, except
that recovery occurs rather more slowly. The fall in platelets
is of the greatest importance, since it is responsible for the
haemorrhages which are such a characteristic feature of
radiation sickness. Increased fragility of the blood vessels
after irradiation is a contributory factor, but the most
important cause of haemorrhage after irradiation is the
reduction of platelets and the consequent failure of the blood
to coagulate. The severity and most common site of these
haemorrhages vary from species to species and depend
on the dose. Although they are unlikely to be the cause of
death following an irradiation with a dose sufficient to kill
all the animals (i.e. substantially greater than LD~Ot)h,e
severity of the haemorrhages may often determine whether
an animal lives or dies after a dose near the lethal range.
A little extra exertion or a small additional injury, such as
a cut or abrasion, may greatly affect the severity of the
haemorrhage because of the virtual absence of platelets.
The red cells themselves are extremely radiation-resistant,
and doses of tens of thousands of roentgen are necessary
before any change can be detected in their behaviour.
Exposures of the order of those which produce radiation
sickness will leave the circulating cells entirely unaffected
and allow them to continue their normal function. Since
they persist for many months, interference with the formation
of their precursors by stopping cell division in the bonemarrow
cannot make itself felt for many weeks, by which
time normal cell division – as shown by the recovery in the
lymphocyte count – will have set in. Nevertheless a diminution
in the red blood cells is observed after whole body doses,
about one week after irradiation, and continues for about
three weeks; it is at a minimum when the lymphocytes and
granulocytes are nearly back to normal. The reason for this
drop and the general anaemia always found after severe
irradiation is the haemorrhages, which often result in
serious loss of blood. Chronic irradiation may give rise to
protracted anaemia, even though the white cells are normal,
because the areas of the bone-marrow in which the red cells
are formed have less power of recovery from radiation
damage than those producing white cells. With a single dose
permanent loss of generative power is generally small and
the immediate effects on the blood are due to temporary
inhibition of cell division, resulting in a deficiency, followed
by release of immature and abnormal cells, which tend to
upset some of the many functions for which the blood is
responsible. The status quo is eventually re-established if the
dose has not been too great. Protracted irradiation may
effect an irreversible change by permanently reducing the
number of blood cells produced.
f

to lose weight (see Fig. 23) because of the general symptoms
of severe radiation sickness which lead to a complete loss of
appetite and to diarrhoea. Animals which do not survive
continue to lose weight until death, but the curve for
survivors passes through a minimum, at a time which
depends on the species and the severity of the radiation, and
then goes up again to that before irradiation. If young
animals which are still growing are used, a second weight
drop can be observed. This is clearly brought out in Fig. 24,

