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REPORT OF THE

UNITED NATIONSSCIENTIFIC COMMITTEE
ON THE
EFFECTS OF ATOMIC RADIATIONGENERAL ASSEMBLY

OFFICIAL RECORDS : TWENTY-FOURTH SESSIONSUPPLEMENT No. 13 (A/7613)

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UNITED NATIONSNew York, 1969

NOTE
Symbols of United Nations documents are composed of capital letters
combined with figures. Mention of such a symbol indicates a reference to a
United Nations document.

Annex B

EFFECTS OF IONIZING R.\DL<\TJON O~ THE .:"ERVOUS SYSTEMCONTENTSParagraphs

Paragraphs

I.

J:-;TRODt;CTIO:-;".. ... .. ... . .. •. ... .. . . . .. .•..

1-11

3. Functional efferu . . . . . . . . . . . . . . . . . . . . . .

99-114!I.

EFFECTS 0:-1 THE DE\'ELO!'IXG NERVOUS SYSTE?.!

12-72

B. Periphcrnl uen·es, sy11aps.-s a11d receptors . .

115-123

A. E.r,'>erimc11tal results

12-38
12-21
22-38

R.\DIATIO>< AS A STL\IVLL'S FOR SENSORY ORGANS

124-133

1. Structural changes
2. Functional changes

B. Effects in ma11 ......•....•..•.•.....••••
1. Pre-natal irradiation .................. .
2. Irradiation during childhood

JII. EFFECTS ON THE ADULT ORGA:-IISM
A. Central nervous system ................ .
1. The central nervous system radiation syndrome .............................. ..
2. Structural changes ................... .
(a) Cellular and subcellular changes ... .
(b) Histological and related metabolicchanges ....................... · ·.
( c) Late (delayed) effects of irradiation(d) Repair .......................... .

JV.

A. Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 125-127
B. Olfactio11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128-129
C. Se11so1·y systems and belzadoural reactions 130-133

39-72
39-63

64-72
V.

73-12373-114
73-78
79-98
79--86.........••.....••....•.•

134-154

A. Effects in a11ima/s ..................... .
B. Effecls in 111a11 •••••••••.••••••••••••••••

135-149
150-154

SYSTEMIC EFFECTS

VI. (O:-;"CLt;SlONS

155-159
Page

87-88
89-92
93-98

TABLES.......•...

REFERENc1;s ............................... .

85
87

ous and other systems of the organism and the multiplicity of end-points whereby changes in the nervous
system can be recorded.
4. Direct damage to the nervous system is generally
not lethal, except at doses \veil above those necessary
to cause lethal damage to other organs and systems,
though radiation may produce serious structural andfunctional changes. The relationship between these two
types of change cannot always be established. In someinstances, the response of the nervous system is secondary to damage in other tissues so that doses to thenervous tissue are not the relevant ones for assessing
the risks of such particular effects.
5. The functional changes in the nervous system towhich radiation exposure may give rise are manifold
and often reversible. \Vhether any particular one
should be regarded as damage, and its occurrence asa hazard, is largely a matter of judgement. Thus,
a number of functional changes are merely transientphysiological responses of certain receptors to a stimulus(ionizing radiation) that the organism does not recognize as different from those that the receptors aredesigned to detect. While this kind of response ca::ihardly be viewed as damage in normal circumstances, 1t
mav involve a hazard in such exceptional situations as
might. for instance. occur in space flights. in which theindividual required the full command of his reactions to
sensory perception.
6. In this review, radiation-induced changes will be
primarily considered from the point of view of the resulting prolonged impairment of the functional integrity

I. Introduction
1. Exposure to ionizing radiation brings about effects that involve all systems of the organism. The
type and frequency of such effects are strongly dependent on the dose of radiation absorbed and on theconditions of exposure. The purpose of this review
is to describe certain aspects of the response of thenervous svstem to irradiation, to assess this response
in terms of hazards to the e.xposed individual and to
explore the possibility of evaluating the e.xpected frequency of particular effects according to dose, that is.
of estimating the corresponding risks incurred by man.

2. The effects of radiation on the nervous systemwere briefly considered by the Committee in its 1962
report to the General Assembly 1 within the generalcontext of somatic effects. Much information has accumulated since that time. As a consequence, the importance of the impairment of the nervous system andof its functions that radiation may occasion is now
better appreciated, and it was therefore felt that amore detailed revie\v had now become appropriate. The
range of the observations is so vast. however. that no
attempt at covering it exhaustively has been made inthis review which is largely confined to discussing
those topics that are of immediate relevance to theactivity of the Committee.
3. The study of the effects of radiation on the
nervous system is particularly difficult because of thesystem's own morphological and functional complexity,
the close and intricate relationships between the nerv-

69

of the individual. \Vhile this review deals with effects
of both high and low doses. it is in the low dose rangethat results are particularly emphasized, for it is in
this range that the population is exposed. As in earlier
reports of the Committee, doses of 50 rads and less are
considered to be low. The distinction between high andlow doses is merely intended to separate by means ofan arbitrary cut-off point doses which are likely to
produce early clinical (so-called acute) effects fromthose that do not.
7. Data on the response of the nervous system of
man and on the effects of radiation upon it are scanty
and come mainly from four sources : (a) survivorsof the nuclear bombings at Hiroshima and Nagasaki;( b) patients irradiated for medical reasons; ( c) people
occupationally exposed: and ( d) people irradiated accidentally. The reliability of data from each group has
limitations. Dosimetry is not always accurately known,
and in most cases irradiation has taken place in circumstances that were. for obvious reasons. not well controlled.
8. Survivors of atomic bomb explosions (group a)were e.'\:posed not only to radiation but also to blastand heat and generally experienced a disaster unprecedented in their lives. The associated trauma may haveaffected their nervous systems in various ways. ·when
patients receive therapeutic or diagnostic radiation exposure (group b), it is often difficult to separate theeffects of radiation from the consequences of the condition or disease for which radiation was administered.
In medical radiation series, particularly those performed many years ago, the adequacy of dosimetry isoften questioned. Finding adequate control groups isoften difficult. while the use of inadequate ones may
easily lead to biased conclusions. particularly whencertain functional effects that are difficult to diagnose
objectively are considered. When satisfactory control
subjects are available. it is advisable to set up paired
statistical controls and to use double blind techniques.
For radiation workers (group c). it is also difficult
to find adequate control groups. Most of the occupational groups receive very low doses. a~d the relatively
few groups who have been exposed to higher dose levelsin the past received their exposures when dosimetry
monitoring was still far from adequate. In serious
accidental situations (group d). attempts are usually
made to reconstruct the dose distribution within theworking space and to determine the occupancy by thethe exposed workers when the situation occurred. Since
accidents usually involve negligent procedure, only
rarelv can the dose distribution be accuratelv established.
9. Because of the paucity of human data. a largepart of the evidence on the induction of effects in the
nervous svstem is necessarily derived from animale."'\:periments. Unless this evidei1ce is supported by wellcontrolled observations in human beings, extreme cat:tion should be exercised in extending conclusions toman, since the response of the nen•ous system to radiation differs from species to species and even between
strains within the same species. The need for caution
is particularly acute when observations, even negative
ones. on the effect of radiation on the behavioural responses of one specie3 are used to infer the possibility
oi similar effects or lack of them in man.

quantitative knowledge of the underlying dose-effectrelationship. Such knowledge is largely unavailable
for the nervous system. The number of different doses
for which effects have been studied in individual experiments is in most cases e.xtremely small, sometimes
limited to one dose level only. As there is no reasonable theoretical ground for establishing dose-effectcurves. no meaningful extrapolation can be made. On
the other hand, a major hindrance to the proper
evaluation of the resuls of neuro-radio-biological studies
is often the lack of statistical analvsis and sometimesof adequate knowledge of the dose-s involved. All too
often data are reported \vith so little information onsuch details as rate of deliverv, fractionation scheduleand quality of radiation as to make assessment andintercomparison of results all but impossible.
11. Most of the experimental results are reported
in terms of exposure rather than dose, since it isusually the exposure (in roentgens) that is controlledduring the experiment, although the absorbed dose(in rads) is the relevant parameter. \Vith small animals (mice and rats) and the radiation usually employed, however, the assumption that the numericalvalue of the exposure and that of the dose are thesame involves an error that, in the present conte.xt. is
trivial. Whenever this has proved reasonable. roentgens
have therefore been treated as equal to rads in thisreview. In other cases. the stated units of e.'\:posure havebeen retained. and available details about kilovoltage,
filtration, distance. etc. have been included. Unlessotherwise indicated. irradiations must be read as single,
short-term. whole-body. Dose rates are given only
when special significance attaches to them. \Vhen thequality of the radiation is not mentioned, it may be assumed to be that of x rays or gamma rays. This is
the case with the majority of irradiation experiments
involving the nenrous system.
II. Effects on the developing nervous system 0

A.

EXPERIMEXTAL RESULTS

1. Structttral changes
12. Pre-natal irradiation of experimental animals
produces damage in a number of organs and may resultin macroscopic or microscopic abnormalities at birth.
The cells of the developing nervous system show varying
reactions to radiation. Immature cells undergo mitotic
delay or become unable to reproduce in large proportions. the proportions being dependent on dose. Particularly in the early stages of development. cell killing
may be so extensive as to prevent further development" The main stages in the development of the nervous system
are the following;'.!. 3(a) Period of cell di~·ision. During this period, the numberof neurons reaches almost that found in the adult. This lasts
until birth in the rat and until 210 days after conception inman.
(I.>) Period of cell growtlz and differc11tiatio11. In this period,
there is an increase in the size oi the brain cells and rapid
outgrowth of axons and dendrites from the nerve-cell bodies.
This occurs during the first ten days after birth in the rat andfrom 210 days after conception until birth in man.
(c) Paiod of -rapid 111scli11atio11. Electrical activity can now
be detected in the brain. Gro\\'th of cells is considerably lower
than it was previously. This period extends from ten :o about
twenty days after birth in the rat and from birth to 120 days
later m man.
(d) Period of slrnucr 111yc!i11atiou. It is difficult to determine
exact!~· when this final period begins and ends. In the rat,myelination ends between five and six weeks of age and, inman, between five and ten years of age.

10. The quantitati,·e assessment of rates of inductionof functional or structural changes, and therefore theestimation of the attendant risks. requires a detailed70

of the embryo. Because different primordia and anlagenof the various parts of the nervous system follow differing patterns of mitotic activity. the ultimate outcomeof the irradiation nries not only with dose but alsowith time of exposure. 4 As differentiation proceeds
and less and less cells are dividing. the resistance of theyarious structures of the nervous system increases.
Eventually, mature neurons can usually absorb a doseof at least 1.000 rads without apparent structural
damage.
13. The results of pre-natal irradiation have beenstudied particularly in the mouse and the rat. In both
species. malformations of the nervous system can beobserved during the subsequent course of developmentof the animals. Although reports of these malformations are more abundant in the rat than in the mouse,
this may merely reflect the fact that the two species
have been studied by different investigators with different techniques and for different purposes.
14. In the mouse, the most extensive studies" haveconsidered primarily the way in which skeletal defects
depend both on dose and on pre-natal age and haveindicated that it is mainly in the period of majororganogenesis (between six and a half and twelve anda half days after conception) that most malformations
are brought about by radiation. These studies havealso indicated that. within this period, the interval during which any one type of malformation can be inducedby doses of 200 rads is limited to the period fromtwenty-four to forty-eight hours, though it becomessomewhat wider at higher doses. During the first six
days of pre-natal life. irradiation results in high prenatal mortality and very few malformations. After organogenesis. the ability of radiation to give rise to
structural abnormalities is very much reduced, andthe yield of malformations becomes progressively lower
after the twelfth day of gestation.
15. Other investigators&-0 have focused particularlyon central nervous svstem malformations in mice irradiated at various ti{ues between the seventh and thetwelfth <lay of pregnancy. Exencephalia, myelodysplasia with spina bifida occulta. encephalocele and arrhinencephaly are observed after 200 or 300 rads
between the seventh and the ninth day, whereas later
irradiation tends to produce hydrocephalus. 9 Microphthalmos. anophthalmos and microcephaly arise after
both early and late irradiation at the same doses.
There are differences, however. in the temporal sequence between the two strains investigated. one ofthem, for instance, showing two peak incidences ofhydrocephalus, whereas the other presents only one.
16. vVhile most investigators agree that malformations can only be induced during major organogenesis,
there have been reports 10· 11 of e.xencephaly being induced by doses of 15 rads given 0.5 and 1.5 days
after conception. The occurrence of exencephaly after
irradiation at that early stage. however. appears to bea rare and erratic phenomenon for which no clear doseeffect relationship has been demonstrated so far. Exencephaly has been observed to arise spontaneously insome strains of mice, and there is some indication thatits incidence may show seasonal fluctuations. 12 Larger
and strictly controlled experiments must be performed
before the view can be accepted that irradiation in the
pre-implantation period brings about major malformations involving the nervous system.

