SOURCES AND EFFECTS
OF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
UNSCEAR 1993 Report to the General Assembly,
with Scientific Annexes

UNITED NATIONSNew York, 1993

NOTE
The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Forty-eighth Session, Supplement No. 46 (N48/46).
ll1e designation employed and the presentation of material in this publication do not imply
tl1e expression of any opinion whatsoever on the part of tlie Secretariat of the United Nations
concerning the legal status of any country, territory, city or area, or of its authorities, or concerning
tl1e delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those tliat were in use at thetime the data were collected or the text prepared. In other cases, however, the names have been
updated, where tliis was possible and appropriate, to reflect political changes.

UNITED NATIONS PUBLICATION
Sales No. E.94.IX.2
ISBN 92-1-142200-0

ANNEX H
Radiation effects on the developing human brain

CONTENTS

Pagc..........................................806
I . THE HUMAN BRAIN ....................................806
A. DEVELOPMENT ....................................806
B. DEVELOPMENTAL DEFECTS .......................... 810
1. Cerebral and cerebellar abnormalities ................... 811
2. Abnormalities of the brain adnexa ...................... 811
INTRODUCTION

11. RADIATION EFFECTS ................................... 812
A. PRENATAL EXPOSURE TO ATOMIC BOMBINGS . . . . . . . . . . 814
1 Severe mental retardation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
2. Small head size .................................. 816
3. Intelligence test scores .............................. 818
4. School performance819
5 Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .820
6 Pathologic and other findings of brain abnormalities ......... 821
B. OTHER HUMAN STUDIES ............................ 825
1 Prenatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
2 Exposure of the infantile and juvenile brain . . . . . . . . . . . . . . . 827
828
C. EXPERIMENTAL STUDIES

.

.
.
.
.

................................

............................
III . RISK ESTIMATES ......................................830
A. RISK FROM ACUTE EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . 831
1. Mental retardation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .831
2. Small head size ..................................831
3. Diminution in intelligence and academic performance ........ 832
4. Seizures ........................................833
B. RISK FROM FRACTIONATED OR
CHRONIC EXPOSURE TO NEUROTOXINS ................ 833

.

C
IV

1. Ionizing radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
2. Neurotoxic chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
UNCERTAINTIES ................................... 836. FUTURE PERSPECTIVES ................................ 839

CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840

UNSCEAR 1993 REWRT

806..................................................

Tables842
Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Rcfcrcnrcs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860

INTRODUCTION
1. The developing human brain has been shown tobe especially sensitive to ionizing radiation. Mental
retardation has been observed in the survivors of theatomic bombings in Japan exposed in lrrero during
sensitive periods [M2,M3,01,
P I , T I , W 1, W2], andclinical studies of pelvically irradiated pregnant
women have demonstrated damaging effects on thefetus [GI, 11, M I , 241. The sensitivity of the brain
undoubtedly reflects its structural complexity, its longdcvclopmental (and hence sensitive) period, thevulncnbility of the undifferentiated neural cells, theneed for cell migration to functional position and theinability of the brain to replace most lost neurons.
Previous UNSCEAR reports have considered the2.
general dcvclopmcntal effects of prenatal irradiation.
In the UNSCEAR 1977 Report [U4], mainly animal
data were considered. In the UNSCEAR 1986 Report[U2], more recent animal data and, to the extent
possible, data on cffccts in humans were considered inorder to derive risk estimates. The risks of effects,
including mortality and the induction of malformations, leukaemia and other malignancies and mental
retardation, were assessed to be 0.4 Gy-' at the timeof peak sensitivity and 0.1 Gy-' in less sensitive
periods. These values were derived on the assumption

I.

that the induction of effects is linear with dose. In the
UNSCEAR 1988 Report [ U l ] , these findings weresummarized with the further statement that the risk
estimates "may need substantial revision downward(particularly in the low-dose ranges)" and that "theCommittee intends to review this in the near future".
These points are considered in the further study
outlined in this Annex.

3.

most

point to inves,igatc isrevised dosimetry system pS86) IR1l forsurvivors of the atomic bombings inallen
the interpretation of results previously gained and,
therefore; requires the risk cstimatcs to be changed. In
particular, it will be necessary to establish whether itshould be assumed that therc is linearity of the doseresponse and whether there may be thresholds of doses
for effects at particular stages of fetal development.

In this Annex the emphasis is on reviewing the4.
results of the study of the survivors of the atomic
bombings in Japan. The results of other human epidemiological investigations and of pertinent experimental
studies provide supplementary information, and thesehave been considcred as well.

THE HUMAN BRAINA.

DEVELOPMENT

5.
The brain is the culmination of a long andinterrelated sequence of molecular, cellular and tissue
events. Some of these occur before birth and someafter. Those occurring before birth are classifiable on
the basis of the time after fertilization at which theyoccur as either embryonic or fetal. Conventionally,
embryogenesis describes the phase of prenatal
development from the appearance of the embryonicdisk to the end of week 8 after fertilization. After thistime, the developing organism is called a fetus. Mostof the structural complexity of Ihe brain evolves in the
fetal period through a series of ir~terconnectcdevents
involving the production of neuronal cells, theirmigration from the periventricular proliferative zones
to the cortex, their further differentiation, their growthin size and complexity of slructural and molecularorganization, and the establishment of primary neuritic
processes that contribute to the emerging fields of

ANNEX I I: RADIAION EFIXCIS ON THE DEVELOPING I IUMAN BRAIN

connection. The details of these developniental events
have been described elsewhere [C6, C7, 11, Ma,M9,
0 1 5 , R2, R6, R10, R11, S17, U2] and will not be
rcvicwcd in depth here. In this Annex, discussion will
be limited to certain general principles of brain development that have emerged largely in the last several
decades and to recent experimental and epidemiological findings that bear on an understanding of themechanisms through which prenatal exposure toionizing radiation can lead to brain dysfunction.

6 . One of the first differentiation events in the very
carly embryo is the appearance of discrete neural precursors, the neuroblasts, which separate from a defined
region of the primitive ectoderm. These cells areaggregated around the ventricles of the developing
brain, and their descendants will populate the cortex.
The mechanisms that operate within this ventricularzone to determine the ultimate fate of immature cortical cells are not well understood. Howcver, evidence
accumulates that in early corticogenesis there is acooperation among the cells in the proliferative zone.
For example, recent studies have .shown that theneuroblasts in the proliferative zone are physiologically coupled by gap junctions into clusters of 15-90
cells [IA]. This has been demonstrated through the useof a low molecular weight dye, Lucifer yellow, thatcan be injected into a single cell and can easily passthrough gap junctions from one cell to another. To
distinguish between coupling through gap junctions
and coupling through cytoplasmic bridges, possibly
stemming from membrane fusion, the investigators
also injected into single cells horseradish peroxidase(HRP), which does not pass through gap junctions
because of its molecular size but can pass throughcytoplasmic bridges. The injected HRP was invariably
restricted to a single cell, indicating that the coupling
was not due to cytoplasniic bridges. Similarly, experiments designed to decrease the conductance of gap
junction channels and thus increase membrane resistance showed that the membrane resistance of cells
within clusters was increased, but there was noincrease in membrane resistance among non-coupledneurons in the cortical plate. The coupled cells,
identified by the cell to cell diffusion of Lucifer
yellow, form columns within the ventricular zone. The
clusters themselves allow direct cell-to-cell interaction
at the earliest stages of corticogenesis, and these interactions could participate in determining the fates ofthe developing neurons. This behaviour suggests aninterdependency of the fate of these cells such that thedeath of one, whatever the cause, could lead indirectly
to the impairment of the developmental polential ofothers. Once migration commences, however, thenumber of cells within the clusters decreases, andapparently the individual immature neurons divorce
themselves from h e clusters, since they can no longer
be shown to be dye-coupled.

807

It is importiint to note here that experimental
7.
studies currently suggest that each cortical neuron has
not only a designated date of birth but also a definite
functional address (see, e.g. [R16]). Since cerebral
neuronal cells proliferate in specific peri- or circumvenlricular zones, proper function implies migration.
The event (or events) that initiates the movement o f
post-mitotic, undifferentiated neurons from the proliferative zones to their normal sites of function is still
unknown. However, once initiated, the movement ofcells extends over weeks in aggregate, although anindividual cell may reach its destination in a matter ofdays at the most. The migratory proccss itself is anactive, timed phenomenon dependent to a large degree
on an interaction between the surface menibranes of
the neurons and their guidance cells, on matrix
materials such as cytotactin and on the subsequentmorphological shaping of the two different families ofcells, neurons and neuroglia. Not all of the factors
involved in this phenomenon are known: however,there is experimental evidence that a modification ofcell surfaces or spaces on or near the glial processes,
which guide the neurons during their nlovement, isinvolved [Fl]. The cells probably advance by making
adhesive contacts at their leading edges, or growthcones, and then pulling themselves fonvard. Edelman[E2], for example, has shown that specific molecules,
known as cell adhesion molecules, whose structure andfunction are apparently under genetic control, play acentral role in these movements and that they do sothrough local alteration of the cell surface. It has also
been demonstrated experimentally that within the optic
tectum the growth cones are able to read gradients ofsurface-associated information in the process ofaxonal
path-finding [BlS]. Thus, any damage lo the surface
membranes or impairment of these molecular processes, however transitory, could impair the timing of
migration. It is known, for example, that blockade of
the cell surface adhesion molecules with appropriate
antibodies prevents proper migration of external granule cells in cerebellar slices in culture [C9,H12, L3]
and would presumably also do so in vivo.

8.

Two waves of neuronal migration take place[RlS]. The first of these commences at about week 7
after fertilization and appears to involve cells from theinner area of proliferation, the ventricular zone. (Hereand elsewhere, unless specifically stated otherwise,time is expressed in weeks following fertilization,
estimated from and therefore assumed synonymouswith time of ovulation.) The intermediate zone Ihroughwhich they pass is then sparsely structured and contains few impediments to their movement. This wave
ceases at about week 10, when numerous nerve fibres
appear in the intermediate zone, which thickens
markedly. The second wave, numerically much thelarger, begins about week 10, normally terminates
about week 15 or s o and involves cells from a zone

1993 REPORT

further from the lumen than the zone from which theearlier migrants came. This time the migratory cells
must traverse a denser intcrmcdiate zone and move
past those earlier formed tlcurons that have alreadymigrated, are positioned and have fonned connections.
The later-formed ncurons arc assistcd on their way tothe cortical plate by the long processes of specialized
cells, Ule radial glia. At a subsequent time, the radial
glia will begin to divide ancw and become differentiated into astrocytes. However, at this juncture, theyseemingly serve two functions: first, to guide themigrating neurons through the densely packed intermediate zone and secondly, to ensure the faithful
mapping of the ventricular surface onto the expanding
and convoluted cerebral cortex by preventing or minimizing the intermixing of cells generated in different
regions of the proliferative zone. While the majority ofyoung neurons do migrate along these radial pathways,
some mixing of these clonally related cells occurs.
Walsh and Cepko [W8],using a retroviral marking
method in vivo, have shown that in the rat somelabelled cells appear to migrate up different radial glial
fibres and even along the ventricular surface, perpendicular to the fibres themselves. The latter form of
migration could cause a wide dispersion of related
cells and suggests that the pathways for neuronalmigration are far more con~plcxthan the simple routes
offered by radial glia. It is not yet clear how common
this occurrence is, whether it is species-dependent orwhether all of the labelled cells are indeed clonal orreflect an inhomogeneous distribution of the viral label[K13]. However, these authors, using a new method to
identify the functional specification of the progenitors
in the cortex, have recently confirmed their earlier
findings and argue that this widespread and numerically significant dispersion of neuronal clones implies
that the functional specification of cortical areas
occurs after neurogenesis [W14]. O'Rourke et al.
[014] have confirmed these observations with timelapse confocal microscopy.