f

where it can be seen that the initial weight loss follows the
lymphocyte count and is reversed on the general recovery
of the animals within the first week. Then suddenly, about
two weeks later, a second drop occurs which coincides with
the fall in the number of red cells, and this weight loss is a
measure of the haemorrhages. If these haemorrhages nrp
very severe because of some additional factors, death will
occur at this time. That is, the animal has survived the first.
shock of the radiation which normally kills at lethal doses,
but its platelet shortage has prevented it from surviving the
subsequent haemorrhages.
This explains why there are two distinct periods of death
after irradiation with a dose which is in the lethal range but
not invariably fatal. There is death after about ten days
following the initial weight loss – this is the period in which
death occurs with doses sufficient to kill all animals – and an
occasional death after two to three weeks. In man very little
can be done to prevent death in the first period (see p. 84) ;
but these late deaths can be prevented by medical treatment
for haemorrhages, since the number of platelets will be going
up again, parallel with the recovery of the white cells in
general.
Infection. Healthy mammals have the capacity for forming
substances, known as antibodies, which combine with and
thereby put out of action foreign bodies which enter the
system. This is one of the major defences of mammals
against disease-producing organisms. When, for example,
bacteria from food which has gone bad are absorbed, antibodies
against them are made by the animal and will keep
the infection in check so long as the invaders are not too
virulent and do not damage the host too severely before
sufficient antibodies have been made. Immunization consists
of stimulating the body to make antibodies against a
particular bacterium or virus which is dangerous. This is
usually done by injecting the virus in an attenuated form, in
which it still stimulates antibody formation but does not
produce the symptoms of the disease (compare p. I 99). After
immunization the body has the antibodies in readiness, or
the antibody-forming organs have ‘learned’ how to make the
particular antibody required and can produce it more
rapidly the next time. Then when it comes into contact with
the invader again the immunized animal is able to combat
lie dangerous organisms immediately, before they have a
rhance of becoming established.
One of the most typical symptoms of radiation sickness is
the much greater susceptibility to infection. Small and
insignificant wounds turn septic after a whole body irradiation
and many infections set in spontaneously. The reason
for this is twofold; the mucous membranes of the intestine
become thin and ulcerated and aided by local haemorrhages
the bacteria from the intestine gain access to other parts of
the body. This in itself would probably not be sufficient to
make the infections as serious as they are, but the body has
at the same time lost its capacity to form antibodies. These
are probably produced inthe blood-forming organs, and
interference with them is another aspect of the effect of
radiation on the blood. Whether the cells which actually
make the antibodies are destroyed and become replaced by
new ones, or whether radiation merely temporarily inhibits
their protein-synthesizing activity, is not known. However,
the dose required before loss in immunity-producing pro-
~ertieiss observed is of the order of several hundred roentgen.
Shielding part of the blood-forming organs from the
radiation prevents the interference with antibody formation,
and this must contribute to the great protective effect of
excluding parts ofthe body from irradiation (seep. 75). These
infections are a very serious part of radiation sickness, and
if not treated can lead to death, but they are not the normal
cause of death with doses of radiation in the lethal range.
Effect on reproduction. It is necessary to distinguish between
localized irradiation confined to the sex organs, and whole
body irradiation. Permanent sterility can be produced by
irradiating the ovaries with about I,OOO r; in the male this
dose will give only temporary sterility, and permanent
destruction of the organs in which the sperms are generated
requires several thousand roentgen in most mammals,
including man.
Following a whole body irradiation of 400 r or more the
male remains fertile for many weeks, but then becomes
sterile for a protracted period of several months. Recovery
of the reproductive organs takes longer than that of othn’u,
and sterility can be said to be the most protracted symptom
of radiation sickness. The reason for the delay of about two
weeks between irradiation and the diminution in tlir
number of sperms – complete sterility requires a minimum
of 400 r and occurs as late as a month after a single dose of
radiation – is due to the fact that the mature sperms arc
very radiation-resistant, so that successful mating is possible
by a male who has received a lethal dose and will shortly
die. The earlier stages of the germ cells are radiation-sensitive,
so that the supply of mature sperms is interrupted by
the irradiation. The long delay before fertility occurs again
is due to slow recovery of the germ cells coupled with the
fact that it takes several weeks for a newly formed germ cell
to develop into a mature sperm. Complete recovery occurs
in animals and, so far as can be judged from the limited
number of ‘atomic accidents’ and the Japanese casualties,
in man also.
Ovarian tissue is much more sensitive and it has been
claimed that a whole body irradiation of 150 r has caused
permanent sterility in mice. Again the generative cells are
the most sensitive, while the fully differentiated ovum is
unaffected. Menstruation will therefore continue for a time
even after a very heavy dose (with mice two litters can
occasionally be got after irradiation before permanent
sterility becomes apparent), but will cease for a long period
or completely if the dose exceeds the so-called castration
level (about 300 r for human beings),* which is however
rather variable even within one species.
The skin. In March 1896, only three months after Rontgen
published his discovery of X-rays, their destructive action
* The practice of gynaecologists of stimulating fertility by irradiating
the ovaries with 175 r is no contradiction of this, since this is a localized
exposure as opposed to a whole body dose. Reference is made on p. 125
to the harm which could occur if this form of treatment were carried out
widely.

on living matter was revealed by their depilatory action.
Irradiation with a few hundred roentgen by all types of
rays causes hair to fall out about a week or so later. This
is a local effect and the whole body need not be exposed:
the part irradiated can be recognized from the loss of
hair, This is particularly noticeable following exposure
to &rays, given off by a radioactive substance, since these
only penetrate a small fraction of an inch and do not, unless
ingested, produce general radiation sickness. Usually the
hair growth returns and no permanent damage is left
behind with doses of two or three hundred roentgen. This is
illustrated by the photographs on Plate ga, which show a
young South Sea Island girl, on whose head had settled
radioactive dust released in an American hydrogen bomb
trial. A year later the hair had returned to normal. For most
human beings more than 500 r permanently damages hair
growth and the new hair will be sparse and weaker. Larger
irradiations still cause permanent baldness; but for all these
changes it is difficult to give a definite threshold dose, since
there are remarkable variations not only between species
but even from one person to another.
After fairly big doses the appearance of the hair and
sometimes also its colour are altered. These changes are
permanent, indicating that cells responsible for secreting
the pigment or other substances associated with the hair
have been permanently destroyed. An effect of this type is
shown most markedly in certain strains of black mice,
whose hair is turned permanently white after irradiation;
all new hairs in the irradiated region are white, and the
pigment never returns. Plate 8a shows the greying produced
by irradiating a mouse with 800 r of X-rays in a narrow
beam. The X-rays are very penetrating and go right through
the mouse, so that the white colour occurs on both sides of
the animal. Since this dose was confined to a very small
volume only, no symptoms of radiation sickness were
produced.
The effect of radiation on the skin is extremely well
defined, and was used as a means of measuring the dose
from X ray machines before physical methods had been
developed. The changes produced depend only the local
dose received, and are independent of radiation to the
remainder of the body. Damage to the cells in the skin is not
influenced by irradiation of other organs or of other skin a1
some distance away, and differs very markedly in this
respect from irradiation of the blood-forming organs and
the associated general symptoms of radiation sickness.
Injury follows a general pattern; within a few hours after
exposure the affected parts redden temporarily. This effect
is usually very mild and sometimes is not observed at all;
it wears off after a day or so. More than a week later definite
reddening develops and the extent of this so-called erythema
varies very much with dose and dose rate. This reddening
is an inflammation of the kind which is evoked in damaged
tissue by many forms of injury, not only radiation. The skin
shows remarkable power of recovery, so that by extending
the time over which the dose is given to more than one hour
the damage is greatly decreased; as the dose rate decreases,
the total dose necessary to produce a certain degree of
erythema is increased. This is shown in Table VI, which
gives the total dose necessary to produce in man a fixed
intensity of skin reddening at two weeks following the
irradiations. Narrow beams were used, so that the total
areas involved were very small.
t
The dose at which definite erythema sets in is usually the
same as that causing loss of hair; it is quite temporary and
causes little distress. It is often followed by slight changes
in pigmentation, and large freckles may be seen. In coloured
races loss of pigmentation may occur (see Plate 9b).