17. In rats. formation of the nervous system begins
on the tenth day after conception. Results of in utero
71

irradiation are basicallv similar in all strains investigated. A close of 200 r~ds given on the eighth day kills
the embryo, whereas lower doses neither kill the embryo nor produce malformations. 'Vith 100 rads on
the ninth dav. severe malformations of the forebrain
and upper head (anencephaly, pseudoencephaly) andeye malformations (anophthalmia) may be obsen·ed.
Some malformations occur even after 50 rad5, but
only eye anomalies at 25 rads. The effects are lesson the tenth day, though anophthalmia is still observed
at 100 rads. Irradiation (200 rad) on the eleventh
clay gives rise to a high frequency of hydrocephalus
with dorsal encephalocele of the third ventricle. 13-1 7
18. Between the twdfth and the twentieth day
after conception. doses of 200 rads produce a varying
degree of reduction of the size of the forebrain accompanied by hypoplasia and disorganization of the corticalneuron layers. 18• 19 Absence or abnormalities of the
corpus callosum may occur after irradiation between
the twelfth and the eighteenth day. and the presenceof aberrant thalamo-cortical fibres is particularly evident in animals irradiated on the sixteenth and seventeenth days. Irradiation from the eighteenth day onwards, and well into the first week after birth, may
produce major disturbances in the development of thecerebellum that affect its size and the proportion ofits various parts and that disrupt the orderliness of
its cellular structures.20
19. Detailed histological studies21 have shown that
doses between 20 and 50 rads on the sixteenth dayof gestation are followed, in the rat, by disorganization of the cortical structure. Neurons in the outer
cortex are smaller and fewer than in controls. lessdifferentiated and with little tendency to vertical arrangements. Certain cortical layers are thinner andless sharply defined, ''layer six" in particular showing
cellular deficiency and jumbling of neurons. \Vhile atmaturity the orderliness of the carte.'\: is partly restored,
particularly when doses were Im.,,·, layer six remains
deficient and disorganized even after 20 rads. Similar
but less striking effects are observed after irradiationon the eighteenth day of pre-natal life. Retardation
and alteration of growth of the cortex is clearly evident after a dose of 10 rads on the day after birth,
but the damage becomes more and more difficult to
detect with time, and no significant structural abnormalities can be detected in mature animals. thus indicating apparent recovery. No data are available on theeffects on cortical structure of low doses given before
the sixteenth day of intra-uterine life.
20. It is very difficult to predict, on the basis ofwhat has been observed in rodents, the malformations
to be e.xpected in man. even allowing for the different
time course of development. The relevance of the e.xperimental studies that are reviewed here is mainly
in showing the importance of the time of irradiation
for the production of malformations of the nervous
system in general and of particular anomalies involving this or that structure. The timing of irradiation is
so important that, by adjusting it carefully, it is possible to ';design and build'' abnormal rat brains. Doseis naturally an equally important factor. It is remarkable
that, with the exception of exencephalia. whose induction by radiation is still open to question, gross malformations of the nervous system have not been described in the low dose range. Even though a thresholddose for the induction of damage to the developing
nervous system has not been established. lasting microscopical changes are clearly observable in the rat cortex

after doses around 20 rads. The available data suggestthat the radio-sensitivity of the fretal nervous system
is of the same order as that of the most radio-sensitive
tissues of the adult.
21. In certain mammals, at least during the periodof organogenesis, structural changes involving thecentral nervous system have been observed following
e.xposure to a wide range of mutagenic or teratogenic
agents. These changes are similar, if not identical, topreviously described radiation effects such as microophthalmia. anophthalmia, microcephaly and gross deformities of the spinal cord. The agents implicated andobserved to be causative include parts of the vitamin B
complex. Prussian blue. certain ""pesticides" and certain viruses. The induction of changes appears to bemuch more directly and precisely related to the particular stage of organogenesis at which exposure occurs
than to the "dose" of the mutagen. It is not at present
known if the same basic mechanism is involved as in
the case of radiation, nor whether there is a threshold
effect.

2. Functional changes
22. Gross malformations such as those observed
after pre-natal doses of 100 rads and higher, if compatible with survival, are naturally accompanied bysevere functional impairment. The following paragraphs
will review functional changes in animals that do nothave overt structural malformations of the nervous
system.
23. Adult rabbits exposed to 300 roentgens of wholebody radiation (190-kV x rays, 1 mm Cu, 0.5 mm Al}
on the twenty-third day after conception (last thirdof gestation) show reduction of the amplitude of theencephalogran1 and of the spike frequency and very
poor response to light stimuli. 22 Another investigation
has shown electro-encephalographic changes after x-ray
exposures ranging from 150 to 400 roentgens.23 In
rabbits irradiated around the fifteenth day of gestation, there was an increase in the proportion of highfrequency ·waves, whereas, in animals irradiated aroundthe twenty-third day of gestation, there were increments in the amplitude of low-frequency waYes and adecrement at higher frequencies.

24. These changes in the wave spectrum may reflectstructural disturbances in the different parts of the nervous system during corresponding stages of embryogenesis. In general. low-frequency waves reflect activity of subcortical structures, whereas high-frequency
waves reflect activity of cortical structures. Since radiation in the middle of the gestation period has more profound effects on subcortical than on cortical structures,the electro-physiological changes seem to be correlatedwith the morphological changes.

25. Electro-encephalograms and electro-corticograms
have been recorded in rats given 200 rads on thes~venteenth. nineteenth or twenty-first day of gestation. or on the third day post-natally. 24 Such prenatally irradiated animals when at rest exhibit a relatively high frequency of "spik-y" waves. This may be
attributed to impairment or absence of the outer corticallayers which are usually linked with the thalamus andwhich inhibit thalamic discharges. Amplitudes, both in
the electro-encephalogram and in the electro-corticogram.
are somewhat smaller than in normal animals. In the
exposed animals. auditory stimulation blocks less readilyt~e large-amplitude slow-wave activitv. Animals irradiated post-natally do not differ from· controls. On thewhole. the changes in electro-cortical activity are lessmarked than the structural damage. On the other hand,no electro-encephalographic abnormality has been observed two weeks after birth in rats that had received
100 rads nine days after conception. 25
26. The auditory threshold for sound-stimulated
seizures has been shown to be lowered in rats thatreceived x-ray doses of 25 to 100 rads between the fifteenth and the twentieth day of gestation, 26 whereas
doses of 5 to 15 rads did not change susceptibility.27
Studies with electro-convulsive shock have produced
results similar to those obtained with auditory stimulation. Rats which have received 100 rads on the fourteenth day of gestation show an earlier response and alowered threshold for shock-stimulated seizure. The
results may be ascribed to impairment of inhibitory
elements in subcortical areas.
27. Motor reflexes in rats are also affected by prenatal x irradiation. In animals irradiated on the tenthday of gestation. 20 rads are ineffective, but 100 rads
induce ataxia. In addition. righting reflexes are affectedin female animals, while males exhibit myoclonus. Bothmales and females that have received 185 rads on thefifteenth day of gestation show deficits in righting and.hopping reflexes, as well as ataxia, myoclonus, spasticity, seizures and other neurological motor defects.!! 8
Various locomotor tests have also demonstrated deficits
in animals receiving doses of SO rads or more prenatally and early post-natally.29 • 30 In general. thedeficit is directly related to the dose and. between
the fifteenth day of gestation and the first few postnatal days. is less pronounced the later the exposure.
Attempts to correlate the motor deficits with cerebellar
damage have yielded ambiguous results. 31 Tests ofmotor performance have involved non-motor nervous
activity, thus complicating the problem of finding simple
correlations between structure and function. It has
also been shown that fractionated daily exposure
throughout pregnancy ( 1 to 2 rad per day) reduces
locomotor activity.32
28. Different measurement techniques used by anumber of investigators have shown that rats receiving from 20 to 200 rads between the thirteenth dayof gestation and birth show hyperactivity when placedin novel environments.~ 3 • 33 •3 " Although the minimal
effective dose depends on the measurement techniqueused, it clearly varies with the age at the time of
exposure. \Vhen irradiated animals become familiar
with the situation. they do not differ from controls.
Hyperactivity is part of a general syndrome seen in
pre-natally irradiated rats and mice, which may be
defined as increased arousal by novel stimuli. It manifests itself in increased, non-directed. locomotor activity and slower specific response to novel stimuli, 34
more rapid conditioning in simple aversh·e situations.36• 37 increased heart-rate reactivity. 34 slower adaptation to food-and-water-deprivation schedules35 andslower adaptation to the en\'ironment.39
29. 'While most investigations reveal increased apprehensh·eness and restlessness in animals thus irradiated. negative findings have been reported after 150
rads on the thirteenth or fourteenth day of gestation.:;.1

30. Behavioural alterations in rats are also apparent from studies of brightness-discrimination learning which has been reported to be reduced at six
months of age after some 150 rads on the fourteenth
day of gestation and after 300 rads on the eighteenthday. 40 Likewise. olfactory discrimination is drastically72

36. In summary, even when gross structural malformations are absent. functional and behavioural disturbances. particularly of the ]earning processes. areconsistently seen after birth in animals exposed prenatally to high doses of radiation at an appropriate
time. These observations are not very surprising inview of the histological changes that high doses ofradiation consistently produce in the developing brain.
However. clear-cut correlations between the various
functional disturbances and morphological malformations
have not been established. Although there is extensive
literature on both structural disturbances and functional changes. few attempts have been made to integrate the two lines of research.

reduced in rats after 200 rads of x rays on the sixteenth
day of gestation:11 and distance discrimination after
100 rads.~ 2 Performance of visual pattern discriminations. on the other hand. appears to be unaffected by
150 to 200 rads. as tested on the thirteenth. fifteenth.
sevente~nth or nineteenth day of gestation despite themajor cyto-arch:tectural alterations present in the cortex:•

31. Alterations of maze performance after pre-natal
irradiation have been reported from a number of laboratories. Though most investigations show a deficient
response (as measured by learning time and the number of errors in selecting alternative routes) in ratsthat have received 100 rads or more during the second
and third week of gestation,4 3 • 44 as well as in rats irradiated during the first few days after birth, 45 there
have been observations33 of improved performance afterin utero exposure, particularly in females.

37. Though comparisons are difficult. conditioned
responses appear to be generally affected at doses lower
than those required to impair maze performance or
discrimination learning, although it should be pointed
out that not all indicators of conditioned reflex activity
always demonstrate deficits. It may also well be 52 that.
when the whole nervous system is challenged by a tasksuch as running a maze, the deficit of individual conditioned reflexes is virtually balanced by the intervention of alternative and still undamaged processes andpathways.

32. The effects of pre-natal irradiation on learning
processes are also shown by studies on the acquisitionand consolidation of conditioned reflexes. Most of theinvestigations used light and sound as stimuli for conditioning rats to perform a mechanical operation, suchas opening a gate. necessary to obtain food. 'While 200
racls on the fifth day after conception failed to produce
significant changes in the conditioned performance, 46
irradiation on the twelfth day altered significantly mostof the indices by which it was assessed. Thus. the consolidation of a negative conditioned reflex after the
positive one had been established was significantly accelerated after 50 rads. but delayed after 100 and 200
rads as compared with unirradiated controls. In general.' the alteration of the conditioned reflex activity
became greater with increasing dose:17

38. It is not clear whether the results of the animal
experiments can be extended to human situations. All
that these experiments show is that certain processes
which involve higher nervous activity may be affectedby pre-natal irradiation. In higher animals. including
man. similar effects may occur, but to what extent andat what doses these may impair the functional integrityof the individual can only be ascertained throughobservations in the species concerned.