9. The cellular and molecular mechanisms of cell
migration are not yet well understood, and little attcntion has heretofore been paid to cell membrane propertics and changes in ionic concentration during cell
movement. Only recently, for example, has it beenrecognized that migrating neurons in the developing
cenlral nervous system express voltage-sensitive ionchannels bcfore thcy reach thcir final destination.
These channels appear to play a transient but specificdevelopmental role in directing the migration of
inmature neurons. Thus, Kornuro and Rakic [K14]have shown, using laser scanning confocal microscopy, that in the mouse cerebellum, granular neurons
will not migrate ur~til they have begun to express
N-type (conotoxin-sensitive) calcium channels on theirplasmalemmal surface. If these specific channels are
inhibited by the addition of conotoxin to the tissue

culture medium, the neurons will not migrate; however, the illhibition of other calcium channels, as wellas those of sodiunl and potassium, had no cffcct on
the rate of granule cell rnigr;ttion. Accordingly, thcy
speculate that "the early expression of conotoxinsensitive calcium channels in postmitotic cells may bean essential prereq~lisiteto boll1 the initiation and theexecution of thcir rnovcmcnt".
10. Once migration has ceased, the fate of the
migrating cells will ultimately dcpcnd on their abilities
to connect with other ncuronal cells; formation ofthese axonal paUlways is a competitive phenomenon,
and those cells that do not form the connections thatallow stimuli to be passed from one cell to anotherwill die and disappear. How these growing neurons
find their targets has been one of the central problemsof neurobiology for the last 40 or so years. It is now
generally believed that the answer lies in chemoaffinity, that is to say, that the biochemical
specification of growing axons is crucial in leadingthem to their appropriate targets [SlS]. The precise
nature of this process is unclear, and competingtheories exist. Some speculate that there is a structuralor strict chemospecificity in which the ultimate pattern
rests on the complementary recognition of mutuallyspecific cell surface markers, but this implies theexistence of a very large number of such markers,
I
Others argue
much larger than has yet ~ C C I identified.
that the pattern arises through a regulatory or dynamic
modulation of a relatively small number of specificities (see, e.g. [E2]). Evidence in support of this latternotion can be found in the fact, as previously stated,that late-formed neurons must migrate past those thathave already migrated, are positioned, and haveformed connections. Chuong el al. [C9] have shownthat modulation of the neural cell adhesion niolecule(N-CAM), which is present on all neurons (but not on
the glia), or of the neuralglial cell adhesion molecule(Ng-CAM), which binds neurons to glia or glial
molecules such as cytotactin, is implicated in the
differential adhesiveness and regulation of this passing
movement. N-CAM exists in two fonns, an adult andan embryonic, which differ in their degree ofsialylation. The embryonic form, E-N-CAM, is highly
sialylated, whereas the adult form is not. In the
cerebellum, E-N-CAM is never expressed in thegerminal zone of neuroblasts destined to form or
forming the external granular layer. It is, however,expressed by the granule cclls during thcir migration
but ceases to be demonstrable when these cclls havereached their final position in the internal granularlayer. Other cerebellar cell types do express E-N-CAM
as histogenesis unfolds, but they, too, cease to do sowith h e overt cessation of cerebellar histogenesis
p 1 4 ] . These findings suggcst that E-N-CAM is only
characteristic of growing and moving cellular
structures.

A N N U 11: M I A T I O N ERTICIS ON IllIi DEVELOPING HUMAN BRAIN

11. Establishment of the proper axonal pathways
entails coopcrativcness as wcll as competition. It has
been shown that in the developing mammalian tclencephalon there exists a special group of early arisingneurons, the subplate or transient pioneer ncurons, thatarc instru~ncntalin the laying down of the f i s t axonal
pathways arid may be essential to the establishment of
permanent subcort ical projections [K4,M 131. These
subplate ncurons will disappear in postnatal life after
the adult pattern of axonal projcctions is wcll cstablishcd. It is also known that in the development of thecentral nervous system in some invertebrates, thegrasshopper for instance, if the pioneer cells arc
prevented from differentiating through heat shock, thesensory growth cones that would have migrated along
the pathways established by the pioneers are blocked
and fail to reach the central nervous system [K4].
While the death or failure of a pioneer cell todifferentiate may not always preclude the establishment of a specific pathway, since the function of thepioneer may be assumed by another cell, it is clearthat in some instances the pathway will not develop if
the pioneer cell is prevented from differentiating.
Moreover, at least in some insect species, where thegeometry of a specific neuronal pathway may be quite
complex and involve sharp angles, it has been shownthat other specialized cells contribute to the delineationof the pathway. These cells have been called "landmark" cells, and their presence and proximity apparently signal the pioneer to change course. Finally, as
knowledge of the embryology of the brain increases
and recognition of the functional specificity anddiversity that exists among ncurons grows, it becomes
more plausible to assume that the loss of relatively
small numbers of neuronal cclls could have an effecton brain development out of proportion to the actual
number of cells that are killed or whose differentiation
is impaired.

12. Some cerebral neurons, presently thought to berelatively few in number, do not have their origin in
the circumvcntricular proliferative zones but arise elsewhere and migrate into the cerebrum. It has beenshown, for example, that those neurons that secrete thehormone that releases the lutei~lizinghormone, the one
responsible for stimulating production of the sex hormones testosterone and oestrogen, actually have their
origin in the olfactory placode. These neurons, known
as LHRH cells, begin to migrate from their sites ofbirth in Ihe placode through the olfactory bulb andinto the cerebrum at about gestational day 12 or 13 in
the mouse, following the ten~linalnerve (nervus terminalis). Most of the migration is completed by gestational day 16, and the cells, which are ciliated andmorphologically distinguishable from other neurons,
are diffusely distributed through Ihe cerebrum [ S 9 ,W7]. These events in the human would bc occurring
at about 12-14 weeks after fertili7ation.

809

13. Marly areas of the mammalian brain are characterized by repeatcd ensembles of anatomically andphysiologically distinguishable nerve cells. Amongsuch ensembles arc those of the barrels and colurnns
seen in the sonlatosensory cortex, the pattern ofglorncruli in the olfactory bulbs and the columns of
the visual cortex. Understanding the development ofthese neuronal assemblages has an important bearing
on the nature of critical periods, the manner in which
neural information is stored and the age-dependentneuronal response to injury. Progress in this undcrstanding has been slow for lack of suitable study
techniques, and it has not been clear whether the
initial assemblages persist or whether they are lost or
gained as the brain develops. Recently, LaMantia et al.
[L2]have been able to show that with regard to theglomcrular pattern in the olfactory bulbs, the brain is
gradually constructed by the addition of new glomeruli
to a persisting population, without apparent losscs
from the original population. Custoniarily regressive
phenomena (cell death, synaptic loss and axon climination) are known to play an important role in the
devclopnlcnt of the brain, but their findings suggestthat these regressive events must proceed during theconstruction of olfactory neural circuits, if they occur
at all in this region of the brain. However, LaMantia
et al. [L2]note that the olfactory systenl has several
extraordinary features that may lead to an exaggerationin the elaboration of these hnctional units in theolfactory bulbs. These findings suggcst a need toreconcile the observation that some portions of thebrain evolve through ongoing construction with thecomnlonly accepted notion of development through theselection of useful circuits from a larger initialrepertoire (see, e.g. [E2]).

14. Three general features of the development andorganization of the human brain and its adnexa areimportant to an understanding of the nature of its
vulnerability to malformation or maldevelopmcnt,
namely:(a)@)

the brain is one of the most complex organs of
the body, with an involved architecture in which
different functions are localized in different
structures. Differentiation of the latter takes
place at different timcs and for different durations. This is particularly true of the dcvelopment of the ncocortex, which proceeds over along time;brain function critically depends on the dispositi011 and interconnection of structures and cclls,
neuronal and glial, and normal structure andfunction hinge on an orderly sequence of events(cell division; programmed cell death; migration,
including the positioning and selective aggregation of cells of the same kind; differentiation
with the acquisition of new membrane propcr-

810

(c)

UNSCEAR 1993 REPORT

tics; and synaptic inter-co~~ection),each ofwhich must occur correctly in time and space.
Both cooperation and competition are involvedin niany of these cvcnls;
h e neurons of the cerebrum are not selfrenewing. The capacity of neuronal precursors to
divide is exhausted during the populating of thecerebral cortex and culminates in differentiatedncurons that do not undergo further division.

Proper cortical function depends ultimately not only
on the quantity of neuronal cells but their quality as
well, and the latter depends, in turn, upon a variety ofcellular and molecular processes, some intrinsic tothese cells but some not. This has been particularly
well illustrated through studies of the genetic disease,ataxia-telangiectasia (see [B17]).
15. Summary. The majority of neurons in thedeveloping central nervous system migrate from thesite of their last cell division to their final, functional
position. The processes of acquisition of this position,
the endowing of neurons of the six cortical layers of
the cerebrum with their laminar identities and theparcellation of the neocortex into over 40 functionallydistinct areas remain poorly understood and pose amajor problem for neurobiology [S18]. Understanding
these phenomena and the plasticity of the brain, i.e. its
capacity to continually remodel itself, is also central tounderstanding how exposure to ionizing radiation
impinges on the cytoarchitectonic structure of thecentral nervous system and its functioning.

B. DEVELOPhlENTAL DEFECTS
16. Malformations of the brain may occur either inthe course of major organogenesis, or take place during the differentiation and growth of the brain mantle.
Among the former defects are malformations such as
anencephaly and cncephalomeningocele, which represent failures in the normal formation and elevation of
the neural folds and the subsequent proper closure of
the neural tube w l 1 , MIS, 041, and holoprosencephaly, which reflects the failure of the forebrain to
divide into hemispheres or lobes. At this time, theundifferentiated neural cells retain their regenerative
capacity, and tissue damage can theoretically berepaired. The closure of the neural tube and thedivision of the prosencephalic vesicle take place
relatively rapidly, probably within a few days [OS].
These events occur early in embryogenesis, 4 6 weeks
after fertilization.
17. Disturbances in the production of neurons andtheir migration to the cerebral cortex give rise to malformations of the brain mantle [ S l , S2]. Recent advances in developmental neurobiology have shown thatmany of lllesc stem from failures in the normal intcractions of cells (neural and non-neural) during thedevelopnnent of the primate brain. Nonnal interactions
hinge upon (a) production of a sufficient number ofneurons; (b) their appropriate positioning; (c) establishment of the requisite cell shapes; and (d) formationof synaptic connections [R3,R4, R5]. Anlong suchmalformations are, for example, an absent corpus
callosun~or a disorganized cortical architecture, which
may later result in abnormal fissuring of the cerebral
hcmisphcrcs, heterotopic cortical grey matter andn~icrocephaly.
18. The sensitivity of the differentiating neural tissue
to damage changes with age, and so does its capacity
to replace damaged cells. It is therefore inlpossible tosay whether the intrinsic or apparent sensitivity of thestructures changes as a function of time. At any given
time in development, the probability of causing abnormalities, and their severity, changes as the dose o f t h eteratogenic agent changes. Moreover, for a given dose,
damage can vary as a function of the time in development at which the insult occurs, and therefore defects
that arise in the growth and differentiation of the brain
mantle, unlike those that arise in the course oforganogenesis, can also differ substantially in severity.
Broadly stated, the sensitive period for such abnormalities is months instead of days. The longer sensitive
period and the limited repair capability must be
important reasons why these malformations are much
more common than organogenetic ones [D7]. The
complexity of the origin of these defects is illustrated
by the relationship between brain function and cellular
repair that characterizes the human genetic disorder,
ataxia-telangiectasia [B17, C13, C14]. In addition to
the neurological defects ataxia-telangiectasia is also
associated with ininiunodeficiency, an elevated incidence of lymphoreticular neoplasms and in vivolin
vitro cellular radiosensitivity [C13]. Recent molecularstudies suggest that the primary defect in ataxia-telangiectasia may center on the misrepair of DNA
double strand breaks (see Annex E, "Mechanisms ofradiation oncogenesis") and given the dramatic neurological dysfunction that characterizes the disorder it
may be concluded that DNA repair is critical forneuronal development and maintenance.
19. The cells of the different structures of the brain
are produced at different times. If the proliferating
ventricular and subventricular cells are damaged
during periods when a certain cell type is being produced, the loss may be permanent. Thus, a brief insult
may lead to the preferential damage to a particularregion and consequently cause a permanent functionalor behavioural abnormality.