With doses exceeding I,OOO r the erythema becomes
severe, the skin becomes dark red and blisters are formed.
‘I’hese indicate extensive damage to the skin and can turn
into extremely unpleasant running sores which take months
to heal and leave bad scars. In radiation treatment of deep-
seated cancers the dose tolerated by skin without producing
severe erythema is often the limiting factor. Accidental
irradiation and contact with radioisotopes have given rise
to severe skin damage, which clears up quite quickly if the
exposure is not repeated. Plate 9b shows the feet of a native
from the Marshall Islands, which were contaminated by
radioactive fall-out. Some months later they were completely
healed. (Paul’s note: this is an overly optimistic assessment, as later
history reveals, and indeed as the author notes in the captions to
the photographs.)

The effect on the skin of long-term irradiation, such as
exposure of their hands by the early radiologists, is much
more serious. A complex process of damage followed by
periods of repair often results in overgrowth and causes the
skin to dry up. Gradually and insidiously the fingers become
stiff. Once this has occurred recovery becomes impossible,
and even if all further exposure to radiation is then avoided
the affected parts will not improve and may continue to
deteriorate. Typical deformities following prolonged local
exposure to large doses, which did not produce radiation
sickness since only a part of the body was exposed, are
shown in Plate 8b.

The first warning that irreversible damage is being done
to the skin by irradiation over long periods is a change in
the ridges of the finger-tips. This test can be made very
sensitive by taking finger-prints which immediately reveal
the flattening or disappearance of ridges (see Plate 10a). As
the skin is damaged it is replaced, and even when the skin
peels off the fingers the identical finger-print pattern is
re-established. With chronic radiation a time arrives when
the repair process fails to produce an exact copy and the
new pattern remains permanently. Even today many radiotherapists
and surgeons, who take reasonable precautions, reveal their profession
by their finger-tips; certainly the surgeon who inserts radium needles cannot
fail to expose his fingers and must watch the symptoms most carefully,
for radium damage may affect the agility of his fingers on
which his skill depends.

Cataract. One of the most serious of the non-fatal consequences-
of irradiation is the clouding over of the lens of the
eye. This is known as cataract formation, and can lead to
total blindness, although frequently vision is only impaired.
There is a long latent period, and five to ten years may
elapse between irradiation and the appearance of symptoms.
The most important factor is the irradiation of the eye
itself, and exposure of the rest of the body is not important.
In many respects the irradiation effects of the eye follow
closely those of the skin. Dose rate is more important than
total dose, and a single heavy dose is the most effective for
inducing cataracts. About 400 to 500 r of X- or y-rays are
needed, and for all practical purposes it is not therefore a
hazard. Some of the seriously affected victims of the atom
bomb explosions in Japan who survived a big dose later
developed cataracts; in general, the threshold dose for
serious cataract is close to the acute lethal (1-050) dose for
whole body irradiation.
Radiations giving rise to densely ionizing tracks, such as
fast neutrons, are generally more effective in inducing all
types of radiation injuries than X- and y-rays (see p. 206),
but they are exceptionally more effective in producing
cataract. Thus the neutron dose necessary for cataract lies
well below the LD50 for whole body irradiation. This was
first indicated in 1948, when several cases were found in
physicists who had been exposed to neutrons from a cyclotron.

The greatest danger comes probably from accidental
exposure to Beta-ray-emitting isotopes, whose radiations do not
penetrate and do not therefore produce whole body effects;
fall-out from bombs is an obvious source.


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