33. Study of the conditioned reflexes at various ages
showed progressive deterioration of the refle.xes inanimals given SO and ISO rads on the fourteenth day
after conception. the impairment being more pronounced among more highly irradiated animals. 48 Similar observations were made on animals receiving 10rads per day during the first twenty days after conception.49

B.

EFFECTS I~ :MAN

1. Pre-natal irradiation
39. The literature records several scores of sporadic
observations of children with developmental anomalies
who had been exposed in utero, mostly unintentionally,in the course of therapeutic radiological procedures,
including, in a few cases. unsuccessful attempts at
terminating pregnancy. Though doses. as well as thesize of the populations at risk. are uncertain. useful
information on the type of defects produced and on
the critical period for irradiation during pre-natal life
can be derived from these findings.
40. The various reviews of the literature made in
the 1920s and 1930s largely overlapped each other.113-55
Additional cases were surveyed in a recent review.116
The most informative analysis of the published casesof pre-natal irradiation5i-59 compared the offspring of
women irradiated during pregnancy with the offspringof women irradiated before pregnancy. The latter group
comprised 417 live-born among whom three had developmental defects involving the nervous system (oneborn with exposed brain and two recorded as "microcephalic mongol" and ''hydrocephalic mongol", respectively). Among the seventy-five children of women
irradiated during pregnancy, eighteen were reported tobe microcephalic. four had other forms of severe disturbances of the central nervous system and one had developmental defects, mostly skeletal. involving the head.

34. Irradiation on the eighteenth day3:; at doses of
200 rads delayed the occurrence, but particularly the
consolidation, of both positive and negative conditioned
reflexes. The effect appeared to be larger. with reflexes
involving light than with those involving sound as aconditioning stimulus. Differences between controls andanimals treated with SO rads appeared to be smaller
and mostly non-significant.
35. Alteration of formation and consolidation of conditioned reflexes has been reported after a total doseof 20 rads fractionated ( 1 rad per day) over most of
pre-natal life.32 Effects have also been observed after
a single dose of 1 rad to the exteriorized uterus on theeighteenth day after conception:>o, ni in the course of ahighly complex experiment involving a number of different light and sound stimuli. Differences between
irradiated and control rats. as judged by some of theindicators of conditioned reflex activity, such as latent
period and intensity and duration of responses, were
small but significant. The experiment is the only one
showing effects at such a low dose level. Further investigations seem to be required before the functionalchange due to acute pre-natal exposure to very low
doses of radiation can be properly assessed.

41. The proportion of offspring with defects of thecentral nervous system was therefore far higher afterin utero than after pre-conception irradiation. \Vhile73

no microcephalics were observed in the group irradiatedbefore conception, nearly 80 per cent of the malformed
children irradiated in 11tcro were microcephalics. Oneof the microcephalic children was reported as "mongoloid" and most of them as ''idiots" or "imbeciles".
In most cases, microcephaly was associated with eye
troubles of various grades of severity. including twocases of amaurosis. 60
42. Detailed quantitative information is lacking. but
fcetal doses are believed to have been high in most ofthese cases. In many, doses were multiple. and in somethey were received over a period of time from intracavitary sources. The reasons for the irradiation wereusually unrelated to the pregnancy. which in most
instances was, in fact, unrecognized at the time of the
exposure. Among the microcephalic children, all but one
had been irradiated at least once between the secondand sixth month of intra-uterine life, the exception
having been irradiated during the first month only. 60
43. Because of sampling and other uncertainties,
these .early data have limited value. No quantitative
conclusion can be derived from them because doses,
although likely to have been high, are inadequately
known, but results strongly suggest that microcephaly
and mental retardation can be induced by fretal irradiation. Although the irradiations were carried out ona variety of medical indications, it is not possible
entirely to rule out an association between developmental defects and the conditions necessitating theirradiation.
44. The study of children acutely exposed whilein 11tero to the e.xplosions of Hiroshima and Nagasaki,
however, provides independent information on theeffects of pre-natal irradiation in man. This also is
not in itself unambiguous, since irradiation was associated with other physical traumas that might also
have contributed to the eventual effect.
45. Head size and mental retardation were firstrecorded at Xagasaki in 1951,61 subsequently at Hiroshima when the children were nine years old 6!? andagain at Nagasaki when the children were between
thirteen and fifteen years of age. 63 • 6 " The results ofsurveys made at seventeen and twenty years ofage65•67 have now become available. They include 1,613
children. or about 16 per cent of all the live-born inboth cities that were tn utero at the time of bombing.
46. The survey carried out at seventeen years ofage indicated65 that, in both cities and in both sexes,
mean head circumferences were significantly smaller (byabout 1 centimetre or 2 per cent) in the offspring of
those that were within 1.5 kilometres of the hypocentre.
Dependence of the effect on the age of the fcetus at
the time of irradiation was not clearly apparent.
47. The same survey also investigatecl 00 the prevalence of mental retardation. which was diagnosed only
if a subject was unable to perform simple calculations.
to make simple com·ersation. to care for himself or if
he was completely unmanageable or had been institutionalized. The results of the survev are shown intables I and Il,h indicating a striking relationshipb The Xagasaki data in tables I and II differ in two respects
from those originally published: (a) comparison with othersources indicates that. at Naga~aki, a case of mental retardationthat was assigned a distance of 1.7 kilometres actually belonged
to. the proximal group, as shown in the present tables; (b) the
onginal tables were inconsistent with each other with regard totl~e total number oi indh·iduals exposed in the proximal and?1stal groups at :Nagasaki. This inconsistency has been removed
m tlae present tabulation. GS

between prevalence, on the one hand, and both distancefrom the hypocentre and the age of the foetus at thetime of irradiation. on the other. The tables do notcontain data on the offspring of women between 2.0
and 3.0 kilometres from the hypocentre. as these were
not included in the sun•ey.
48. It is remarkable that, in both cities, all cases ofmental retardation within two kilometres from the hypocentre were born between November 1945 and March
1946, corresponding to exposure between the sixth andthe twenty-fourth week of pregnancy, with a peak frequency at thirteen weeks in the proximal group and at
fourteen weeks in the distal one. whereas the few cases
beyond 3.0 kilometres were randomly distributed withrespect to the time of explosions. It must be added that,as indicated in table II. a few (so-called "explained'')cases of mental retardation were associated with diseases
that might themselves have caused retardation.
49. Comparing (table II) the distal group ( 1.5 to
2.0 kilometres) with the combined controls (subjects
beyond 3.0 kilometres or not in the city at the timeof bombing) born during the period November 1945
to March 1946, it appears that the prevalence of mental
retardation in the distal group at Hiroshima is about
2 per cent, which is higher than that in the control
populations, although the difference is of doubtful statistical significance." No cases of mental retardation
were reported in the distal group at Nagasaki.
50. A sun·ey 67 made at Hiroshima twenty years
after the bombings includes further details on cases
appearing in the surveys above. It contains additional
tabulations on the relations between distance, head size.
period of gestation and mental retardation (tables III
and IV). It is interesting to note that. while the resultsof the survey largely bear out the observations madeten years earlier, two subjects considered retarded in
the survey at ten years of age 6!? were not so consideredat twenty years, and two that were considered normal atten years proved to be mentally retarded subsequently.
51. Evidence from the survivors of the bombings
does not rule out the possibilities mentioned earlier thatthe observations might, in part, be the results of trauma
due to blast or fire. but the Committee is not awareof other reports concerning mental retardation or microcephaly attributed to these or other calamities. It ~lso·seems impracticable to attempt to evaluate the possible
role of nutritional deficiencies in this situation.
52. Based on the tabulations in tables I to IV.
there seems little reason to doubt that. at some critical
period during gestation, doses such as were received
in the proximal areas (presumably of the order of
100 rad or more) are associated with an increased
incidence of reduced head size and of mental retardation. Based on currently available estimates of air
doses in the two cities, 69 rough calculations can bemade as to the relationship between incidence anddose at high doses. These calculations suggest that thefrequency of mental retardation w1th reduced headsize is of the order of 10 per cent per hundred rads
(10-3 per rad).
e \\'hen "explained'' cases are excluded, the prevalence in the
distal group at Hiroshima is about nine times that in the Hiroshima controls born during the same five-month inten·al (comprising three ca;es of mental retardation :m1ong 171 e..'i:posed
as against one among 532 controls), but the ratio is reduced to
betwee:1 three and four if controls are broadened to include
those in both cities, regardless of month of birth, "explained"
cases still being excluded.

7453. Similar calculations based on data from the
distal groups mentioned in paragraph 49 might indicate
a similar magnitude of effect. but no firm conclusions
indicating possible effects of low doses can be drawn
from this information. In this instance. the observed
frequencies are small and therefore exposed to widesampling fluctuations. and any conclusions are also
particularly susceptible to other difficulties common toepidemiological sun,eys.
5-1-. The prevalences of mental retardation shown by
the surveys are not to be read as true rates of induction without further qualifications. They are frequencies
observed among conceptuses that have survived intrauterine life and early childhood until they wererecorded in surveys. For further enlightenment on thispoint. the results of surveys of mortality in live-born
children who were in 11tero at the time of bombing6 i, 70
and early data from N agasaki 01 giving information on
fretal mortality in relation to distance have been consulted. The evidence available from these sources indicatesthat ignoring fcetal mortality does not entail an overor underestimate of the rate of induction by morethan 25 per cent in the proximal group and that it
induces no bias in the distal group. There is only asuggestion of a higher mortality among retarded children with reduced head size at Hiroshima than among
controls. but certainly no more than a minor correction in prevalence rates would seem to be indicated.
55. Recent data 68 have been supplied to the Committee, which take into account actual estimates ofdosesd to the individuals shown in tables I and II.
This information is given according to dosage groups,
but not according to month of birth, and is presented
in table V.
56. From this tabulation, there appears to be no
significant difference between. the incidences of thecontrol groups and those of the groups receiving low
doses. that is, less than 50 rads. As shown in columns
A and B of table V. the three groups receiving higher
doses show significantly increased incidences with increasing dose (up to 36 per cent in those receiving
doses higher than 200 rad). In view of the small
numbers of affected individuals in the various groups
and of differences in the quality of t11e radiations
received in the two cities, it does not seem reasonable
to attempt to estimate the form of the relation between
dose and incidence. In so far as the derived percentages
indicate significant differences between control andirradiated groups. the relation between dose and frequency is comparable to that derived from cruder datain paragraph 52. It may be noted that three of thefour cases in the distal group fell into the lowest
dosage category and were so located that they could
not have received more than 5 rads.
57. It is of interest to compare these observations
with those on leukcemia induction rates during a
twelve-year period ( 1947-1958) among the survivorsof post-natal irradiation at all ages in the two cities.71
These figures are given in table VI. On the other hand.
mortality and morbidity surveys at Hiroshima andNagasaki have failed to show any increased prevalenceof leukremiai2 or neoplasms, 73 even among the groups
more heavily irradiated in utero, in striking contrast
with the rise in mental retardation and reduced headsize observed even in lightly exposed groups. Such a
discrepancy is unlikely to be accounted for by differd The doses given include estimated contributions from both
gamma rays and neutrons. These were added without weighting.

75

ences in the resolving power of the various surveys
and suggests that. under conditions of single shortterm irradiation between the sixth and the t\ventyfourth week of pregnancy. the risk of mental retardation is much higher than the risk of leukremia being
induced by radiation at any time during pre-natal life.
58. This conclusion is not disproved by the negative evidence from surveys designed for other purposes. 74• 7 " which have not shown any excess of mentally retarded among children exposed in utero for
medical reasons. Though these surveys have involved
sizable samples, only a small fraction of the children
were irradiated during the critical time for the induction of mental retardation. most of the cases having
been e..xposed during the last four months of pregnancy.
Even if, at the low doses that were presumablyreceived. the rate of induction had been that suggestedby the Hiroshima data. the e..xpected excess of retarded
children would have been too small for detection.
In the present conte.."\:t, therefore, these surveys merely
confirm that mental retardation is not induced byradiation during the last stage of gestation.
59. It may be emphasized that theoretical considerations are of little help in suggesting what sortof relationship may exist between dose and incidence ofmental retardation, since the mechanism by which itis brought about is almost wholly unknown. It might
be supposed that both mental retardation and microcephaly. when due to pre-natal irradiation. reflect
destruction and disturbance of the arrangement oflarge numbers of cells in the cortex, and hence theproportions of affected individuals might not be
amenable to the same relatively simple types of formulation that have been used to relate dose and effect insuch cases as genetic and cywgenetic damage. Also,
since the distributions of head size and intelligenceare continuous, the sorting out of individuals into thoseaffected and those unaffected requires choice of anarbitrary cut-off point as the criterion of damage.