20. The period of maximum sensitivity orvulnerability to developmental disorders is understoodA N N M 11: RADIATION EFFECTS ON Tl IE DEVELOPING I IUMAN BRAIN

as that pcriod in dcvclopment during which definedteratological effccts are most likely to be produced.
This does not imply that some malformations can beproduced only at certain times but rather that a givendose is more effcctivc at some stages [U4] and thatthe duration of the pcriod of effectivericss may bebroadcned by increasilrg the dose. Table 1, adaptedfrom Williams [WlO], sets forth the weeks after fertilization at which major developmental features of thebrain cvolve. By extension, it would be possible tosuggest the damage that could ensue if the normal
pattern of orderly differentiation and development did
not occur (see also [J2, 221).

1. Cerebral and cerebellar abnormalities
21. The critical period for abnormalities in thedevelopment of t l ~ ecerebral cortex occurs when thetelcncephalic matrix cells uridcrgo their last cellulardivision, begin to migrate to the cortical plate anddifferentiate into specific phenotypes (see, e.g. [K8]).
The production of neuronal cells accelerates and theirmigration to the cortical plate commences at about
week 8 after fertilization. Cortical neuron production
has largely terminated by week 16 after fertilization.
Subsequently the laminar cortical structure becomesapparent and dendritic arborization, a process that
extends into postnatal life, begins. Migrational errors
involving the superficial cortico-cortical cells of thedeveloping brain, or tbe loss of some of these cells,
can lead to convolutional abnornialities [C2,G7],
which since neuronal function follows position, may
in turn contribute to the origin of functional andbehavioural abnormalities.

81 1

24. Hypoplasia with derangcd cortical structure
stemming fro111 illjury to the external granular matrix
is the most comrrion abnormality of the cerebellum.
Although some ccll classes, e.g. the Golgi Type Il
cells, are generated early in the cerebellar anlage,other and niore riunierous cells, such as the granular
neurons, are generated late. Overall, cerebellar growthstarts later, procecds more slowly and therefore ends
later than that of the rest of thc brain. This bimodaland protracted growth may account for the diffcrential
susceptibility of the cerebellum to growth restriction[R3]. In all major respects, the development of thehuman cerebellum resembles that in other mammals,
when allowance is made for the different timing ofbirth relative to brain development [D6]. Because of
its unique developmental sequence, in which two
populations of neurons are generated at opposite sidesof the cortical plate and migrate in a subsequent phase
to bypass each other, the cerebellum is the mostfrequent site of genetic abnormalitics [Cl].
2.

Abnormalities of the brain adnexa

25. Abnormalities involving the brain adriexa arise
from either maldevelopment of the cnd-organs thernselves, the eyes or ears, for example, (see [ O l l ] for a
description of the early normal development of theseorgans), or in the processing of the signals transmitted
from these organs to the brain, or both [ 0 6 ] . Failuresin signal processing could be the consequence of adefect in the optic or auditory nerves or in the various
cortical areas involved in auditory, olfactory and visualfunction.

22. Disorders such as the dyslexias (severe inabilities to read) appear to be due to aberrations in specificcortical areas [G5,K2]. Galaburda et al. [G6], forexample, have described a severely dyslexic child withsmall focal wartlike accumulations of ectopic neurons
in layer I and scattered focal cortical dysplasias; theseaberrations were confined to the speech region of theleft hemisphere. Other cases with comparable
structural abnormalities have been described
subsequently.

26. Defects in the optic tract, for instance, could be
manifested as aberrations in the field of vision, theirnature and extent depending on the severity of thedamage. Total destruction of the retina or the optic
nerve would result in blindness. Damage to the optic
chiasm could give rise to total or unilateral blindness,
depending on the location and severity of the lesion.
Damage to the iris could culminate in a coloboma or
be manifested as heterochromia or other pigmentary
disturbance. Neither of these latter defects have been
seen, however, among the prenatally exposed survivorsof the atomic bombings [K12].

23. Similarly, auditory, olfactory and visualanomalies could be the consequence of damage to thespecific cortical areas involved in these sensory
functions rather than to the end-organs themselves orto specific sensory fibres in the corpus callosum [Gg].
In the case of olfaction, at Icast, damage canapparently arise through a failure of the LHRH cells
to migrate into the cerebrum, since anosmia is a partof the syndrome of hypogonadism and hyprgonadotrophism known to be associated with migrational
errors in these cells (S9].

27. Rhinencephalic damage could, if severe, produce
anosmia, and if less severe, an inability to perceive
specific classes of odours, a selective arrosmia.
Whether such prenatal damage to the brain adnexa canbe subsequently ameliorated is unclear; however, someexperimental evidence, based on the exposure of only
a portion of the brain, suggests that the undamaged
areas can compensate for the loss of function in thedamaged rcgions. If such amelioration is possible, theeffects of prenatal irradiation will be more difficult toassess. Special neurons in the nose are capable ofdetecting a myriad of odors and communicating theseto the brain. These neurons, unlike most others, when
they age and die, are replaced with new ones derived
from a population of progenitor cells in the nasal
epithelium. These new neurons will acquire chemosensitivity and form synaptic connections in the olfactory
bulb of the brain. This process occurs continuously,
but despite this constant change the sense of smell isnormally quite stable. Whether this would be true
following exposure to ionizing radiation is not known.

28. Summary. The cells of the different structuresof the brain are produced at different times, and hencetlle sensitivity of these structures to damage changes
with age at exposure. A brief insult that might at one

stage of embryogenesis have little or no effect can, at;inotI~erstage in development, lead to preferential
damage to a particular region and consequently cause
a pemianent functional or behavioural abnormality. At
any given time, the probability of causing abnormalities and their severity change as the dose of the tcratogenic agent changes. For a given dose, however, defects that arise in the growth and differentiation of thebrain mantle, unlike those arising in the course oforganogenesis, can differ substantially in severity,
since the sensitive period for such abnormalities ismonths instead of days. Thc longer sensitive period
and the limited repair capability must be importantreasons why these malformations are much morecommon than organogenetic ones [D7].

11. RADIATION EFFECTS
29. Cells that are actively dividing are more
responsive to radiation than those that only divide
occasionally, or cannot divide. Given the number ofproliferating cell populations in the embryo or fetus,
it is to be expected that their tissues would be especially prone to radiation injury. This damage could
take a variety of forms, ranging from necrotic to apoptotic death (see, e.g. [ G l l , HlO]) to the impairment of
the cell membrane without death. Apoptosis, that is,programmed cell death, is the most common form ofcell death in the body and is particularly important inembryo- and fetogenesis in the shaping and reshapingof tissues and organs. It differs from death due tonecrosis in a number of ways. Normally the cell diesquickly, within four hours or so, rather than through aprocess that extends over a much longer period, as in
necrosis. Moreover, in apoptosis the cell membrane remains intact as death occurs, whereas in necrosis theintegrity of the membrane is rapidly lost. Inoue el al.
[I61 have demonstrated that radiation-induced cell
death in tbe external granular layer of the cerebellumof newborn mice is of an apototic nature.

30. Where and how exposure to ionizing radiation at
crilical developmental junctures acts to impair brain
function is unknown at the moment. However, ionizing radiation could interfere in a variety of ways
-jB3,
~ 4 HI,, H2, Y2]:
(a)

(b)

radiation effects could arise from the death atmitosis of glial or neuronal precursors or both,or the killing of postmitotic, but still immature,neurons;such effects could result from an intrusion oncell migration
either through- an alteration of thecell surface phenomena that are involved,
through the death of the glial cells that guide themigrating neurons or through infringement on

(c)

(d)

(e)

gap-junction-mediated intercellular communication [Fl]. Tt is not clear whether neuronal andglial cells are equally radiosensitive; however,disturbances of myelin formation, a mature glial
function, have been described in brain stem fibre
tracts in experimental situations following irradiation and appear more severe after exposure toneutrons than to x rays [GA;abnormality might reflect an impaired capacityof the neurons to connect correctly. The development of neuronal connections, or synaptogenesis,
is a multifaceted phenomenon; it involves timing, space, surface-mediated competition and,possibly, diffusible agents;
irradiation could also lead to disoriented dendritic arborization, or a reduced number of dendrites or dendritic spines per cerebral corticalneuron [BS,B6];
programmed cell death, which is essential to thedevelopment of the normal brain and its adnexa,
could also be accelerated or otherwise altered byionizing radiation.

If cell death is not the sole mechanism through which
irreparable damage occurs and if ionizing radiation cancontribute to one or more of the levels or sites atwhich neuronal variation can arise, then there are
numerous possible effects. Edelman [E2], for example,
has identified seven major levels of neuronal variation,
and within each of these there is cornmonly more than
one site at which variation can be envisaged (seeTable 2). Relatively few of Ulese sites or levels ofvariation have been studied Gom a radiobiological perspective.
31. Distinguishing between the possible alternative
mechanisms of damage and sites of altered variation,although formidable, is essential to more completeANNFX I I: KADIATION E F E C I S 0IN TilE DEVELOPING I IUMIW BRAIN

understanding of the nature of the effects of io~lizing
radiation. How rapidly this undcrstar~dirig will beattained is unknown, but there are promising developments. For example, the study of neuron-specificproteins such as neuron-specific cnolase, a cytosoiic
fomi of lllc glycolytic enzyme enolasc (phosphopyruvale hydralase), may provide a means to discriminate
between cortical dysfunction stemming from radiationrelated ncuronal death or necrosis, on the one hand,and errors in migration, on the other [14]. Enolasc isa dinicric enzyme composed of various perniutationsof three immunologically distinct subunits (alpha, beta
and gamma). Immunohistocheniical studies, using antibodies to the gamma subunit, have localized alphagamma and gamma-gamma dimcrs specifically withinneuronal and neuroendocrine tissues. It is this spccificity of distribution that makes neuron-specificenolase a useful marker not only for ncuronal damage
but also for neuroendocrine tumours. Coquerel ct al.
[C8], for example, have shown that chc level of neuron-specific enolase in the cerebrospinal fluid increases as the necrosis volume increases and that atbirth, the cerebrospinal fluid level of this enzyme ishighly prognostic of infants who will subsequently
exhibit confirmed brain darnage. It has also beenreported that cerebrospinal fluid as well as serum
levels of neuron-specific enolasc are elevated in nonfebrile seizure disorders but not in cases of siniple
febrile convulsions [KlO]. It is, however, not yet clear
whether similar elevations occur in well-recognizedmigrational disorders, such as schizencephaly, a rare
abnormality of the brain in which clefts extend acrossthe cerebral hemispheres; if they do not, this enzyme
might provide a siniple tool for separating cortical
functional errors associated with neuronal ectopias
from abnormalities stemming from neuronal death.
32. Progress in the understanding of brain organization and function entails not only the use of newer
tools but also the formulation of testable propositions[F5.U ] . One such organizational notion is the radialunit hypothesis of Rakic [R12, R13], who argued thatthe cortex is a collection of ontogenetic columns, eacharising from a spccific proliferative unit and clonal innature. Substantial data support this contention.
Mountcastle [M12], for example, showed that the ncurons within a single column in the somatosensory cortex are responsive to a specific modality and receptive
field of stimulation. Other sensory and association
areas in the cortex behave similarly. It is thought thatthose columns innervated by a single thalamic nucleus(subnucleus or cell cluster) serve as a basic processir~g
module. If this perception of cortical organization (andindirectly function) is correct, the loss of a few cells,
conceivably even a single cell, could result in thc loss,
or compromise, of specific somatosensory or association abilities, if the loss occurs in the formative
periods for these processing modules.

813

33. This radial unit thesis can only explain how
neurons acquire proper positions; it docs not define
what initiates or governs their subsequent differentiation, including the course of sy~~aptogencsis,
nor doesit necessarily cstaldish when the specification of functional areas of the cortex occurs [W14]. Moreover, it
docs not provide answers to questions such as what
pmnipts the shift from symmetric division of the neuronal stcm cell, with one stcm ccll giving rise to two
others, to asymmetric division, with one stcni ccll producing another stcm cell and also an undifferentiatedneuron that divides no further? If a single progenitor
in the proliferative zone can produce more than one
ccll phenotype, how does this happen? What mechanism or mechanisms switch on the migratory process?
How docs the migrating neuron dissociate itself fromits guidance mechanism when it nears its functionalsite? What further clues does it need to position itself
properly within its functional domain?

34. The causal relationship between irradiation of theembryo and fetus at specific stages of development
and the subsequent morphologic and functional
damage to the brain, if not the molecular events
involved, are well established in a number of cxperimental animals. There is abundant information on the
biological effects caused by prenatal exposure of
mammals to ionizing radiation. Much of this evidence
has already been summarized in the UNSCEAR 1986
Report [U2].These data give, however, little quantitative insight into effects on the brain in humans,
although they serve to identify possible effects.
35. The liniitations of the human data make studies
on other spccies inevitable, if h e risks of exposure are
to be understood. There are, of course, differences inthe brain development of different species. These arc
attributable partly to the differing complexity of theadult organ, but especially to the different rates ofbrain growth and the different time of birth in relation
to developmental cvents in the brain [Dl]. In general,the histological structure of the brain is comparablefrom one species to another, both in composition andfunction, and the sequence of developmental cvents inall mammalian species studied is also similar. However, the sizes of the various cytoarchitectonic areas of
the cortex devoted to spccific functions can and dovary greatly. For example, Ihe primary visual cortex
occupies 115 of the neocortical surface in monkeys but
only 1/30 of it in humans, and Broca's language area
exists only in the human species. This suggests Ihat
the target zone associated with specific cortical functions differs in different species and that the exwapolation of experimental observations on subhunian forms
must take account of these dissimilarities. Finally,
although structures in a particular part of the brain arc
broadly alike in animals of the same and even different species, as previously stated, at the finer level of

LJNSCWR 1993 REPORT

814

axonal and dendritic ramifications and connections
there is a considerable degree of diversity among individuals within a species.
36. In order to cxarni~ie the radiation effects
observed in laboratory animals and to relate them tohu~iianobservations, the timing of an insult, in relation
to the developmental events in the brain that dictate
die consequences, must be considered [D6, D7]. Experimental procedures must be applied at comparable
stages in brain growth rather than at comparable gestational periods. The duration of exposures must also
match the different time-scales, but if these factors aretaken into account, even the small laboratory species
can provide at least some qualitative information of
relevance to the human. The complexity of the nonhuman primate brain obviously makes it valuable formany experimental purposes, and its protracted spanof development increases the resolution of temporalsequences in neurogenesis; but the use of rats andmice can much more conveniently and quickly lead toa better understanding of human teratogenesis than has
sometimes been supposed. Although extrapolations
must be made with care, the use of experimental animals is vital to progess in understanding the effects ofionizing radiation. At the same time, direct evidence,
especially that of a quantitative nature, must be continually sought from human studies and will eventually
be the most convincing.
37. In this Chapter the primary epidemiologicalstudy of the prenatally exposed survivors of the atomic
bombings in Japan is reviewed. These results are s u p
plcmentcd by additional but much more limited epidemiological investigations of other exposed individuals.
Experimental studies may be particularly important toclarify mechanisms of actions. Some comments on
recent Endings from this field conclude this Chapter.

Effects Research Foundation (RERF), have establishedseveral overlapping samples of individuals prenatally
exposed to the atoniic bombings of Hiroshima andNagasaki. These samples, the studies and the findings
are described in sornc detail in this Annex because of
their inherent imporlance and to illustrate the breadthand corisistency of the effects that have emerged.
40. Study samples. The earliest observations, thoseof Pluriimer [ P I ] and Yamazaki et al. [Y3], werebased on opportunistic samples and made no systematic attempt to be complete. They were restricted in theniethod of ascertainment and in structure; often only
one city or a limited prenatal age distribution was
involved. In 1955, however, the construction of an
exhaustive clinical sample of the prenatally exposed
survivors was started. This gave rise to what has beentermed the PE-86 Sample. Its menibers were ascertained through a variety of sources but primarily
through birth registrations, interviews with women
who were enrolled in the genetics programme in 19481954 and were possibly pregnant at the time of thebombing, thc National Census of 1950, and earlier ad
hoc censuses conducted by the city authorities and the
ABCC. No attempt was made to match, by sex or prenatal age at the time of the bombing, the more distally
exposed or the non-exposed with those sukivors exposed within 2,000 meters.
41. In 1959, this sample was revised [B7] according
to the following considerations:(a)A. PRENATAL EXPOSURE
TO ATOMIC BOMBINGS
38. Few population-based studies of the effects ofprenatal exposure on the developing human embryoand fetus exist. Present knowledge rests mainly on theobservation of those survivors exposed prenatally
during the bombings of Hiroshima and Nagasaki and,to a lesser degree, on studies carried out on children
who were prenatally exposed to radium or x rays in
the course of radiotherapeutic treatment of theirmothers and on comparative embryological studies.
Among these, however, the size, length of study,
variability in dose and post-ovulatory age at exposure
make the experiences in Hiroshima and Nagasaki themost important source of data.

39. Over the years, the Atomic Bomb Casualty
Commission (ABCC) and its successor, the Radiation@)

the earlier (1955) sample contained a disproportionate number of prenatally exposed survivors
who were thought to have received doses of lessthan 0.01 Gy, and since clinical facilities andpersonnel were limited, examination of these
individuals strained resources and seemed unproductive in view of the probable exposures. In theinterests of clinical efficiency, sample size waslimited, at the loss, presumably, of little or no
information:
special censuses conducted in 1950 and 1951 by
the ABCC appeared to offer a better basis forthe selection of a comparison group of non-exposed individuals than had previously obtained.

42. This new sample, known as the Revised PE-86
Sample, or the Clinical Sample, 'differs in several
important respects from the unrevised one:
(a)
@)

(c)

it includes no survivors prenatally exposed at
distances between 2,000 and 2,999 meters;
exposed individuals are limited to thosesurvivors prenatally exposed wilhin 2,000 meters(the proximally exposed) or between 3,000 and
5,000 meters (the distally exposed):
non-exposed persons include only those individuals who were beyond 10,000 meters at the(d)time of the bombing and wcrc criu~nrratedin thc
special censuses;
the survivors within the 3,000-5.000 lnetcr zone,
as well as the non-exposed, wcrc matched forsex and age @y trimester of prcgnancy) withthose cxposed withir~2,000 nictcrs.

Thcsc steps reduced the clinical burdcn substantiallybut rcsulted in little changc in the number of persons
within 2,000 metcrs. Both snmplcs include virtually all
individuals who received substantial exposures (thosc
with estimatcd tissue absorbed doses of 0.5 Gy or
more) and differ primarily in the number and ascertainment of individuals in the dose range 0-0.01 Gy.
It is this group that has been the basis of most subsequent analyses (see, e.g. [M3, W1, W21).
43. The data on severe mental retardation are
restricted to the Clinical Sample, since it involves the
only individuals on whom extensive clinical observations are available in both cities. In so far as
intelligence tests and school performance data areconcerned, attention is focused on the earlicr,u ~ e v i s e d sample to bring the largest practicable
number of observations to bear on the issue ofpossible brain damage more subtle than severe mental
retardation. The intelligence tests were conducted andthe school performance data obtained in 1955, that is,
before the definition of the revised sample.

44. Dose estimates. The analyses of the effects ofprenatal exposure to ionizing radiation to be describedin the paragraphs to follow all employ the estimatcd
absorbed dose to the mother's uterus based on the
DS86 dosimetry ([Rl]; see also [H5, K3]), unlessotherwise specifically noted. Estimates of the absorbed
doses to the fetus itself are not yet available and may
not be for some time. Parenthetically, it should be
noted that the organ absorbed doses computed under
the DS86 system are actually age-specific population
averages rather than individual-specific estimates,
since the mean dose to an organ dcpcnds not only on
the energy spectrum of the gamma rays and neutrons
involved but also on the size of the organ. This willvary with the size of an individual survivor, which is
not known. The organ doses estimated are, therefore,
based on a "reference"man or woman, a hypotheticalindividual whose size approximates that of the average
Japa~icseman or woman at the time of the bombings.
The doses are derived from a mathematical phantom
that simulates the human body by a series of simple
geonietn'c shapes: ellipsoids, elliptical cylinders andcones, or parts of these. The size of tbc phantom canbe adjusted to represent individuals of different ages
or gcnders. Six different phantoms were used: an
infant, a juvenile and an adult for each of the hvo
sexes. When one of these phantoms is used in concert
with a computer program that models the transport ofneutrons or photons through the body by Monte Carlo

methods, an estimate of the averagc absorbed dose inan organ can be calculated.
45. The element of uncertainty introduced by thismethod of estimating doses is presuniably not scrious
except, possibly, in the case of a pregnant woman.
Hcre the difficulty arises bccause the reference woman
uscd in the DS86 calculations was assumed not to be
prcgnant, as was certainly true of the vast majority ofwomen survivors. However, in the pregnant woman
the size of the utcrus changes dramatically as prcgnancy advances, and as the uterus enlarges, the otherorgans of the abdomen are shifted from their normal
position and compressed. Thus the estimated dose to
the uterus based on the reference woman describes theactual dose to the uterus more poorly in the laterstages of prcgnancy than in the early ones, before theuterus has undergone much changc in size, and it may
therefore be a poorer surrogate later in pregnancy.
Although the error in the dose this may introduce ispresumably small, given the energy spectrum involved,
it should be noted, nonetheless, that to the extent that
doses are overestimated, the risk to the embryo or
fetus will be underestimated, or conversely if thedoses are underestimated.

Developmental age. One of the most importantfactors, aside from dose, in determining the nature of
the insult to the embryo or fetus resulting from exposure to ionizing radiation is the developmental age.
Accordingly, since, as previously stated, different
functions in the human brain are localized in different
structures and since the differentiation of these takes
place at different stages of development and overdifferent periods of time, the estimated post-ovulatory
ages at exposure (here taken to be synonymous with
developmental age) have been grouped s o as to reflect
these known phases in normal development. Post-ovulatory age has been estimated to be 280 days less thenumber of days between the bombing and the birth.
The averagc duration of a pregnancy, measured fromthe onset of the last menstrual period is taken to be
280 days. Fourteen days are subtracted from the daysof pregnancy at time of bombing to account for thetime between the onset of the last menstrual period
and ovulation (and fertilization of the oocyte). Fourage periods have been uscd: 0-7 wecks (0-55 days),
8-15 weeks, 16-25 weeks and 26 or more wecks after
ovulation.

46.