60. Since there is doubt about the magnitude ofthe e..xpected incidence of mental retardation at doses
below those received by the proximal group at Hiroshima. it 'Nill be important to confinn or disprove,on subjects other than atom bomb survivors. the existence or degree of radiation induction of mental
retardation during early pregnancy. Sufficiently large
suneys of the offspring of ...vomen irradiated at low
doses during pregnancy may disclose an excess of inutero exposure among certain categories of retarded
children. On the other hand, no effort should be spared
to secure all the additional information that can bee..'{!racted from the survivors of the bombings.
61. i\ilental retardation is not the only serious effectin the nervous tissue that is associated. with pre-natal
irradiation. Increased frequency of in utero irradiation
for medical reasons among children dying of malignancies of the nervous system compared to controls has
been observed in two surveys. Both were retrospective,
but one76 relied on the memorv of the mothers ofthe deceased children . whereas ·the other 77 took advantage of information from hospital records. The
observed excess in the latter survey indicates that theincidence of malignancies of the nervous system isabout 40 per cent higher among irradiated children
than among those that were not irradiated-a relativerisk close to that observed for Ieukremias in the same
survey.

62. As with all medical surveys. the possibility
cannot be excluded that the increased radiation risks
may be, at least in part, spurious, since there is no
way to separate the effect of radiation as such fromthat of the maternal condition that may have prompted
the exposure. Average doses to the fcetuses are unkno"-'"11 but are unlikely to have been higher than 5rads. Because the sun'eys are retrospecth·e, rates of
induction cannot be given in absolute terms without
making assumptions with regard to the prevalence of
nervous tissue neoplasms among non-irradiated children. Information is insufficient to ascertain the critical
period for the induction of nervous tissue malignancies.
63. No excess of these malignancies has been reported in subjects irradiated in utero at Hiroshima
and Nagasaki. 70 The number of subjects so e..xposed
was too small. however. for increases of tumours of
the nervous system to have been detected in those
populations. unless the rates of induction had beenmuch higher than the surveys previously referred tosuggest.
2. Irradiation during childhood
64. Irradiation of children during the first years oflife has been reported to result in a number of functional effects.' 8 Thus, deep somnolence lasting for up
to fourteen days and arising from six to eight weeks
after irradiation of the scalp for epilation purposes (70kVp x rays, 5 mA. 0.5 mm Al. 26 cm focal distance,
13 min exposure) was observed in thirty among 1, 100
children so treated. 79
65. Im·estigations 80 of another group of children
treated with high cumulative doses (up to several
kilorads) for hcemangiomas and for various neoplastic
conditions between birth and thirteen years of age
showed a high frequency of functional changes thatwere observed two to seven years after irradiation.
Seventy children underwent electro-encephalographic
tests which showed local or generalized alterations in
fifty cases. These alterations consisted of a general reduction of amplitude of the bio-electric activity of thebrain and, in fifteen patients. of rhythm changes in theelectro-encephalogram. Locally, those alterations weremore pronounced when irradiation had been localized
to part of the brain. Bradycardia and hypotension were
present in 50 per cent of the children that had received
irradiation to the head alone. Similar incidences werereported by other authors. 81 · 8 ~66. Despite their intrinsic interest, the value of allthese investigations is limited by the absence of controls which makes it impossible to separate the effectsof irradiation from those of the disease for which thetreatment had been applied.
67. Increased incidence of tumours of the nen'ous
system within the radiation field (three neurilemmomas.
one neurogenic sarcoma and one tumour of basal
ganglion in 36,000 man-years. against one astrocytoma
and one brain tumour of unspecified type in 54,000
man-years untreated sibs), has been reported among
subjects irradiated in early infancy for thymic enlargement and followed up for an average period of twentythree years. 83 • S-! In this population, the highest excess
of malignancies is in respect to carcinomata of the
thyroid (nineteen cases against none in controls) as aconsequence of the direct exposure of the gland to the
x-ray beam and with regard to leukcemias (six among
irradiated children and two among controls). The

excess of tumours of the nenrous system is significant,but the pertinent dosimetry is unknown so that it is notpossible to compare even crudely their rate of induction
with that of the other types of malignancies. A similar
survey of children irradiated between eight and elevenyears of age and followed up until the aYerage age oftwenty-two years has shown a non-significant e.."cess ofbrain tumours among them (two in about 17,000 manyears) as compared to their untreated siblings (twoin 58.000 man-years).85
68. Other evidence for the induction of tumours of
the nervous tissue by radiation is prodded by a surveyof children whose scalps were irradiated for depilatory
purposes in the treatment of ringworm infection. 86 • s•
Most of the brain was estimated to have received doses
within 20 per cent of 140 rads.ss The age at irradiation
was about seven years, and the follow-up time wasaround fifteen years. A group of children with ringworm, who had been treated at the same time bv meansother than radiation. sen·ed as controls. The twogroups appeared to be comparable with regard to sex.
race and family income distribution. Microsporum
lanos1111z, however. was comparatively more frequent incontrols than among irradiated children.
69. Three confirmed brain tumours (two astrocytomas and one malignant glioma) were reported among
the irradiated (approximately 30.000 man-years). as
against none in the control group (approximately
20,000 man-years). \Vith the doses mentioned in theprevious paragraph, this would correspond to a yieldover a period of some fifteen years of about ten cases
per rad per million exposed. if proportionality of doseand incidence were assumed. Other malignancies also
were obsen,ed among the irradiated subjects including
four cases of leukremia, or roughly the number expected for adults from the man-years at risk and themean marrow dose (about SO rad) that is obtained byaveraging over the whole bone marrow the dose received by the bone marrow contained in the skull.
70. The induction of nervous tissue malignancies byirradiation is therefore suggested by three surveys ofirradiated children. Data are still too scanty to permit
a reliable estimate of the rate of induction per rad forany given radiation exposure, though at least the survey
referred to in the previous paragraph suggests that, at
a dose between 70 and 175 rads. the rate is likelv to
be of the same order as that of leuk~mia inductio-n in
the adult.
71. The same survey also reveals a significant excess
of confirmed cases of mental disorders among theirradiated, the over-all incidence being 2.5 times higher
than in controls. Mental disorders include personality
disorders (eighteen irradiated cases, three controls),
psychoneuroses (twenty-five irradiated, six controls)
and psychoses (twenty-one irradiated, nine controls).
the latter all invoh·ing schizophrenia. with a higher
relative prevalence of the paranoid type among theirradiated than is obserYed among controls.
72. These observations are of the highest interest
but must be taken with a great amount of caution.
The incidence of mental disturbances is notoriously
affected by a number of social, environmental andgenetic factors that are difficult to allow for. In thesurvey under review. only race and the income bracketof the subjects have been considered. It would appear
that a very close analysis of further variables is required before final judgement on the results with76

regard to the induction of mental disorders can beformed. Such an analysis is in progress. 89 The resultsof a similar. but larger, survey currently under way 90
may also be useful in clarifying the issue.
III.

Effects on the adult organism

A. CEXTRAL NERVOUS SYSTE~I

cerebral and the cerebeliar co:-tex. The changes, ingeneral, were those of a vascular permeability disturbance. They were similar to the changes found in control cases of aplastic amemia. To what extent brainchanges were directly induced by radiation and to what
extent they were abscopally determined thus remains
problematic.
78. In ten patients Sltrvh·ing accidental gamma andneutron irradiation (average body dose 500 to 600
rad. average head dose 800 to 1,000 rad) cerebral andmeningeal signs. as well as changes in the ocular
fundus. were seen soon after the irradiation. 104 In
another accident involving one person. gamma irradiation of the abdominal and lumbar regions and of theleft thigh >vas massive. doses in the lumbar reg-ion of
the spinal cord having been estimated at 3 to ~5 kilorads.104· 10 " The observed clinical signs of cord damage
could be correlated with findings seen at autopsy eighteen days after the accident. There was severe oedemaof the lumbar segments of the cord with occlusion of
the spinal canal and severe degenerative alterations inneurons of the anterior and posterior horns as wells
as in the fibres of the spinal cord.

1. Tltc central nervous system radiation syndrome

73. The radiation dose needed to induce dramatk
early neurological disturbances in adult animals, withthe exception of the burro. 01 is much larger than thedose needed to cause gastro-intestinal or haematopoietic
death. The so-called central nervous system radiation
syndrome, ,vhere death within one to three days isdue to irradiation of the head alone or to the wholebody. requires. in the mouse for instance, doses of theorder of 10 kilorads. 92
74. In guinea pigs receiving 25 kilorads to thewhole body, initial depression of motor activity isfollowed by enhanced motor activity and by extensor
rigidity. 93 • 94 In whole-body irradiation of hamsters
with 8 kilorads. disturbances of equilibrium develop
quickly. but seizures do not occur. 94 In dogs, only
lethargy after whole-body exposure to 10 kilorads isseen, 95 whereas burros become aggressive. 96 In rabbits
receiving 4 to 9 kilorads to the head only, a two-phase
syndrome consists of initial apathy. which is doseindependent in the range studied, followed within
hours by ataxia. posture disturbance and epileptiform
seizures. 97 The second phase is strongly dose-dependentand has been reported to show a threshold of about
6 kilorads (however, see paragraph 102).

2. Structural changes(a) Cellular and subcellular changes

79. 'When special methods are used, structural
alterations in cellular components of the brain arecommonly seen at doses of 100 rads or more. A few
general, mainly qualitative. remarks regarding cellular
reactions are pertinent here.
80. The neurons of the adult are stable amitotic
cells, as shown by their inability to incorporate radioactive precursors into their DNA. 106• l07 In general,they have a high intrinsic resistance to radiation.
A dose in excess of 250 1-d.lorads is required to destroy
the nerve cells of the cerebral cortex of the mousewithin thirty days after irradiation by a beam ofdeuterons 25 micrometres in diameter.10 s. 109 A fieldof this size contains relatively few blood vessels sothat the effects may be more directly related to neuronaldamage. Alpha-particle irradiation of a large field of
the cerebral corte..x of the rat in a peak dose of 15
kilorads destroys nerve cells within sixty days." 0
The greater effectiveness of the radiation under thelatter conditions is probably due to the supplemental
factor of tissue ischremia brought about by altered
blood flow in the transirradiated blood vessels.'111
Species differences in vulnerability e..-xist. Granule cellsof the cerebellar corte.x become necrotic within a day
or two at 5 kilorads in the mouse.112 but not in monke,;sin the same period at a larger dose given to a 'vider
field. os, 113

75. In monkeys. severe neurological signs and deathin the central nervous syndrome are seen within twodays after ·whole-body doses of about 10 kilorads. 98
Doses between 2.5 and 30 kilorads usually give riseto an early hypere..xcitability followed by an earlytransient incapacitation. 98• 99 Partial recovery, the duration of which is inversely related to dose, follows thisearly incapacitation. Subsequently and abruptly. aphase of permanent complete incapacitation sets in. No
partial recovery is seen after 50 kilorads, and permanent incapacitation within 30 seconds is seen in nearly
all animals at 100 kilorads. 90
76. One case of radiation accident in 1958 has
shown. after an estimated head dose of about 10 kilorads of mixed gamma neutron (2 :1) radiation, clinicalsymptoms primarily associated with damage to thecentral nervous system.100 The course, from exposure
to death, lasted thirty-five hours. The sequence ofclinical signs and symptoms fell within the pattern
predicted on the basis of animal experiments. The
main neuropathological finding in the brain was asevere oedematous condition. 101
77. Extensive studies102 • 103 were made of the brainsof forty-nine Hiroshima and Nagasaki casualties \vho
died between sixteen days and six years after thebombing. J\Iental and neurological disturbances werenoted in several of these patients. No correlation between these disturbances and distance from the hypocentre could be found. All casualties showed signs ofacute radiation sickness. and all became severely anaemic.
Pathological changes varied from mild to pronounced
and consisted predominantly of hremorrhages and perivascular neuroglial nodules. In some cases. foci ofnerve cell destruction of varied size were found in the