At the post-ovulatory age of 0-7 weeks (0-55
days), the precursors of the neurons and ncuroglia. thetwo principal types of cells that give rise to the
cerebrum, have emerged and are mitotically active. At
8-15 weeks, a rapid increase in the number of neurons
occurs; they lose their capacity to divide, becoming
perennial cells, and migrate to their functional sites. At
16-25 weeks, differentiation in siru accelerates,

47.

UNSCEAR 1993 REPORT

816

synaptogenesis that began about week 8 increases, andthe definitive cytoarchitecture of the brain unfolds. At
26 or Inore wccks, architeclural and cellular diffcrentiation and synaptogcncsis of the cerebrum continue,
with, ;it the same time, accclcrated growth and developme111of tllc cerebellum.
48. Experir~lcntal studies [ H l l ] have shown that
irradiation at about day 16 in the rat (roughly week 28
in the human) will produce gross distortions of the
Icaf-like gyri, or folia, of the cerebellar cortex, as well
as deficiencies in the granular and molecular layers of
Ihc cerebellum. The defects in these layers are evenmore common when exposure occurs shortly after
birth, although the folial changes are not. In the rat,
when irradiated between day 19 and day 21 (about
week 31 to week 35 in the human), disordered cerebcllar migration is a common occurrence (C12, H201.
49. Effects on brain growth and development. So
far, only two conspicuous effects on brain growth anddevelopment have emerged in the study of prenatally
exposed survivors of the atomic bombings of Hiroshima and Nagasaki. These are some cases of severe
mental retardation and some of small head size
without apparent mental retardation. Additionally,groups within the survivors have shown an increased
frequency of u~~provokedseizures and significantly
reduced intelligcnce scores and performance in school.
The severe mental retardation and the reduced intelligence scores and school performance may be manifestations of the same process, in which all the individuals significantly exposed in the relevant stages ofpregnancy suffer some dose-related reduction in cortical function, thus increasing the number of thoseclassified clinically as being severely retarded.

absorbcd dose 0.03 Gy; posl-ovulalory age 20 wccks)
in infancy, and a fifth, in
had Japancsc B c~~ccpl~alitis
Hiroshima, had a retarded sibling (dose 0 Gy; postovulatory age 20 weeks). It is co~~ceivablc
that, inthese iesl;lnccs, tllc mcnt;~lretardation was n~erclya
part of Uic forrner syr~dro~iie
or secondary to the infection, but ia either e v e ~ not~ t radiation-related.
52. Whcn lhc prcnalally cxposed survivors, exclusiveof tile tl~reccascs of Down's syndronie, are distributed
over the four post-ovulatory age groupings describedin paragraph 47 and the frcqucncy of mentally retarded individuals is examined in the light of their estimated doses and the post-ovulatory age at which they
were irradiated, the following emerges (see Table 4
and Figure I) [Ol]:
(a)

@)

(c)

(d)

1. Severe mental retardation
50. Individuals classified here as severely mentallyretarded are those who cannot form simple sentences,
perform simple arithmetic calculations, care for themselves, or have bcen or are institutionalized or unmanageable. Thirty cases of severe mental retardation
were observed in the 1,544 individuals included in theClinical Sample for whom DS86 doses can be computed (dases were not available for 55 survivors inthis sample at the time of this analysis). Details of
exposures and clinical findings for the 30 cases ofsevere mental retardation are given in Table 3.
51. Three of the scvcrely nicntally retarded children,
all in Hiroshima (cstiniated uterine absorbed doses 0,0.29 and 0.56 Gy; post-ovulatory ages 36, 13, and 12
wecks, respectively), are known to have or to have
had Down's syndrome (one child died in 1952). A
fourth child, also in Hiroshima (estimated uterine

the highest risk of severe mental retardation
occurred with exposure 8-15 weeks after ovulation. This exceptionally vulnerable period
coincides with the most active production ofcortical neurons and when all or nearly all of the
migration of the immature neurons to the cerebra1 cortex from the proliferative layers takes
place;
within this critical pcriod, daniage expressed as
the frequency of subsequent severe mental retardation increases as the dose estimated to havebccn rcccivcd by thc fctal tissues increases.
Some 75% (9 of 12) of fctuses exposed to 1 Gyor more in this period are nienL?lly retarded; thisis an incidence more than 50 times greater thanthat in the unexposed comparison group;a period of lesser vulnerability appears to exist
in the interval 16-25 weeks after ovulation.
However, no increase in incidence is seen atdoses estimated to be lcss than 0.5 Gy;
there is no apparent increased risk before week
8 or after week 25. Whether the seeming absence of an effcct in the first two months after
ovulation is real, or merely reflects the fact thatembryos exposed at that stage of development
commonly fail to survive to an age at whichmental retardation can be recognized, is unclear.
However, experimental studies (see, e.g. [ H l l ,H13]), have also failed to find effects on thedeveloping mouse or rat nervous system at doses
as high as 3 Gy in the first 8 days after fertilization, a period of time corresponding to thefirst 8 wccks or so in the human.

2.

Snulll h e l d sizel l sizes to which reference has been
53. The s l ~ ~ ahead
made were two or more star~darddeviations below themean head size of all of the individuals in the revised
study saniple. About 10% of these individuals with

ANNEX I I: RADIATION EI:m.CE ON TliE DEVELOPING IlUh4AN HRNN

sniall head sizes wcrc also 11ic111allyrctardcd. Arnong
the nientally retarded in the 1,598 births in the entirc
saniple [B2, M2, M3, M4, TI ] , I 8 persons (60%) havebccn prcviously reported to have or to have had
disproportionately sniall llcads [ W l , W2]. This valuc!nay be spuriously low, sincc l~cadcircu~nfcrcnccwas
not standardized against body size and sincc ~ncntal
retardation is often seen in individuals whose headcircumferences arc disproportionatcly sniall for theirbody sizes. It is commonly thought that the developnicnt of the bones forming the vault is closely associated with tlic dcvclopment of the brain and dura, and
it is known that in fctal life thcsc bones move with thegrowing brain. It is not clear, therefore, how independent this sceniing abnormality may be of severe niental rctardation nor what small head size may imply
about the nature of thc radiation-related damage. It is
tempting to believe that the s~iiallerhead arises as aresult of fewer neurons (because of ccll death), but
this may not be so. Reyners et al. [R14] have foundthat in the rat at low doses of x-radiation (0.090.45 Gy), the numerical densities of neurons and glial
cells arc actually increased, although the sizc of thecells is significantly reduced. The authors suggest thatthe brain has undergone a "miniaturization" rather than
necrosis. However, as previously noted, glial cells
rctain their proliferative ability and could replace lost
tissue mass, as D'Amato et al. ID21 observcd experimentally. If so, brain volume could remain the sameand head sizc develop nonilally, but cortical function
would be diniinished.
54. Recently, Otake and Schull [013] re-exaniined
the relationship to radiation cxposure of small hcad
size among the prenatally exposed population in Hiroshima and Nagasaki, using thc cstimated DS86 doses.
The study population consistcd of the 1,598 individuals (Hiroshima 1,250, Nagasaki 348) used by Otake
et al. [ O l ] in the analysis of scvcre mental retardation.
DS86 doses were available on 1,566 of these persons(1,242 in Hiroshima and 324 in Nagasaki; this rcprescr~tsan addition of 22 cases to h e number describedin 1011). Among these subjects, 1,473 had their headcircumference measured at least once in the period
from 9 to 19 years of age.
55. As stated above, an individual with a sniall headsize is defined as someone with a head circumference
less than 2 standard deviations below the mean observed at his or her specific age at measurement. It
should be noted that often, in the past, these individuals have bccn described as ~~licroccphalic.
This tcmi
scenis inappropriate, however, for two reasons: first.
microcephaly denotes a clinically recognizable smallness of the head, which is often misshapen as well,and secondly, the clinical diagnosis generally isapplied to individuals whose hcad is even smaller incircurnl'crc~~ce(oftcn 3 skindilrd deviations or riiore

817

below tlic niean) Illan the criteria used here. Accordingly, citl~erof two temis, "atypically sniall head" or"small head size" would sccrn to be niore appropriate
to dcscribc thc ir~dividuals siitisfying the criteria
dcscribcd above.
56. Of tlle 30 cases with scvcre rncntal retardation
described elsewhere 101],26 wcre included among the
1,473 study subjects. Three of the four lost cases died
before 1954, that is, before they were 9 years of age.
The one remaining case, a non-exposed individual,
survives, but she did not have a physical cxarnination
between 9 and 19 years of age.
57. Among the sample of 1,473 individuals, 6 2 hadsmall hcads according to the criterion previously
described. It should be noted that the criteria aredifferent for males and females of the same chronological age; the differences range from -0.98 to 1.34 cm.
58. Small head size and trimester of exposure. The
frequency of individuals with small head sizes, withand without severe mental retardation, is shown in
Table 5 by trimester at exposure and estimated DS86
uterine absorbed dose. Figure I1 gives the proporlionof small head sizes by trimester at exposure. As isevident from Figure 11, the incidence of individuals
with small head sizes in thc first trimester unquestionably increases with increasing estimated dose; it also
increases in the second trimester, but to a lesser
extent. Hardly any increase is observed in the third
trimester. Of the 26 mentally retarded individuals, 15(58%) had small hcads (Table 5). About 24% of the
62 individuals with small head size (determined by
agc-specific criteria) among the 1,473 clinical subjects
from both cities were mentally retarded. This ratc
increases to 29% (13145) when only those survivors
exposed to 0.01 Gy or more are considered. These
rates, it will be noted, are greater than that (10%)
previously reported by Wood ct al. [Wl, W2].
59. Almost all of the individuals with small headsizes were exposed in the first or s e c o ~ ~trimester,d
55% in the formcr and 31% in the latter. The risk ofan atypically small head and severe mental retardation
observed among individuals exposed in the second
trimester to an estimated 0.01 Gy or rnorc is 57%(8/14), but only 19% (5127) in the first trimester.
Alternatively stated, among individuals with an
atypically small head and severe mental retardation,
the bulk, 62% (8/13),were cxposcd in thc second
trimester.
S ~ n a l headlsize and posl-ovulalory age (weeks)ul exposure. The proportion of individuals with small

60.

head size for the four post-ovulatory periods, namely,
0-7 weeks, 8-15 weeks, 16-25 wccks and 226 weeks,is also shown in Table 5. The proportion of indivi-El 8

UNSCMR 1993 IEPORT

duals \vitlr srnall hcad size increases with increasing
cstiniated dose in only Ure first two periods, and an
especially sharp rising trend is seen in h e 8-15 week
period (Figure 11).
61. I11 tile 17 individuals froni both cities with asniall Iread in Ure 0-7 week period there was no apparent mental retardation. Twelve of these individuals
were exposed to an cstimatcd dose of 0.01 Gy or
more. One of two (50%) of the individuals exposed to
r1.00 Gy had s~nallIread size and two of four (50%)
cxposcd to 0.50-0.99 Gy had srnall head size. There
were 29 individuals with small head size in the 8-15
week period. 26 of whom received an estimated doseof 20.01 Gy; 12 of them (46.2%) were severely mentally retarded. Seven (87.5%) of the eight small headcascs who were exposed to r1.OO Gy had severe menial retardation. Thus, 12 (80%) of the 15 individuals
with an atypically small head and severe menial retardation occurred at the most radiosensitive period, 8-15
weeks after ovulation. In the 16-25 week period, only
one (33.3%) of the three individuals with small headin the >0.01 Gy group was mentally retarded, and hehad been exposed to a dose of more than 1.00 Gy.
6 2 The rubric "small head size" may, indeed
probably does, cover a variety of different develop
n~ental"abnormalities". Among the individuals withsmall head size and severe mental retardation, forexample, some clearly invite the clinical diagnosis of
microccphaly, since the head is not only unusuallysmall but misshapen, often pointed or oxycephaliclike. Still others, and they are more common, have a
hcad size that is proportionate in all dimensions, albeit
small. Moreover, since head size varies in all populations, it can be assumed that some of the individuals
here designated as having sniall head size merely
rcprcsent the lower extreme of normal variability.
Indeed, based on the criterion for srnall head size usedhcrc, if head sizes are approximately normally distributed, sonic 2.5% of "normal" individuals would be soclassified.

63. Silice the rneari intelligence quotient (IQ) and its
standard deviation among the 47 individuals having
small head size without severe mental retardation
approximate the values seen in the entire clinicalsample, it is conceivable that a significant fraction of
Ulcsc individuals are the "normals" alluded to above.
Accordingly, Otake and Schull I0131 attempted toestimate the excess number of individuals with small
hcads ostensibly attributable to exposurc lo ionizing
radiation (see Table 6). Among the 62 individuals wilhsmall head size, some 37 would be expected normally,
and thc observed and expected numbers agree reasonably well whc11 exposure occurred in the 16th week orlater. I-Iowcvcr, there is a striking excess prior to thistime, wliere 16 are expected but 46 were actuallyobscrvcd, an excess of 30 cases. If it is assumed that
UIC s~riallhead size among those 12 individuals withsevere ~nental rctnrdation is secondary to brain
darnagc, tliis lc;lves 1 8 CiiSes tlrat might represent
radiation-related illstances of growth retardation
wilhout accompanying mental impairment. But canthese I;~tter individuals be distinguished from those
expected by chance? To explore this possibility, thelocations of the 47 cases of small hcad size without
lnental retardation wcrc determined in a bivariate plotof standing vcrsus sitting height expressed as age- andsex-standardized deviates based upon the full sample
of 1,473 individuals. The individuals with a smallhead size but no apparent mental retardation werefou~rdto be disproportionately represented among thelower values defined by either the 95% or 99% probability ellipse (see Figure 4 in [013]). Three individuals
were outside the 99% ellipse, but only one of thesethree received an estimated dose of known biologicalconsequence. Specifically, the DS86 uterine absorbed
doses in the mother were 0, 0.04 and 0.49 Gy. Theseobservations suggest that small head size is not an
independent teratogenic effect but is either secondary
to mental retardation or to a more generalized growth
impairment without clinically recognizable mental
retardatio~r(see [016]).

3. Intelligence test scores
64. Intelligence has been variously described as theability to manage oneself and one's affairs prudently;
to combine the elements of experience; to reason,compare, comprehend, use nunlerical concepts andcombine objects into meaningful wholes; to have thefaculty to organize subject-matter experience into newpatterns; or to have the aggregate capacity to act purposefully, think rationally and deal effectively with
one's environment. Given such differences in definition, it is natural that the bases of measurement shouldvary.
65. Intelligence tests differ one from another in thei~nportance given lo verbal ability, psychomotor
reactions, social comprehension and so on. Thus, thescore attained by an individual will depend to somedegree upon Ule specific test used: generally, however,individuals scoring high on orre test tend to score highon other tests. It is important to note, however, thateven with tlie sanle test an individual's score is not an
immutable value, as retesting has shown. Thus, achange of a few points in a particular child's score
may not he clinically significant, but a change of only
a few points in the mean score for a population ofchildren can have important public health implications,
resulting iri a higher proportion of socially dysfu~ictional individuals. Most intelligcrice tests are so structured that the distribution of test rcsulls follows an

ANNEX 11: RADIATION EFFECTS ON

approximately normal curve, with a mean of 100 anda standard dcviation of 12-15 points. Thus, nornlally
some 95% of the population will havc scorcs in therange 70-75 to 125-130, that is, will fall within two
standard deviations of the mean. Individuals whose
scorcs lie, consistently, two standard deviations or
1110rc below the mean would commonly be describedas rctarded. In the Japanese experience, the nican
Koga score of some 1,673 tested children was 107.7(standard dcviation 16.08) [S4], and the highest IQ
achicvcd by any of the clinically diagnosed severely
mentally retarded children was 64 [Ol].
66. Schull ct al. [S4] havc dcscribcd an analysis of
the results of intelligence tests of the prenatally
exposed survivors of the atomic bombings of Hiroshima and Nagasaki conducted in 1955 by trained psychometrists. This analysis of the Koga test scores [ K l ,T2],which also used estimates of the DS86 uterine
absorbed dose, reveals the following (see Figure 111):

(a)

@)

(c)

there is no evidence of a radiation-related effecton intelligence among those individuals exposed
at 0-7 weeks or >26 wceks after ovulation;for individuals exposed at 8-15 wceks after
ovulation, and to a lesser extent those exposed at
16-25 weeks, the mean test scores, but not thevariation in scores about the mean, aresignificantly hetcrogencous among the four
exposure categories;
the fact that the mean test score declines significantly with increasing estimated dose withouta statistically demonstrable change in the variance of the test scores suggests a progressive
shift downwards in all individual scores withincreasing exposure.

67. While intuitively it is reasonable to assume that
achievement on intelligence tests is related to thequality of brain function, and that the diminishedperformancc described above reflects some functional
impairment, the biological basis (or bases) of that
impairnient is far from clear. Performance on intelligence tests can be affected by factors other thanionizing radiation, such as motivation, socialization athome and in school, and physical impairment (defectivc vision or hearing, for example). Of necessity, since
information on these extraneous sources of variability
does not exist, they must be assumed to be part of therandom error in the analyses of such tests, but thepossibility that they change systematically with dosecannot be ignored, although there is no evidence that
this is so.
68. Qualitatively, these findings are consistent with
the interpretation that there is a dose-related shift in
1Q and that this could explain the increase in clinicallyclassified cases of severe mental retardation.

4.

School performnnce

69. As a part of the continuing assessment of theeffects on the developing embryonic and fetal brain of
cxposurc to ionizing radiation, thc school perfonnances of prcnatally exposed survivors of the atomic
bombing of Hiroshima and a suitable comparisongroup have been studied [02].
70. The Japanese place strong emphasis on school
pcrforniaiice and school attcndance [B9]. As a consequence, the Japanese child rarely misses school without good cause and places high value upon achicvemcnt in school. If a child's attcndance record is correlated with illness and performancc with innate ability,
attendancc might be conelated with exposure as a consequence of more (or less) frequent illness, andperformance might reflect the nature of the developmental events that took place when exposure occurred.
Accordingly, with the approval and assistance of theMunicipal Board of Education in Hiroshima and thewritten consent of the parents of those prenatally
exposed, their school records were microfilmed in
1956. At that time these children were 10-11 years
old, and niost had recently completed their fourth year
in elementary school. The records themselves include
infomiation on school attendance, performance invarious subjects, behaviour and physical status.
71. The attendance records of the public schools ofJapan indicate the actual number of days of school andthe total number of days of school missed by a specific child, the number of days tardy and the number ofdays the child left school prematurely. The days
missed arc further subdivided into absences because ofillness and absences for other reasons, such as deathor illness of another member of the child's family.
The ratio of the days missed through illness to thetotal days of school affords a crude measure of thehealth of a given child.

72 With some 250 school days per academic year,
the typical child in these years failed to attend school
fewer than 5 days a year. On average, school absenccs
for illness tend to increase generally with dose among
the four post-ovulatory age groupings, when the clinically recognized mentally retarded cases are i ~ ~ c l u d eindthe sample analysed. Absences also tend to diminish
in number as the child advances in school. This continues to be true when the nicntally rctarded, who are
more prone to illness, are excluded, but the ovcrall
effcct of radiation on attendancc beconies more equivocal. Whcn one turns to age-specific categories, i t isobserved that (a) the number of absences continues todiminish in all age groupings as the child advances inschool; and (b) the largest arid most consistent effectof radiation, with and without respect to sex, involves
the age group exposed 8-15 wccks after ovulatio~~.

73. In the first four ycars of clcmcntary schoolingt l ~ cJapancsc child studics scvcn subjccts: thc Japancsc
I;t~~guagc,
civics, arithmctic, science, music, drawing
and handicrafts, and gyr~inastics.Every student's pcrf o r ~ n n ~ ~withc c rcspcct to tl~cscsubjccts is cvi~luatcd
routi~~cly,and at thc C I I ~of cvcry scmcstcr (thcrc arc
thrcc in thc acadcnlic ycar) a scorc is assigricd forcach. At thc cnd of tlic acadcn~icycar, thcsc scorcs arc
summarized into a sit~glcvaluc for cach subjcct. The
lattcr varies, non~ially,in unit stcps fronl +2 to -2Thc
highcst and lowcst livc pcrccntilcs of the class are
assigncd scorcs of +2 (vcry good) and -2 (poor), rcsl)cctivcly. The ncxt highcst nnd lowest 20 pcrccntilcs
arc givcri +1 (somewhat above avcragc) and -1 (sonicwhat below average), and finally, thc niiddlc 50% arc
givcri zcro (average). Otakc ct al. [ 0 2 ] have convcrtcd
thcsc assigned valucs to a fivc-point scalc (5, 4, ..., I),
giving the highest and lowcst scores the values 5 and1, rcspcctivcly, and so on. Sonie scorcs for somc individuals wcre cithcr missing or illegible in the copiesof thc original rccords; all of the information that wasavailable was uscd in UICSC instanccs.
Before determining what measure of school pcrfonnancc should bc fitted to the dosc data, given thei~~tcrdcpendcncc
of the various school performancescorcs, the investigators cxamined the structure of thematrix of conelation cocfficicnts among thc scvcn
subjccts previously cnunicratcd. The corrclatior~swcre
high, ranging from 0.62 to 0.82, suggesting a strong
intcrdepcndence of the scorcs. Accordingly, to dctermiuc whether some combination of the scores would
provide a more suitable mcasure of radiation-rclated
damage than the scores individually, summary charactcristics of the corrclation maeix wcrc computed.
Tl~csccomputations rcvcalcd that assigning approxinialcly equal wcighls to the scores and summing thc
product of the scorc and its weight would account for
75% of the collcctivc variability. More mathematicallystatcd, the vast n~ajority of the variability was cxplaincd by the first cigcnvcctor, which since it weights
subjccts equally, is tantamount to the mcan o l theindibidual subjcct scorcs. No othcr combination of thc
scorcs cxplaincd morc than 6% of h e variability, andall wcrc associated primarily with a singlc subject, thesecond with music, Uic third with gymnastics, ctc.
74.

75. Achicvcmcnts in school of h e prenatally
cxposcd survivors, as judgcd by the relationship of the
avcragc school pcrforniar~rcscore in thcsc subjects,
caa be sunimarizcd ;IS follows (see Figure Ill):
(a)

(b)

for 8-15 wccks aftcr ovulation, scholastic
achicvcnicr~t i ~ r school diniinishcs as thecstimatcd absorbcd dosc inncascs;
a similar diminution is seen for 16-25 wccks
after ovulation. This trcnd is stronger, however,in the earlicst ycars of schooling:(c)

ill thc groups cxposcd 0-7 wccks after ovulationor 26 or morc wccks aftcr ovulation, thcrc is noc v i d c ~ ~ cofc a radiation-rclatcd cffcct on acadc~ilicpcrl'ormancc.

Not u~~cxl~cctcdly,
givcn 1l1c corrclation bctwccli
avcragc scliool pcrformancc and IQ scorc (r = 0.54),
thcsc rcsulls parallcl thosc ~)rcviouslyfound in prcnalally cxposcd survivors with rcspcct to achievcnicnt
tcsts in childhood.
in standard i~~tclligcr~ce

5.