81. Glial cells are. in general, far more radiovulnerable than nerve cells, 'vhether cell death or structural changes are taken as an end-point. Astrocytes
respond within two days, by glycogen deposition, at
a dose as low as 500 to 600 rads. 114"116 This is probablya reflection of reduced aerobic metabolism of the brain
tissue. 117 As revealed by metallic staining, astrocytes
may become hypertrophic within three weeks orlonger after doses of 100 rads or more. 118 tl1is being areflection of altered vascular permeability to proteins.
Oligodendroglial cells,. associated with the myelination
process, undergo acute swelling or hypertrophy also
in a wide dose range. In rats and mice.. but not inother animals investigated, these cells may selectively
77

dose. 15 krad). 136 In another study on the cerebral
cortex (guinea pig), the capillary endothelium wasfound unaltered although adjacent cells were necrotic(surface dose of alpha particles, 20 krad) .137 In a
study of the cerebellar corte..x (guinea pig). vessels
appeared spared. yet tissue cells were severely damaged(gamma-ray doses, 1-2 krad).12!?

undergo necrosis after an x-ray dose of 150 to 200
rads.11 9 • 120 Microg/ial cells become activated, andblood-borne lymphoid cells may enter irradiated brain
tissue at doses of 100 rads upward. 118 Subependymal
glial cells become necrotic at doses of 150 to 250 radsin rodents, 119 • 120 but not in monkey or man. 111
82. Blood vessels also are relatively radio-vulnerable.
Tiny vesicles found in endothelial cells within one
hour after x irradiation at doses of 100 rads or moreare probably a morphological expression of alteredvascular permeability. The response, which can be seen
also in pericytes, is reversible at doses up to 500
rads. 121 ·1:!2 The time period at which altered vascularpermeability commences varies with the species. At agiven dose of high-energy alpha particles the bloodvessels in the brain of the monkey show a much earlier
increase in permeability to sodium fluorescein than dothe vessels of the rabbit. and the vessels of the rabbit
a much earlier increase than do those of the rat. 123
In the rat. it has been shown that vessels suffer first(in the form of circulatory stasis, followed by leakageof trypan blue) and that necrosis occurs in nerve cells
afterwards (10-20 krad, >185 MeV protons).121
Support of the view that nerve-cell damage is vasculardependent comes also from the observation that diapedetic hremorrhages in the diencephalon precede nerve
cell alterations after x-ray doses of 20 kilorads.m
The distribution of damaged nerve cells in the irradiated cerebral corte.x occasionally assumes a laminarpattern, which has been taken as evidence of inadequacy of the circulation to meet local needs. Sucha pattern has been noted in the rat following 50-rad
fractions given once a week up to a total of 250 rads. 126
83. Effects of radiation on neuronal ribonucleic
acid (RNA) at low doses 127 and their possible relation to functional alteration are of interest because theformation of RNA in nerve cells may be related tomental acthdtyP 8 • 129(b) Histological and 1·elated metabolic changes. 87. Depending on radiation quality. dose and fieldsize, structural alterations of the nervous system may
appear as acute effects within hours or davs after
irradiation and may involve varying patterns of
exudative phenomena, glial cell hypertrophy and celland tissue necrosis. Large-field irradiation ot the brain
can even result in rapid tissue necrosis. as has been
obsen·ed within a few days following doses of 7 kilorads (23 l'vieV x rays) or more.1ss. 139
88. \Vhen equal doses are absorbed. whole-body
irradiation is more effective than head-alone irradiation in bringing about certain changes in the brain,
greater depression of RNA labelling in the cytoplasmof nerve cells in the brain (at 500 rad) .Ho greater
water increase in the brain tissue in certain areas (at100 rad) 141 and greater reduction in alkaline phosphatase in vessel walls and brain tissue (at 10 krad).H2(c)

Late (delayed) effects of irradiation

89. Experiments with implanted seeds containing
radio-nuclicles have provided information on the effectsof continuous irradiation. For example, after intracerebral application of gold-198 or yttrium-90 in dogs,
necrosis developed within the range of the beta radiation after a period of three to six days corresponding
to a cumulative dose of 10 to 20 kilorads. 143·H5
90. The evolution of the late reaction in the brain
and spinal cord varies widely. 111 •143 •154 In monkeys.
late tissue necrosis has been observed at doses of 624
rads (2 MeV x rays), 118 800 rads (14 MeV fastneutrons, 55 MeV protons)lll·155 and LSOO rads (250kV x rays, 23 :MeV x rays).15 6-159 In man. the smallest
x-ray dose known to have produced late tissue necrosis
is 1.250 rads; in this case, exposure was through multiple ports at intervals over a twelve-hour period. 160
The observation in experimental animals. that latency
for the development of late necrosis is inversely
related to dose and volume irradiated. 101 • 162 finds
many exceptions in patients given fractionated irradiation. A fractionated dose which, in man, usuallycauses necrosis within three to twelve months may, inother cases, not result in necrosis until after a lapseof five to eight years. 15::?, 163. 164

84. Differing radio-vulnerability exists for various
subcellular structures. It has been found that, in spinal
ganglia, karyosomes suffer first. then the endoplasmic
reticulum (20 krad, 185 :r-iieV protons). 180 Labelling
techniques have shown that radiation effects on interphasic cells include conspicuous interference with theformation of RNA, a DNA-dependent process.131· 133
Interphase cell death has also been connected withdirect radiation damage of cytoplasmic organelles. inparticular of the mitochondrion (the self-replicatingorganelle involved in cellular energy metabolism) andof the lysosome from which destructive hydrolases may
be liberated after membrane damage. 131
85. The dose-survival relationships in nerve cells
are highly complex. This is illustrated. for example.
by a study of retinal cells in mice irradiated between
four and ninety days of age. 134• 135 As the visual cells
undergo maturation. the survival function changes
from a simple exponential to highly complex cun·eswith high extrapolation numbers (> 1.000) andwide initial shoulders.

91. Late necrosis of brain or spinal cord tissue
sometimes occurs in human subjects gi-.;en fractionatedradio-therapy for intracranial or e.xtracranial tumoursor other conditions. The suggested lowest fractionatedx-ray dose (field size. 100 ei-n 2 ) that may produce
cerebral necrosis in adults has been estimated to be.
for example, 3,300 rads given in 10 days and 5,200
rads given in 50 days. 165 Late radio-necrosis of thelower brain stem and upper spinal cord following
transirradiation of these parts of the nervous system
for tumour in the cervical region may occur. forexample. within one year after 5 kilorads given in
se\'enteen days. 166 • 167

86. Electron microscopic observations have shownthat the relative vulnerability of yessels, comparedwith that of the astrocytes. varies. In one study on
the cerebral cortex (hamster), capillary damage wasconsidered the initial event, mainly on the basis that
oedematous swelling became apparent in astrocytes before changes could be found in endothelial cells. implying a vasculo-astroglial permeability defect (x-ray

7892. Since there are many kinds of late radionecrosis, ic is likely that pathogenesis varies. Increasing oxi-reductase acti,·ity in astrocytes. increasing
mitotic activity in vascular endothelial cells and oligodendrocytes and increasing cell population may. it has
been contended, contribute in various ways to a progressive metabolic deficiency which may terminate intissue necrosis. 1 " 3 On the other hand, the close spatial
relationship of incipient parenchymal lesions to alteredyessels has been taken as eYidence of a primary roleof circulatory and vascular disturbances in tissue
breakdown. 168 Long-term electron microscopy observations of the cerebral cortex of rabbits receiving 2,500
roentgens of x or gamma rays haYe revealed ultrastructural changes in virtually all cellular elements but
no tissue necrosis. 169 This suggests that some additional factor is responsible for the necrosis. Circulatory
disturbances reaching a certain threshold incompetence
may be that factor.
(d)tion of myelin occurs in axons demyelinated bv laraedose irradiation.170 •17s"'
97. In human subjects whose spinal cords hanbeen irradiated in the course of radiation therapy fortumours of other organs. the damage that occasionally occurs in the cord following exposure above "tolerrance ''doses is usually irreversible. That in some instances
the pathological process might be reversible is suggested,hm,·eyer. bv certain clinical obsen-ations. 166 • m i\ eurological sig1is and symptoms consistent with radiation
damage of the spinal cord have developed in suchcases but have later vanished: the clinical disturbances
have appeared after an average latent interval of fourmonths. following radiation doses of 2.600 to 4,200
rads to the cord delivered in forty-six to 100 days.
Autopsy in two cases of this kind has revealed noevident histological change. 17 9
98. \Vhen adult nervous tissue is in a process of
reparative cellular proliferation. decreased resistanceto radiation should be expected. This has been experimentally verified by studying DNA synthesis in
the regenerating hypoglossal nucleus of the rabbit
after crushing the hypoglossal neffe. 180 DNA-synthesizing neuroglia and endothelial cells are decreasedin number hy more than 50 per cent from twentyfour to forty-eight hours after 100 rads of 200 kV
x rays, although no changes are observed in the retrograde reaction of nerve cells or in astrocytes.

Repair

93. Dose-rate studies have gh-en an indication that
reparative processes may occur during the period of
irradiation. Oligodendrocytes (in rats) are more
severely altered when the brain receives x-ray dosesof 3 kilorads at 600 rads per minute than at 150 rads
per minute. 170 Granule cells of the cerebellum (inmice and rats) become necrotic at a dose of 1 kilorad if gh·en at 1 kilorad per minute but not at 100
rads per minute.171

3. Functional effects
99. In this section, only those effects are consideredwhich either occur according to a delayed time schedule
or involve a permanent change. suggesting that compensatory or reparatory processes may be involved.
100. In rats, studies of electro-encephalographic
patterns after whole-body x irradiation (700 rad) revealed characteristic modifications up to ten days after
exposure. 1 8 1 At three to twelve hours after irradiation.
there was a significant decrease in both "high'' (15 to
30 cps) and ''low., ( 1.5 to 7 cps) frequency electricalactivitv. Within the next two to three days. therecordings were nearly normal. In the subsequent fourto ten-day period, only the low frequency component
decreased below the control level. The early changeof frequency seems to correspond in time with a peri?dof conditioned reflex depression found in another 111vestigation after head-alone irradiation. 182 The latterdecrease similarly coincided in time with the conditioned reflex depression that occurred in1mediately
before and during acute radiation sickness.
101. The electrical activity of the prepyriform cortexof the rat brain was studied after x-ray whole-bodycloses of 250 and SOO rads. The animals presented anincreased amplitude and slightly decreased frequency
in the spontaneous electrical activity, as well as shorter
latency of evoked potentials. :rhese ch~nges occurred
for the duration of the experiment (thirty-five days)at the higher dose but only during the first few days
at 250 rads. 183 • ins
102. In rabbits, a slowing of the frequency of theslow-wave component of the electro-encephalogramwith a concomitant rise of the amplitude was seen
after doses of 100 to 400 rads. 18! A whole-body gamma
dose of 400 rads gave rise to trains of slow waves(I to 4 cps) that appeared to originate from the hippocampus and from there to spread to the whole co~tex.
occasionally accompanied by spike activity. 209 Ep1lep-

94. That nerve cells can undergo repair shortly
after irradiation is inferred from electron-microscopic
studies in seriallv sacrified animals. Nerve cell damage
evident in anim~ls sacrificed within a few hours may
not be found a day later in other animals. This applies.
for example, to cerebral cortical cells (3.5 krad)1 72
and hypothalamic cells ( 5 krad) .173 Biochemical
studies also indicate that repair is possible. If damageof nerve cells is limited to the level of biochemical
disturbances, the cells have the potential for recovery.
In rabbits exposed to 2 to 3 kiloroentgens of x rays,
nerve cells removed from the brain stem and studiedin vitro showed increased cell mass, potassium excess.
increased RNA content and succinoxidase activitv.1' 4
By the twenty-fifth day, repair following 3 kiloroentgens was apparently achieved. A tritiatecl thymidine
study of the rat spinal cord showed that the processof repair runs its course in a maximum of about two
weeks.167
95. The capacity of different kinds of nerve cells
to undergo repair varies. Following irradiation.
cerebellar Purkinje cells incorporate tritiated leucine
in proteins at an accelerated rate in twenty-four hours.
while granule cells take up none at all. suggestingthat Purkinje cells, as opposed to granule cells. arecapable of repairing or compensating the initialmolecular damage by stepping up synthesis.175
96. Increased synthesis of RNA and protein inneurons and glia may be closely related to regrowthof damaged or interrupted a.'Cons and dendrites. In
the rat, starting at about two weeks after irradiationof the cortex at doses capable of destroying individual
cellular elements, axons grow in great abundance into
areas of cell depletion. These axons become myelinated, but the role of oligodendroglial cells in thisprocess has not been established. i.\foreover. regenera-