Seizures76. Scizurcs arc a frcqucnt scqucla of impaircd brain
dcvclopmcnt and could thcrcrorc bc cxpcctcd to affectmorc cl~ildrcnwith radiation-rclatcd brain damagc thanchildrcn without. Dunn ct al. [D3] have dcscribcd ttic
incidcncc and typc of seizurcs among the prenatally
cxposcd survivors of the atomic bombings and thcir
associ;ltion wit11 specific stagcs of prcnatal dcvclopmcnt at the time of irradiation. Histories of scizurcs
were obtaincd at biennial routinc clinical cxaniinatio~~sstarting at the age of 2 ycars.
77. Scizurcs, as here dcfi'incd, include all refcrcncesin thc clinical rccords to "scizurc", "cpilcpsy" or "convulsion". All of the medical rccords of participants inthis I)rogr;lnime of examinations who wcrc coded lor
scizurcs wcrc revicwcd to characterize the naturc of
the scizurc (i.e. ils scverity, clil~icalsymptomatology,
prcscncc o l fcvcr, cause of the scizurc, duration), theprcsencc of other neurological disease, developnicntal
landmarks, school pcrformancc, and any olhcr medical
problc~u.Thc rccords wcrc 1101sufficiently explicit nor
were clcctroc~~ccphalograpliicfilldings available topern~itdetailcd clinical classilication. Howevcr, thcrc
was c ~ ~ o u description
gl~to allow a limited catcgorization of scizurcs by actiology for epidemiologic purposes. Starting with all scizurcs, cascs wcre classificd
as lcbrilc, acutc symptomatic (scizures due to acutc
ccr~tralncrvous system insult, such as hcad trauma)
and utlprovokcd.
78. Cascs of ur~provokcdscizurcs arc those scizurcs
without a rccord of a conconlitant acutc insult, that is,a known precipitating causc o r a scizurc, c.g. fcvcr,
traunla. post-vaccination reaction, or anoxia during an
acutc postnatiil cvcnt. A scizllrc was so classificd if
the rnctlicnl rccords rcvcalcd no clear statcmcnt of
cxposurc to ;III accompallyillg infectious, traunialic or
fevcr-produring agcnl. Strictly nconahl s c i ~ u r c s(witl~inthe first month post-par tun^) wcre difficult to
asccrtitin in this study, which did not begin until thc
children wcrc 2 years old. Sincc nconatal scburcs
appcar to have a diffcrcnt actiology and were most
likely undcrasccrtaincd, thcy wcrc routinely cxcludrd.

ANNEX I I: IWDIATION EFIFCTS ON Ti lE DEVELOPING I IIJMAN BRAIN

79. Fcvcr is thc lilost comlnon prccipitating causc of
scizurc in infancy or childhood. In thc cvcl~t ofmulliplc scizurcs, howcvcr. fcvcr niigllt accornpasy
only o ~ i cscizurc, arid thcn not licccssarily thc first,
and scoring thcsc cascs was undoubtedly arbitrary. The
invcstig;~lors adoplcd the followiag colivcntio~i: if
fcvcr accompanied o~ily one of scvcral scizurcs,
niakilig il doubtful that fcvcr was a gcncraliy prccipitating causc in an individual, thc casc was scorcd asunprovokcd.

80. No scizures wcrc rccordcd among individuals
cxposcd 0-7weeks aftcr ovulation at cstimatcd doscs
higher than 0.10 Gy. In the group cxposcd 8-15 wccks
aftcr ovulation, thc incidcncc of scizurcs was highcst
among thosc who rcccivcd doscs cxcccding 0.10 Gy
and incrcascd with lhc lcvcl of fctal cxposurc. This
was the casc for all scizurcs without regard to thcpresence of fcvcr or prccipitating causes, arid forunprovokcd scizurcs. When Lhc 22 cases of scvcrc
mcntal rctardation were cxcludcd, thc incrcase inscizurcs was only slighlly significant, and thcn only
for unprovokcd scizurcs. After cxposurc at later stagesof dcvclopmcnt, tlicrc was 110 inncasc in rccordcd
scizurcs.

81. Othcr data on the occurrence of scizurcs
following in urero cxposurc arc sparse, and thcrc islittle to which thesc observations can be compared.
Howcvcr, two case rcports suggcst that the pcriod
bctwccn 8 and 15 wccks may bc a vulnerable timc forcxposurc of the human fetus to radiation, with subscqucnt devclopmcnt of scizurcs IG101.Thc first individual was a male cxposcd in thc secorld to fourth
month of gestation in lhc course of his mother's radiotherapy (dose unknown) for utcrinc myomatosis. HC
thcn dcvclopcd epilepsy at he agc of 3.5 years. Thc
sccond was a female cxposcd during months 2 and 3,
again in lhc course of maternal trcatmcrlt for utcrinc
myoniatosis (dose unknown): she developed cpilepsy
at 2 ycars of age.

82. Sunrttiaty. To summarize paragraphs 50-81,
studics of the prcnatally cxposcd survivors of theatomic bombings of Hiroshima and Nagasaki haverevcalcd a statistically dcmonstrablc dose-rclatcd
incrcasc in thc frcqucncy of mcntal rctardation,sci~urcs, individuals with atypically small hcads,
diminution in intclligcnce test scores and acadcmic
achicvcn~cntThcsc cffccts arc rriost conspicuous inu.ccks 8-15 following ovulation; howcvcr, Ihcrc is asignificant increasc in thc nunibcr of individuals withsmall hcads in the first two months post-ovulation (12o f 8 l ) and somc cvidcncc that mcntal retardation niay
be more common than expccted in post-ovulatory
wccks 16-25, particularly at doscs estiniatcd to be
0.5 Gy or more, whcrc 3 (12.5%) of 24 children wcrc
rc~ardcd.

6.

82 1

I'c~tholagic and other findingsof brain abnolnlnlities

Thc biology of nicntal rctardatiol~ rcmains
cnigniatic, arid without a clcar understanding of thc~~iolccularand ccllular c v c ~ i btliat culmin:~tc in thisfunctional dcfcct, tlic rolc ionizing radiation may playin its origin is clusive. Dcspitc important recent
advances in diagnostic rncthods, causation is unknown
in Ihc great majority of cascs of mcntal rctardation.
Oftcn (100~20%of cases) thc brain appears normal
by all standard rncthods of ncuropathologic cxamination. Evcn more frcqucnlly the structural changes thatarc sccn are mild and non-specific: the brain may bc
small, the grcy niattcr may bc aggregated abnormallyin the subcortical arcas, the columnar arrangement of
cclls niay be unusual or the ncurons may be moretighlly packed than customary. However, two observations arc common: a dysgcncsis of dendritic spines on
thc cortical pyramidal neurons and impaircd growth of
dcndritic trees of pyramidal neurons, affecting bothbasal and apical dcndritic branches [H18]. These findings suggest dcfccts in the geometry of the cerebral
cortcx, which form a plausible, but obviously notestablished, basis for the mcntal rctardation. They
further suggest that the difference betwccn the normal
brain and the retarded onc may be as much quantitative as qualitative. But the brain is a structure that
uridcrgocs major postnatal dcvclopmerital changes,
including the pruning and rcarrangcmcnt of synapses,and these continue into adolcsccnce. Since this postnatal growth may modify errors that arosc prcnatallyor pcrinatally, ncuropathologic abnormalitics seen in
the cortex may depend on the age at which the individual was studied. Catch-up growth has bccn obscrvedin some instances in cxpcrimcntal animals, but theprcvalcnce of this in the human is unknown. Postnatal
growth changes niay mcrcly lead to mismatched conncctions and a brain with the normal numbcrs of synapses, which havc not. howcvcr, been incorporated
into functional units.

83.

Whcther tlic cases of nicntal rctardation seenamong thc prenatally exposcd survivors of the atomic
bombings of Hiroshima and Nagasaki rcprcsent malformations or instances of maldevclopmcnt is not
clcar. The issuc is more than semantic; it strikes at therncchariism of damage. This mcchanisni can bc pcrceived as involving a dose-rclatcd large effect on asmall numbcr of individuals, i.c. as a malformation, or
as a srriall cffcct on a large nu~nbcrof individuals. i.c.
as ~iialdcvclopmc~~t,or, conceivably, as a mixture of~ h c two. In nialdevelopnicnt, mcntal rctardationr c f l c c ~a dosc-proportional cffcct on a variablc that iscontinuously distributed. Otherwise statcd, cxposurc
rcsulls in a shifting downwards of the distribution of
capacities for intclligcricc and rcsulLs in somc
individuals whose capacity falls bclow that associated
84.

822

UNSCEAR 1993 REPORTwith clinical judgnicnt5 of rctardation. An analogy
involvcs small-staturcd individuals, some of whom aresmall bccausc of a singlc gcrle cffcct, such as theacl~ondroplasticdwarfs, and othcrs mcrcly reprcscnt
lowcr cnd of the nomially occurring variation in
staturc. Othcr analogies could bc drawn, such as spcrmatogenesis or hacmatopoiesis.
85. Patl~ological findings are still too liniitcd toprovidc an unequivocal answcr to the origin of mental
rctardation following exposure to ionizing radiation.
Thc information available from studies performed ispresented here.
86. Four individuals of thc Clinical Sample who diedhave been submitted for autopsy; two were mentallyrctarded and two werc not. Of the two with normal intelligence, a 9-year-old male exposed in wcck 20 after
ovulation to a dosc estimated to be less than 0.01 Gy,
died from granulocytic Icukaemia; autopsy disclosed
extensive brain haemonhages, which werc thought tobe the final cause of death. His brain had a normal
wcighl of 1,440 g and a normal structure. The death ofthe other, a 29-year-old female, was ascribed to cardiac insufficiency. She had been exposed in fetal
week 24 to an cstimatcd dose of less than 0.01 Gy.
The autopsy revealed multiple bilateral pulmonary
infarcts and cvidencc suggestive of autoimmune disease (the clinical data were too scanty, however, topursue this possibility). Cut sections of the cerebrum,ccrcbellum, brain stem and spinal cord showed noabnormality on gross or on microscopic examination.
The brain had a normal weight of 1,450 g; there was
no evidcnce of cdcma, which would have increased
brain weight.
87. Both of the mentally rctarded individuals had
brain weights substantially below normal. One of these
individuals, a 20-year-old overweight female (MF400133) exposed in week 31 after ovulation to an estimated dosc of less than 0.01 Gy, died of congestive
heart failure. Hcr body mass index (defined as weightin kilograms divided by the square of the height inmeters) was 28.6; a body niass index of 27 or greater
is commonly used to define obesity. Autopsy disclosed
scvcre cdenia and congcstion of both lungs as well as
markcd, diffuse fatty infiltration of the liver. Multiple
transcctions of the brain, which weighed 1,000 g,
rcvcaled the usual pattern of grey and white matterand no evidcrice of cdcma. Her mental retardation was
prcsuniably not related to hcr cxposure, given the very
low dose involved. The othcr mentally retarded individ ~ i i la, nialc (MI; 142623), dicd of acute mcaingitis at
the agc of 16 ycars IN3,Y l ] . If he had been carried
to the normal krmination of a pregnancy, he would
have been cxposcd 12 wccks after ovulation, but given
his birth weight (1,950 g), he was undoubtedly premature. His weight suggests that he was actually