79

toid seizures in rabbits were seen in some cases after
doses of 400 rads or more. 185
103. The hippocampus appears to be the brain
structure giving the strongest electro-physiologicalresponse to whole-body or head-alone irradiation.186 • is 7
Spontaneous hippocampal spike activity has been seen
for at least a few hours after 100 rads (possibly after
25 rad also) o:- more in rabbits that did not show
spike activity prior to irradiation. 188
104. In addition to recording the continuous electrical activity of the cerebral cortex. electrical changes
evoked by stimulation of sense organs or of some point
along the ascending pathways to the cerebral corte..x
have also been studied. Thus, in rabbits, gamma irradiation ( 400 or 1.200 R) brought about changes in theelectrical activity of the visual nervous system (retina,
lateral geniculate body. optic cortex) which seem tobe related to dose. 189-191
105. In monkeys. acute whole-body exposure with
400 to 800 roentgens of 250 kV x rays failed to produce significant changes in electro-encephalographic
patterns until near death. 192 Head doses of 4.S or 6
kilorads, however. resulted in general slowing of wave
frequency and increase in amplitude within the firstday after exposure, in some cases with patterns of
spih.-ing reminiscent of grand ma! seizures. 103 At thesame time, apathy and asthenia set in. followed bypoor co-ordination, loss of the pupillary light reflex
and myoclonic twitches and seizures.
106. A detailed analysis of the spontaneous andlight-stimulated electrical activity of the brain asrecorded by the electro-encephalogram was made in
twenty-one medically irradiated individuals. 194 Regardless of whether the whole body. the head or otherparts of the body had been irradiated. changes wererecorded both immediately after the termination ofirradiation and later. Generally, depression of bothspontaneous and evoked activity was seen both after
the first irradiation and during the course of repeatedradio-therapy (150 R twice a week or, in one case,
200 R daily. up to a total of 300 to 2.000 R). PersisteHce of the alpha waves was accompanied by depression of other electrical activity.
107. Studies of the threshold for the induction ofelectro-shock seizures in irradiated rats provide further
evidence that irradiation gives rise to changes incortical processes. 196 • 197 The threshold for the seizure
decreased after x-ray doses of 450 and 9SO rads whetherdelivered to the whole body, to the head alone or to
the body alone. This has also been seen after doses of
500 and 10,000 rads of 50 Me V protons to the head.
After x-ray exposure. the threshold drop persisted fora period of two to four weeks depending on dose in
the group receiving body-alone irradiation, but for six
months after irradiation involving either the headalone or the whole body. "'ithin the dose range e..xplored. proton irradiation produced similar drops
which lasted until the death of the animals or the endof the experiments (two months in this case). The
duration of the clonus was drastically and lastingly
reduced after 5 and 10 kilorads of protons. whereas
lower doses only produced small and transitory changes.

flash as conditional stimulus disappeared199 completely
fifteen to twenty minutes after a whole-body exposureof SOO roentgens ( 180 kV, 0.5 mm Cu
1.0 mm AI.
70 cm) . This ·was accompanied by the pronounced
weakening of the electric activity that usually accompanies the conditioned reflex. The depression of theconditioned reflex lasted from three to seven days, but
its recovery was not complete as the responses of theanimals remained unpredictable. A similar response
was elicited by irradiation of the head alone. In dogs,
single and fractionated whole-body exposures of 100
to 190 roentgens caused a temporary reduction of theintensity of the conditioned reflexes. 520• 20 2-2oa+

109. At doses much lower than the lethal range
for whole-body irradiation. reports are conflicting.
The most severe but temporary disturbances are foundwhen complex sequences of interacting conditioned
reflexes are used. such as those requiring differentiation between stimuli of different type or different
strength. 192 Thus. in dogs, serial conditioned motorreflexes were only slightly depressed for a period of
two to iour months after whole-body doses of 30 to 40
rads and subsequently returned to normal. 204 On theother hand. in dogs given 10 to SO rads to the parietal
region, the intensity of conditioned salivary reflexes
increased at the same time as disturbances of the internal inhibitory processes of the cerebral cortex
occurred. 205 In another study, 206 no changes of theconditioned salivary reflexes of dogs receiving for thirtyseven weeks weekly whole-body doses of t11e order of
20 rads were observed. In this investigation, however,
only positive conditioned reflexes were e..xplored, andthe authors did not exclude the possibility that a more
complicated situation involving discrimination of stimulus patterns and their temporal relationships might haverevealed effects not seen in simple conditioning.
110. Contrary to what is seen in conditioning
experiments, studies of learning and discrimination
carried out with different techniques have. in general.
revealed no effect or only small deficits after irradiation of adult experimental animals, except at doses
at least close to the lethal range. 207 • 208 In some cases,
the performance in accomplishing certain simple tasks
is even improved in irradiated animals until they arenear death.
111. With adult irradiation, as with individuals
irradiated antenatally, the response of conditioned reflexes appears to be a more sensitive instrument for
exploring the effects of radiation on the nervous systemthan other behavioural responses. but considerations
similar to those made in paragraphs 37 and 38 apply
to adult irradiation as well.
112. Alterations in spinal cord reflex activity havebeen seen in dogs after whole-body irradiation withx ravs. 160 and in rabbits after irradiation of the spinal
corci' only (SOO to 1.000 rad) .161 Reflex activity initially increases, then declines. and finally returns to
pre-irradiation levels. Suppression of spinal cord reflexes reaches its maximum when radiation sickness
signs are severe. In animals that have survived irradiation. normal spinal cord function is gradually restored.
Other studies demonstrate that the latent period o:the shin-flexor reflex changes after whole-body x
irradiation (10 rad) of the rabbit.rn 2 Initially, theresponse time is shorter and the reflex shows greateroscillations than nonnal. Repeated irradiation increases
the latent period, sometimes beyond control values.

108. The action of irradiation on alreadv establishedconditioned reflexes has been the subject of a large
number of investigations.:; 2 · i 9 s Thus. a conditioned
aYoid~1ce response obtained in the rabbit by using anelectric shock as unconditional stimulus and a light80

113. In man. local and whole-body doses (therapeutical or accidental) of hundreds of rads (up to
1.000 rad) may result in changes of unconditioned
spinal reflexes which persist for years but eventuallydisappear. Such changes are found only through special
investigations ( electro-myography. ref!exometry. myotonometry. chronaximetry. etc.). They can be observed
for five to ten years after irradiation.10.-, :no, 211transmission after fifteen to twenty minutes. After anhour or so, inhibition is observed. 22 '. 120. Cutaneous. ~nd vi.sceral receptors respond tohigh doses of radiat10n with structural alterations but
also with functional changes. Thus. even during thefirst hour after local irradiation ( 500 rad) distinct
changes can be detected by recording spontaneous bioelec:rical potentials in the branches of the cutaneous
nerve. These potentials show an increased frequency
very soon after irradiation. They e..xhibit long periodsof increased activity even in the absence of tactile
stimuli. The reactions of the nerve to such stimuli
also become more intense. 200 It has not been determined\vhether these changes reflect a direct effect on thereceptor itself or whether the afferent nerves from thereceptor are mainly involved. On the other hand. theincreased splanchnic nerve activity that occurs as aresult of whole-body or abdominal exposure of cats andrats probably reflects alterations in the function ofinteroceptors, 228 -~ 30 and the isolated Pacinian corpuscle
responds to several hundred rads with changes insensitivity to mechanical stimuli.231

114. Clearly the nervous system does show a varietyof changes. From the preceding paragraphs it mav be
obsen·ed that. while changes in spontaneous or evoked
electrical activity may be seen after irradiation andare usually of a non-permanent nature, the behaviouraland pathological significance of such changes has yet
to be appreciated.

B. PERIPHERAL KERVES. SYKAPSES AND RECEPTORS

ll5. The doses required to alter the physiologicalproperties of isolated peripheral nerves are extremely
high-at least 10 kilorads of x rays. Such doses arefollowed by reduced amplitude of action potentials anddecreased conduction Yelocity of nerve impulses. 2 i;;·2 H
Heavy particles in similar doses stop conduction almost
immediately in the isolated sciatic nerve of the frog. 2rn

121. Observations on dogs irradiated and observedfor one year have shown that only when cumulative
doses reach 300 rads ( 150 rad over the year plus 150
rad in a single exposure, or 225 rad over the year
plus 75 rad in a single e..'<posure) is there any significant change in the sense of spatial orientation of the
body. 204 Experiments on rabbits indicate that such
effects depend on the region of the body irradiatedand that they change with the progress of time. 232
Permanent damage to the vestibular system has been
seen at single local doses to the labyrinth larger than
1,000 rads.

ll6. In rat sciatic nerves receiving in situ doses of
3 kilorads of x rays given in three fractions of 1 kilorad
each, no electro-physiological changes were detected
after three to eleven months, but major morphologicalalterations were found in this time period in 25 percent of the animals so treated. The lesions consisted ofmultifocal necroses of the sciatic nerve associated withdegenerative changes of vascularization in it.!! 16
117. The mechanisms whereby changes of the bioelectric activity of nerves, and of receptors as well. areproduced are not well understood. Various experiments
strongly suggest that the effect of radiation involves
at least two processes: (a) induced increase in passiveion permeability and ( b) the impairment of the energydependent ion-transport mechanism. 21 1-220

122. It is difficult to determine whether the effects
on cutaneous and visceral receptors are the direct
result of radiation on them or are secondary to changes
in the surrounding tissues.208 · 233 'Whether primaryor secondary, however, these effects on receptors arelikely to play an important role, when the body but
not the head is irradiated, in triggering central responses
or automatic reflexes responsible for the systemic interactions that will be discussed in section V.

118. In cats, local x-rav doses of SOO to 600 rads
to the lumbo-sacral segme~ts caused an immediate increased amplitude and duration of e..xcitatory synaptic
potentials in motor neurons when corresponding afferent nerves were stimulated.2!!1 During local x irradiation of the spinal cord at a dose rate of 300 rads per
minute, a change was observed in the potentials
recorded from the anterior roots of the spinal cordwhen the posterior roots were electrically stimulated.2 22
These changes may be related to the increased monosynaptic response variability observed in cats after
spinal cord irradiation ( 100 to SOO rad) .223 In mice,pathological alterations of synaptic structures in the
spinal cord were observed as early as one day after awhole-body dose of about 500 rads. Approximately
five weeks after irradiation. some of the degenerated
synaptic structures seemed to disappear, while others
apparently returned to their normal state. 2 7 8123. In man, reduction of tactile sensitivity and skinsensitivity to vibration has been demonstrated incases of accidental irradiation in the lethal range ofdoses104· :?~ 4 and in patients treated locally with highfractionated doses (several kilorads total). 23 G·238 Inversion of sensations has also been reported 239 after
irradiation of the oro·pharyngeal region. salt being"felt" as bitter and bitter as simply cold. Both lowered
taste sensitivity, and inversion of taste sensation appeared to be secondary to a central effect rather thana primary consequence of irradiation. Taste changes
were, in a number of cases. associated with increased
olfactory thresholds, sometimes accompanied by trophic
changes in the olfactory mucosa.240
IV. Radiation as a stimulus forsensory organs

119. Changes in synaptic transmission could be an
important factor in the response of the nervous system
to irradiation. To cause an inhibition of transmission
through an isolated neuro-muscular junction of the frog
or rat. doses of about 20 kilorads are required. 22 -<-!!!! 6
By contrast. much lower doses act on synaptic transmission when irradiation is applied to the whole bodyor to nervous structures in situ. Thus. doses of 800
rads to the upper cen•ical ganglion of cats facilitates

124. It has been demonstrated that brief bursts ofionizing radiation can stimulate certain receptor systems of many organisms in the same \Vay as does theadequate or normal stimulus for the receptor system
involved. The activation of receptors by radiation withsmall doses appears to be within the normal physiological capacities of receptors and does not seem to81induce any significant injury to the system imolve<l.
These e\·ents, therefore. should be clearly separated
from the effects that are discussed in other sections of
this report.
A. VISION

125. The ability of dark-adapted subjects to perceh·e ionizing radiation as a sensation of light wasnoted shortly after the discovery of x rays and is now
firmly established.2-n· 243 Perception of x rays depends
on the capability of the rod cells 242 · 20 • 245 which must
be dark-adapted for production of the visual radiation
sensation. Light sensations have been reported byhuman subjects after as little as I millirad of x raysdelivered in less than a second. 245 Peripheral retinal
regions where rods are most frequent are more sensitive than the central portion of the retina. 240
126. Electro-physiological investigations of the eyehave shown that the compound series of retinal
potentials that arise from light stimulation 248· 249 may
also be elicited bY radiation of the dark-adapted
eve. 24 2. !!H, 245 In hti'mans the ''flash" e..xposure threshoid for such response has variously been reported to
be 500 millirads 249 and from 1 to 5 millirads. 216

C.

SENSORY SYSTEMS AKD BEHAVIOURAL REACTIOXS

130. Changes in the electro-encephalogram are seen
in rabbits within one second after bursts of radiationof I rad or less 18'· 259 · :?so and persist for only a few
minutes. In rats exposed during a quiet period or
during sleep. dose rates as low as 0.25 rad per second produce transient electro-encephalographic reactions within seconds.2:;:; The response increases with dose rate.
The electro-encephalographic changes parallel thearousal response which resembles that seen withstimulation of peripheral receptors. 2"6 • ~ 5 ' The response
can be extinguished by repeated exposures. suggesting
habituation of a sensory system. Arousal responses
can be obtained by irradiating the head only or the
body only. Spinal transection (CrTi;) prior to exposure abolishes the response in animals in which the
body only is irradiated. showing that the arousal resulting from such an e."posure is mediated throughthe spinal cord. Exposure of the head only in suchtransected animals will still elicit the arousal response. :?oo, ::?o 1, 202
131. The effect of radiation on sensory systems canlead to changes in the behaviour of animals towards
further irradiation and towards cues previously associated with exposure. For example. mice and rats
avoid residence in that region of a chamber in which
they have previously experienced irradiation, 208 • :io3 orthey exhibit a reduced preference towards distinctively
flavoured substances previously consumed during anirradiation. 20 ~. 265 Thus. in rats. the consumption ofsaccharin-flavoured fluid during a six-hour exposure
to cobalt-60 gamma radiation at a dose rate of S rads
per hour results in a radiation-conditioned aversion
to saccharin that persists for about four weeks. 260\Vhen mice are exposed to gamma rays from radium
at a dose rate of 20 millirads per minute the thresholddose for the conditioned aversion to saccharin in saline
solution is less than 30 rads. The degree of avoidance
seems to be a linear function of the accumulated radiation dose. 26 i Similar reactions are seen in consumption tests at slightly higher dose rates with cats:?68
and monkeyi!c 9 subjected to combinations of radiationand test solutions.

127. Ionizing radiation may stimulate the retina ina manner related to normal \'isual processes, although
it has been difficult to show whether analogous mechanisms are at work at the rhodopsin level. Absorptionof radiation energy by the rods is apparently responsible for the electro-retinographic response as shownby the fact that 1~0 respopse could he ~l.icit~~o in. thehorned toad an ammal wluch lacks rod v1s10n.- Direct
evidence is ' also gained from the similarity between
the adaptation process for x rays and visual rod
adaptation.:?;.o

B. 0LFACTI01'
128. It has been demonstrated in rats,:?;;i.~ 54 dogs.:?;;;;
cats25;; and monkeys 2 ;;o that the olfactory system isvery responsive to ionizing radiation at small dose
rates (in monkeys. from 8 millirad per second). T~eevidence suggests that the electr?-encephalogra~luc
desynchronization and arousal reactions observed immediately after the onset of x-ray exposure n.1;-iy be due
to stimulation of the olfactory system, smce thesereactions are suppressed by destruction of the olfactory
bulbs. 251, :?~2. :?r.1

132. The mechanisms leading to radiation-conditioned behaviour are not precisely known. The behaviour depends not only on detection of small doses
at low dose rates but also on the induction of amotivational state to avoid a noxious stimulus. Aversive reactions to the same dose are produced more
often by abdominal exposure than by head exposure,270 suggesting that visceral receptors can also be
triggered by penetrating radiations. Splanchnectomy orintraperitoneal procaine injection delays or suppresses
development of the spatial avoidance response in rats. 271
Conditioned reflexes have also been obtained by abdominal irradiation. 261 · 272 suggesting visceral receptor
activation.

129. :Microelectrode recordings from single neurons
in the olfactory bulb of se\·eral species have been used
to identify olfactory stimulation by io~izing radiatio~s.
Radiation exposure generally results 111 a prompt mcrease in the firing rate of these neurons that corresponds to the duration of the exposure 253 • :m; However.
such responses presumably are not the result of aneffect of x rays on the olfactory bulb itself, ~ince t_he
reaction can be abolished by nasal perfusion withsaline or alcohol.2;; 3 A peripheral site of action is also
indicated bv experiments in which ozone in ambient
air was shown to mask selectively the response tox ravs. 2 ;;s It was found subsequently that the responses
occu·r in the olfactory bulb only if the radiation (betaradiation from a strontium-Yttrium source) is confined to the olfactory epithelium located in the nasal
passages.:? 59 From these observations. it appears reasonable to infer that olfactor\' detection of radiation occurs
at the receptor Je,·el rather than in a more central portion oi this system.

133. There is as vet no well-confirmed e\'idence ofreceptor stimulation -by low doses and low dose. rates
of ionizing radiations in man. with the exception ofvisual perception in dark-adapted sub~ects. TI:eevidence for radiation detection and behavtour cond1tionina in other species has been based on relatively
recent"' findings and will require considerably morede\'elopment before their implications for human beha\'iour can be established. In any event. the effects
82

described do not reflect injury to the nervous systemor specific risks to human subjects so exposed.
V.

Systemic effects

134. \Vhile all svstems may show radiation response
through interaction with the nervous system, it ismostlv with rei::,aard to the cardio-vascular and gastrointestinal systems that information is available, andonly these ~vill be discussed here.
A.

EFFECTS IN ANDfALS

135. Hcemodynamic changes occur soon after radiation exposure, particularly at doses in the lethal range.
They may be mediated through neuro-regulatory
mechanisms that are thought to be operative at several
levels of the acute radiation response.
136. As a result of autonomic nervous system involvement, the rabbit is unusual in showing an immediate shock-like hypotensive reaction after x-ray
whole-body doses of 600 rads or more. 108 • 273 Bloodpressure falls within hours after irradiation, and theheart rate increases. 27~· 27;; Atropinization or vagotomy
will reduce the severity of the reaction, and adrenalin
injections effectivelv counteract hypotension. 273 Bloodpressure changes may be seen after doses as low as 50
rads. 276
137. Acute hypotension has also been seen within
one to three hours post-irradiation in rats,:m. 278
cats279, 2 so and monkevs:.: 81 after doses in excess of 1,000
rads. but has not beer~ observed in dogs. 276 · 28:.:138. Rat arterial blood pressure responds differentially to x irradiation ( 485 rad) during the firsttwenty-four hours after exposure. as peripheral bl~odpressure falls. whereas the aortic pressure remams
unchanged. At 970 rads, the aortic blood pressure
also falls and responds weakly to various . stim~1li
during the first few days after whole-body irradtation.283

141. In most species, after a supra-lethal radiationdose to the head. respiration stops before cardiac failure.275· 279 • ~s:.: \Vith artificial respiration, 282 the pressor
response to carotid sinus stimulation disappears in headexposed dogs while arterial pressure and blood volume
remain normal. This suggests that reflex failure after
high doses is due to damage of the medullary vasomotor centre, since the presser response to electrical stimulation of this centre declines in the same manner as the
carotid sinus refle.'-'. This interpretation is supported by the
results of direct irradiation of medullary centres. 294
142. It thus seems that the response of the peripheral vascular bed to radiation may inrnlve several
levels. Shortly after irradiation. it is possible thatchanges in local concentration of metabolites or releases of vasoactive chemicals may play a role insuch responses. Radiation may also interfere withthe autonomic nervous system regulation of vascular
activity. At high doses. a direct effect may be operative on medullary and other higher control centres.
the function of which may in turn be modified by
inputs from a great variety of sensory receptors.
Alterations of respiratory reflexes may also be affectedindirectly as a result of cardio-vascular changes. However. the actual roles of the central and peripheral
nervous systems. as well as of local tissue changes atvarious times after irradiation. need further clarification.
143. Radiation sickness seen after whole-body dosesin the sublethal and lethal ranges is intimately associatedwith !rastro-intestinal
disturbances. Central nervous,~.
as well as autonomic, control may be involved mseveral phases of the gastro-intestinal response.
144. In many species. 295 including primates. 29 6- 298
anorexia is a common and reliable sign of radiationdisease in the first week post-irradiation. In rodents.
it is accompanied by a longer retention of food in thestomach299·301 and can be detected si..x hours after
whole-body doses of 20 to 25 rads. 30 ~· 303.

145. In rats. a dose of 1,0CO rads to the hind limbs
and tail only may also cause gastric retention. 303 Thiseffect is highly unspecific as it can be seen also after
toxin injection. Radiation fails to produce retention
after adrenalectomy. 301 · 304 but large doses of adrenalin
or corticoids given to adrenalectomized animals immediately prior to exposure restore the effect.303 There
are strong indications, therefore, that the radiationinduced gastric retention is an indirect effect. being
part of the general emergency mechanism.

139. The pressor response to electrical stimulationin rabbits is increased the first day after exposure to
800 roentgens (180 kV. 0.5 mm Cu+ 1.0 mm Al).
.
. ul taneous drop 111. bloo d pressure.-~s4
despitea sun
Changes in the sensitivity of the mec~::llli~ms .controlling blood pressure have been seen m 1rrad1atedcats, where peripheral stimulation of carotid baroreceptors or chemo-receptors elicits weaker than normalpressor responses. 280 • 28"·200140. Systemic interactions in the cardio-vasc~!arsystem are effective in the local control of motility
and permeability of the capillary bed. ~or ex_ample.
sectioning the afferent nerve from a skm section on
the back of a rabbit locally irradiated ( 450 rad) reduces such increased permeability.291 Increased permeability in the rat after 750 to 3.000 rads is seen
within twenty-four hours and is at a maximum atthree or four days.292 Anti-histamine drugs prevent
increased permeability up to one day post-irradiation.
suggesting that the early response is due to histamine
mediation. In the rat, the capillary bed of the mesoappendix shows diminished sensitivity to adrenalin forfive days after whole-body x-ray doses of 600 rads,
but reacts more strongly than normal eight to seventeen days after irradiation. Vasomotor activity showsa similar pattern. and the response has been attributed
to circulating vasoactive materials. 293

146. Experiments further indicate that pyloric
constriction or spasm is not an essential mechanism
in gastric retention. 805 It is more likely that the initialdepression in gastric transit is related to a reduction
in gastric motility, which may be more subject tosympathetic or humeral control than to direct local
injury.
147. Intestinal motility and muscle tone may bepromptly altered by x-ray exposure. 306 as shown in
preparations in which the intestine is attached to a
motility recording device. While no changes of in vitro
motility of the cat intestine are seen after 10 kilorads30i or of the guinea pig ileum after 500 rads,308
the exteriorized rat intestine increases its tonus andmotility about one minute after receiving 100 rads.3° 9
The effect persists longer with increasing dose. Vagotomy in the rat before irradiation has little effect,83

showing that pre-ganglionic fibres contribute little to
the responses. 309 On the other hand, results of pharmacological ganglion block suggest that the effect ofradiation is mediated by intrinsic intestinal ganglia.
Rat duodenal segments examined in vitro one to threedays after whole-body doses of 500 or 1,000 rads
show increased motility. with a normal response toacetylcholine. However. the response to serotonin
diminishes, suggesting that mucosa] damage must playa role in the mechanism of motility changes in theacute radiation syndrome.310
148. In many species vomiting is a common response
to median lethal doses. In monkeys, irradiation ( 1.5 to
6 krad) of the head alone does not induce vomiting.
while whole-body irradiation will. 193 • 311 a difference
seen also in dog and cat.312 This sign does not seemto depend on brain injury but on visceral stimuli,
and depends on the feeding schedule prior to exposure,311• 313 • 314 although bilateral destruction of thevomiting centres in the medulla oblongata prevents theimmediate response in dogs (800 to 1,200 rad) 315 • 316
or monkeys (1.2 krad). 317 Vagotomy also prevents
early vomiting in the monkey, suggesting that the
response is peripherally initiated.318 • 319 Abdominal exposure may, therefore, be considered essential to the
response.
149. It can be concluded that gastro-intestinal reactions to radiation. such as vomiting or changes inmotility and retention, mainly involve local neuralelements responding to injury of the radio-sensitive
intestinal mucosa. The response is mediated by central
as well as autonomic pathways.

B. EFFECTS IN MAX

seems particularly pertinent that all of these subjects
showed a significant release of neurohormone four andsix years after e..xposure. This may represent someprolonged biochemical or physiological aberration of thesympathetic nervous system not heretofore described.
152. Extremely detailed clinical examinations3 21 ofradiation workers who received less than 5 rads per
year for a number of years have failed to show effects
of any consequences.322 However, in workers who werereported to have received doses above current dose
limits (that is, from 70 to 100 rad within a period of
ten to fifteen years) a number of objective signs involving various systems were described as occurring
more frequently than among controls. The estimateddoses were based on readings of personal and working
area dbsimetres, and the exposure may have beenhighly inhomogeneous.

153. Among the signs observed, moderate hypotension and bradycardia were significantly more frequent
than among controls. Hypotension was particularly
pronounced in the retinal artery, and plethysmographic
investigations revealed slight changes of vascular tonus
in the limbs. 323 \i\Then these signs were most pronounced, they were sometimes accompanied by electroencephalographic changes, particularly in response to
hyperventilation,324 and by electro-myographic signs ofslight deficiency of tonus and posture control.325
AIJ these signs progressively disappeared in the courseof two or three years after overexposure had ceased.3 !!!!
These types of changes appear to be worth studying
further under strict control of a number of variables
that might distort the magnitude or frequency ofobjective, but non-specific, signs.
154. From the data available it can be concluded
that such changes as have been reported after several
years of exposure to levels of radiation about twice ashigh as current dose limits for radiation workers are
mild. reversible and usually \veil compensated. Subjective complaints that are not uncommon an1ong adults
show an increased incidence, but none of the clinicalsigns that have been reported at those levels of exposure appear to impair the working capacity of thesubjects.

150. The results of animal experiments discussed
in the preceding paragraphs clearly indicate the complexity involved in determining whether a given system does or does not play a primary role in the responseof another system, even with such high doses of radiation as have been used in most of the experiments.
\Vhile this review has been confined to interactions
between the nervous system and two particularly wellstudied systems. there are some indications thatsimilar interactions occur with the hremopoietic andendocrine systems.
151. Observations at high acute doses in man aremostlv derived from radiation accidents. 1• :i3 t The involve~1ent of several systems in the various forms ofradiation sickness are easily inferred, but determining
the role of each of them in the reactions of the others
is complex and deserves further study. Still. an inference as to possible long-tem1 radiation effects on
the endocrine system has become available. 32° Five subjects from Oak Ridge (mixed gamma-neutron dose,
respective averages 226 and 81 rad: fairly uniform
exposure) and one subject from Los Alamos (mixed
gamma-neutron dose. about 130 rad: gamma-neutron
ratio about 3: exposure geometry not stated) weree..xamined. Daily twenty-four hour urines were obtain~dfor the first two weeks after exposure and, for six
hours thereafter, at progressively longer intervals. The_samples were bio-assayed for adrenaline and noradrenaline. with results showing a modest and temporary increase in adrenaline release, and a marked
and prolonged release of nor-adrenaline. The greater
output of nor-adrenaline than of adrenaline suggests
that, after such exposure, the sympathetic nen·es are.called into greater play than is the adrenal gland. It

VI. Conclusions

155. The sensitivity of the nen·ous system to radiation varies markedly with the stages of its development. Only during the period from the second to thesixth month of fretal life does irradiation of thenervous system involve risks higher than those arisingfrom the irradiation of other tissues. Even then. it is
not yet established whether such a conclusion is valid
at low doses, though this can be suspected on thebasis of the limited data available. At other times
during development, irradiation of the nervous tissue
appears to result mainly in increased incidence ofmalignancies, the sensifr,;1:), of the nervous systembeing. in this respect. of the same order as that ofcertain other tissues.
156. \Vhen its development is completed, the major
effects on the nervous system appear onlv after radiation doses of the order of ki!orads. At doses close
to the median lethal dose. the acute radiation svndrome is dominated by symptoms invoh·ing the bloodforming and gastro-intestinal systems. although animal
experiments indicate that some of these symptoms
may be secondary to changes in the nen·ous system .
84

157. Such structural changes as may occur following large or massive doses con:>ist of brain- and spinaltissue breakdown and severe Yascular damage. After
smaller doses, cellular necrosis or progressive reaction
in parenchymal and vascular cells may ensue. Longterm consequences of irradiation of the nervous system at relatively large doses include tissue necrosis andvaried cellular reactions of sudden onset months or
years after exposure.
158. Functional involvement of the nervous svstem
is apparent even at doses lower than 50 rads, but theeffects can be considered as minor. They appear to be
TABLE l.

transitory and to result in minimal impairments offunctional performance. They do not compare in seriousness with the long-term effects in other systems
which consist largely of an increased incidence of malignancies. Quantitath·e relationships between dose andthe intensity and frequency of functional changes in
the nen·ous svstem have not been established in man
and should be explored.
159. Radiation can be detected by sensory organs.
For example, visual sensation of radiation is known
to occur in man at doses lower than 1 rad. There isno e\"idence that this involves any injury to the retina.

PRE\'ALEXCE OF :MEXTAL RETARDATION AT SE\"EXTEEX YEARS Of
AGE A~IONG SUBJECTS WHO WERE ill 11/ero
AT THE TDIE OF DO~IBIXGSa(modified from refcr.:uce 65)
Hiro.slaima-

Distance in mttrcs

Nagasaki

Male

FemaleMale

Female<l,500

Examined
Retarded
Per cent

89
i
7.9

80
6(3)
7.5

18
3(1)
16.5

20
1
5.0

1,500-1,999

Examined
Retarded
Per cent
Examined
Retarded
Per cent
Examined
Retarded
Per cent
Examined
Retarded
Per cent

135
2
1.5
221
1(1)
0.5
201
2(1)
1.0
646
12(2)
1.9

131
2(1)
1.5
211
l
0.5
19i

36
0
0
71
0
0

28
0
0
61

3.000-4,999
Not in city

Total

I

60
l

0.5
619
10(4)
1.6

1.i
185
4(1)
2.2

2(2)

3.3
54
1
1.9
163
4(2)

__

? :;,-a Xumbers in parentheses indicate cases with possibly "e..xplained" aetiology.
TAB!.E II.

PREVALE="CE Of ~NTAL RETARDATION AT SE\"E!ffEEX YEARS OF AGE BY :MO::-ITH Of BIRTll 8(modified from reference 65)
Monlh af birt/1

1945

Di.stanc~ in metres<I.SOO
1,500-1,999
Combined
controls<I,SOO

1,500-1,999

Combined
controls

A11g.

Sept.

Oct.

Nw.

15
0
0
26
0
0
82

19
0
0
21
0
0
80
1
1.2

16
0
0
19
0
0

15

68

i5

1
1.5

0
0

1
0

4
0

0

0

6
1
16.7

5

5
0
0

11

22

31
0
0

Examined
Retarded
Per cent
Examined
Retarded
Per cent
Examined
Retarded
Per cent

1.2

Examined
Retarded
Per cent

5
0
0

Examined
Retarded
Per cent

4
0
0

0

9
0
0

Examined
Retarded
Per cent

14
0
0

19
1( l)
5.3

40
0
0

I(!)

0

1

6.7
23
0
0

0
0

a Numbers in parentheses indicate cases with possibly ''explained" aetiology.

85

Du.

Hiroshima
21
1
4.8
29
1(1)
3.4
91
1(1)
l.l
Xagasak;
4
0
0

0
0

1946

Apr.

Jan.

Feb.

Mar.

29
3(1)
10.3
50
1
2.0
158
1
0.6

30
7(1)
23.3
34
1
2.9
119
0
0

17
1(1)
5.9
2.9
89
0
0

7
0
0
29
0
0
68
0
0

2
1
50.0

8
2(1)
25.0

2
0
0

5
0
0

6
0
0

9
0
0

s

8
0
0

r
-:>

30

2

0
0

31
0
0

8.0

35
1

0
0

May

34
1(1)
2.9

TABLE III.

HEAD SIZE BY DISTANCE FROM HYPOCENTRE AT TWENTY YE..\RS OF •.\GEIN H1Ros::rnr ..... s1

Head siu
minus 2 SD

Examined

Distance in metres::::;i 200
1 201-1 500
1 501-1 800
1801-2200

24
71

11

12

68

8

20

0

a One child with head size minus one standard deviation(SD).

b One c.ltlld with normal head size had Japanese B encephalitis during

TABLE IV.

Retardedor mor~iniancy.

HEAD SIZE AT TWENTY YEARS BY GESTATIONAL AGE IN HlRoSHIM..\67

W uks of gestation

Examined

Head si:e
min1tsZSD
or moreRetarded::::;is

78
50
55

25
3
4

11
4Jlb
0

16-25
26-40

a One child with head size minus one standard deviationb One child with(SD).

head circumference within 1 SD from the mean had Japanese B encephalitis

during infancy.
Note: Oi the fifteen retarded children, ten had head circumference at least 3 SD below themean, three were at least 2 SD below, one was between 1 and 2 SD and one within 1 SD.

T ..\BLE V.

PRE\"ALENCE OF MENTAL RETA.WATION ACCORDING TO DOSE RECEIYED68

Thi? small number of Nagasaki subjects iii the group ,.eccfr,ing 1 to 10 rads is due to thee.rclrlsion of subjects located between 2,000 and 2,500 metres from tire sample establishedin 1958.
A-Includes all cases of mental retardation
B-Excludes cases with possibly ·•explained" aetiology (shown between parentheses
in columns headed "retarded")Nagasaki

HiroshimaDo.s~ in rad.s

NI Ca
< lb
1-10
11-49
50-99
100-199;;?!200
Unh.'1lo,vnc

TotalsRetarded

Total

Rct•rded

Total

3(1)
2(1)
3(1)
2(1)
3(1)
4(1)

399
432
155
178
44
29
14
14

2
2(2)
0

114
137

(I

36
22
14
11
8

5
0

0
0
4(1)
0

6C

Per cent retarded

A
.98
.78
1.86
.93
4.55
9.30
36.0

B
.78
.18
125

.47
3.08
7.13
30.0

a NIC =Not in city at the ti111e of the bombing.
3,000-5,000 metres whose effective dose was zero.
c Unh.110,m = Persons whose shielding configuration was such that no dose estimate is available
at this time.
b <1 =Persons at

T ADLE VI. EXCESS INCIDENCE OF ME:s'TAL RETARDATION AMONG OFFSPRING OF WOMEN IRR.,.
DL.\TED Dl:"RING PREGNANCY AND OF LEUK.-\E:lliA (1947-1958) AMONG POST·N.UALLY IRRADIATED
St.'11JECTS

D:"stancc ;i:. kilo-metres

Mental retardation(e::cess ca.srs
P•r hundred)

Lcukt:rmia(excess cases

per hundred)

Hiroshima

0-1.5
1.5-2.0

11.0
2.3

0.6
0.04

Kagasaki

0-1.5
1.5-2.0

6.0
0.0

86

0.5

0.03

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IThl

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323. ,ll;eHIIcoBa, E. A., R.anHTI1t0-<fln3rro;rori111ecliaJI xapaKTepIIcTIIKa C1I1J,11J>mm nettpo-~.&y.aJITOpHOtt AIICTOHIIII npII •1YlJeDOJII B03)\ettCTBIIII, CTp. 11-30 ra111

a.e.

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324. BapaoanoBa, A. B., He:wropHe II3MenellIIJI B ABIIraTennott clflepe y .iIIIIJ;, pa60Ta10mnx n yc.JOBWIX:IpOHillJecEOfO .llYlJeBOfO B03,i!;el1CTB!Ul. rocyAapCTBeHHhlll KoMnreT rro 11crr0.1h30Bamno aroMBottaueprnn CCCP, AT0:\11!3,D;aT, M., 1968; v.e. United

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Nations document A/AC.82/G/L. 1255.

97