exposed at wcck 8 or 9, sincc a full-term Japancse
infant would wcigh about 3,200 g. Thc cstimatcd
absorbcd dose to tllc utcrus of his mothcr was 1.2 Gy,
and his brain wcighcd 840 g. He was bilaterally
microphd~almicand had ~~iicrocorncac
and bila~eralhypoplasia of thc rctina, particularly in the niaculararea. Posterior subcapsular opacities wcrc prescrit inboth cycs. Coronal sections of the cercbr~rnirevcaledmassive hcterotopic grey niattcr around the lateral
vcntriclcs. Histologically tt~crcwas an abortive laminararrangemcrlt of ncrvc cclls within thc hcterotopic grey
areas, imitating thc normal laminar arrangement of thecortical ncurons. The ccrcbellum and hippocampi were
histologically norn~al,but both mamillary bodies were
missing. Thcsc bodies, which can be seen in reconstructions at 6 weeks after conccption but are notexternally recognizable in their double form until
somewhat latcr, are thought to function as a part ofthe limbic systcni, which controls emotions and motivations, and interestingly this boy was not only
retarded but scvercly emotionally disturbed. Heterotopic grey mattcr was not observed in any of the otherthree cases, including the sccond mentally retarded
individual.
88. Heterotopic masses arc collections of nerve cells
in abnormal locations within the brain. They are due
to an arrest in thc migration of the immature neurons.
They may bc single, multiple, unilateral, bilateral,perivcntricular or located decp within the white matter.
The most common locations arc subcpcndymal andjust below thc ncocortex. They may be isolated or
associated with other anomalies in brain development,such as schizenccphaly, a rare abnormality of the brain
in which clefts extend across h e cerebral hemispheres.
Individuals with isolated hetcrotopias can be clinicallyasyniptomatic; when symptomatic, they often present
with seizures in infancy or carly childhood, but
seizures have also been reported associated with otherneurological defects, such as homonomous hcmianopsia, the loss of vision in one half of the visual
field in one or both eyes [012]. Seizures have also
been scen accompanied by the partial or complete
absence of the corpus callosum [B13]. Most heterotopias are probably n~icroscopic,but if sufiicicntly
large (0.5 cm or so), thcy can be rcadily visualizedwith either computed tomography or magnetic resonance imaging [B13, 0121. The incidcncc of isolated
hcterotopias, either asymptomatic or symptoniatic, is
not known.
sccn in rodents
89. Ectopic grcy Inattcr is corn~no~lly
following exposure to ior~izirlgradiation. Hicks ct al.
[H9] rcported s u c l ~ occurrcriccs niore than three
decades ago and argued Illat they arose from surviving
cells that retained the capacity to divide but did so inan abnornial environmc~~t.
More recently, Donoso el
al. ID81 found that all rats cxposcd to 1.25 Gy ofx-radiation on gcstiitional day 15 dcvclopcd ectopic
areas bcneath thc corpus callosum and adjaccnt to tllc
caudatc nuclcus. It is prcsurncd that these isolatcd
islands, or roscttcs, of neuronal cclls arise throughfaulty rcpair of radiation-rclatcd damage lo tlic
cpcndymal wall of ttic latcral vcntricles, Icading to an
cncirclcnlcnt of milotic cclls. Subsequcr~tdivisions ofthesc cells result in neuroblasts migrating in all
directions. Structurally, the rosettes arc not laminatedbut contain neurons with the shapcs and sizes
characteristic of cortical pyramidal cclls. At 4 wccks
of agc, these cells are immaturc and scldom scen in
the laycrcd cortex above the corpus callosum. At
4 months of age, howcvcr, the immature cclls are nolonger prcsent in thc ectopias, and the cctopic
pyramidal cclls rescmblc those in thc cortical laycr.
Donoso ct al. [D8] found the nunibcr and distributionof spincs on the cctopic pyramidal cclls to bc lower
than for the layered cortical ncurons. They further
found that, whereas the nunibcr of apical spincs
dccrcascd with age in thc control animals, this did notoccur in the ectopic zones. Synapses in the laycrcd
and cctopic cortex wcrc morphologically indistinguishable. Since synaptogcnesis in thc rat is largcly a
postnatal phenomenon, and synapses wcre seen in thc
ectopic areas. these areas may havc rctaincd somefunctional activity.
90. The brains of five of thc ~ncntally retarded
individuals cxposed to thc atomic bombings, all during
week 8-15 after ovulation, have bccn cxamined using
magnetic resonance imaging techniques [S8]. Although
the number of individuals that havc bccn studied issmall, scvcral diffcrcnt ano~nalicsofdcvclopmcnt l~avc
becn scen, and thcse correlate wcll with the embryological events transpiring at the time the individuals
wcre exposed.
91. Two individuals, both nlalcs (MF 404259 and
471693), exposed during wecks 8 and 9 aftcr
ovulation, showed ventricles somewhat larger thannormal and areas of hcterotopic grcy matter adjaccnt
to thc latcral ventriclcs. One of these individuals (MF404259) exhibited an underdcvelopcd arca in the left
temporal region, an antcrior comniissure somewhat
wider than normal and a thickened nucleus accumbcns
scpt. Fonnation of thc caudatc lenticular bridge also
appeared to be poor. I t is noteworthy that this is theperiod when the Grst wave of neuronal migration
develops, the onc that procecds without the support of
the radial glial fibrcs. The findings in thcsc two cases
are strikingly similar but not idcntical to those on the
autopsied casc dcscribcd carlicr. However in these two
instances, unlike the autopsied casc, both mamillarybodies are clearly visible in he images. While this fact
could be attributable to variation in devclopnicntal age,
it could also suggest that the estimated ages at
exposure are not exact.

92. Ectopic grcy niattcr occurs in olhcr instances ofrnc~~tal
retardation not relatcd to exposure to ionizing
radiation, but its prevalence aniong nicntally rctardcd
i~idividualsis not rcliably known, and it may vary with
thc type and scvcrity of Ihc rctardation. Thus, forcxalnplc, Rosman and Knk~lils[R20] havc co~~trastcd
thc brains of six nicntally rctardcd individuals withmuscular dystrophy with those of six dystrophic
patients without ~ncntal dcfcct. The avcragc brain
wcight of the deficient group was significantly lessalan that of the controls. Grossly visible nialfonnationsof ccrcbral devclopmcnt werc present in thrcc of the
deficient patients, four showed pachygyria and all six
had significant microscopic hctcrotopias. Thcre wcrc
no gross lesions in thc control subjects, and significant
microscopic hetcrotopias wcrc prcscnt in only onc of
the patients whosc intelligence was considcrcd to b enormal. A similar comparison of individuals withniultiple neurofibromatosis (von Recklinghauscn's discasc) with and without mental rctardation found thecortical architecture to be grossly or microscopicallyabnormal among the mentally retarded but not among
those who were not retarded [R19]. Thesc architectural
abr~ormalitiesincluded random orientation of ncurons,
a disarray of normal cortical lamination and hcterotopic neurons within the cortical molecular layer.
Among the retardcd individuals they also commonlysaw (three out of fivc cases) small heterotopias in thedccp cerebral whitc mattcr (dcfincd as more than
10 nim from the cortico-white mattcr junction). These
were not seen in the individuals of normal intelligence.
However, subcortical hcterotopias wcre prcsent in all
instances of the discase.
93. Ectopic grey maner is not invariably associatedwith mcntal rctardation. The ncuro-imaging of individuals with the inherited fragile X syndromc, wherevarying dcgrccs of mcntal retardation commonlyoccur, has not revealed this dcfcct. Of 27 il~dividuals
who have bccn studied, eight were found to beabnornial [W13]. Seven of thcse individuals exhibited
only a mild enlargement of the ventricles, but in one
a modcratc, gcncralized dilation was sccn. Autopsy
studies have, howcvcr, disclosed abnormalities in
dcndritic spinc niorphology; very thin, long, tortuous
spines with promincnt heads and irregular dilatations
wcrc notcd [W13]. This suggests a dcvclopmcntal
error occurring after migration was complctcd.
94. Two individuals, both femalcs (MF 401081 andone unrcgistcrcd case not included in thc clinicalsamplc), exposed at 12-13 wccks after ovuli~tion,that
is aftcr completion of the initial wave of migration andlate in the second. exhibit no cvidence of cortspicuous
tnigrational errors but do show a faulty braill structure.
Thcre is an enlargement of the prominc~~llyroundedclcvations of thc brain, the gyri. Thesc clc\~ationsarc
separated by furrows or trenches, the sulci, and the824

UNSCEARlaltcr arc shallower tlian norriii~l.Both i~idividualshavc
a mega cislcnia riiagria, that is, an cnlargcmcnt of thesubarachnoid cistcni that lirs hctwccn the uridcr surface of h c ccrchcllu~iiand llic posterior surfacc of themcdulli~oblo~~gata.
Onc of t l ~ ccascs (tlic unrcgistcrcdonc) studictl :it tl~istinic cxliibitcd a corpus callosun~(tlic ~ ~ c t w o rofk i~crvcsthat providcs comriiurlicationbctwccn tlic two lialvcs of tlic t)rain) markedly smallcr
thaa aonnal and a poorly dcvclopcd furrow imnicdiatcly abovc thc corpus, suggesting an aberration in the
dcvclo~)rncntof the band of association fibres, thecingulum, that passes ovcr thc corpus callosum. Jntcrcstingly, aninial cxpcrimcnLs suggest the cingulum tobc particularly radioscnsitivc IR14. R171. Indirectly,
thcsc findings suggcst cnors in migration.
95. Still latcr in dcvclopmcnt, a male cxposcd to an
estimated dosc of 1.5 Gy at wcck 15 exhibitcd neither
migrational errors nor corispicuous changes in brain
structure (h4F 143818). It is thereforc presumed thatthc functional impairment that exists must bc related
to the dcgrcc of conncctedncss bctwecn neurons. Thereis cxperinicntal cvidcnce to show that exposure at thistinic in thc devclopmcnt of thc brain in primates leads
to a diminished numbcr of conncctions betwcen ncuronal cclls [B6]. If all of ttic conncctior~scan bc prcsunicd to havc fur~ctiorialsignificance, thcn the diminution niust coniprornisc pcrfonnancc in some manner.
96. Arc thc dcvclopnic~~talcnors dcsaibcd in theprcccding paragraphs causal1y rclatcd to prenatal cxposurc 10 ionizing radiation, or arc thcy merely fortuitous, characteristics of mcntal retardation generally?
Two lincs of cvidcncc suggcst causation. First, although the data arc lin~itcd,similar findings havc bccn
rcportcd in othcr individuals who wcrc exposed to ionizing radiation prenatally. For example, Driscoll ct al.
[D5] have dcscribcd thc acute damage to two fetuscs,
one a malc cxposcd at 16 or 17 wceks of pregnancy
arid thc other a fcmalc cxposcd at 22 wecks lo radium
therapy in the course of trcatrncnt of matcrnal squamous cell carcinoma of the ccrvix utcri. Both wcre alive
al the time of hystcrcctomy, a day following thc cessation of lrcatnlcnt in the first instance and six days laterin thc sccond. The doscs wcrc largc, estimated to beabout 4.3 Gy at thc ccnlrc of thc fctal head and 7.7
Gy at the ncarcst point irisidc the cranium in the 16-17
wcck fctus, and about 16 Gy in the sccond fctus. In
both cascs, the brain incurrcd thc grcatest damage, but
thcn it was also closcst to the source of ionizing radiation. Ncuronal ccll loss was shown to be sclcctivc.
Thc pri~iiilivc post-niitotic riiigratory cells were
promptly killcd by thc radii~tion,and in this rcspcct theliadings parallcl those sccn in cxpcrimcntal animals.
Dami~gcto thc ccrcbcllum was lcss cxtcnsivc but still
noticeable, particularly in thc oldcr fctus exposed to
16 Gy. Extcnsivc cl~angeswcrc seen in other organs,notably the bonc niarrow arid lymph nodes.

97. Thus thc f i r ~ t l i ~ ~ofg sDriscoll ct al. as wcll as
tl~oscof otlicr i~ivcstigators(scc, c.g. [M191), clearlyIiigli, scvcreii~dicatrtliiit if thc dosc is sufficic~~tlydamagc lo tlic brain call occur ill StiIgCS in grstationconsislcrit with ll~oscSCCII ill t l ~ csurvivors of thethc agcs at:ito~nicbo~iibingsin Jiip:~n.U~ifortu~ialcly,
cxposurc arc dcscril~cd ill tcrms of wccks of prcgnancy, but if it is assumcd lllat this irnplics t i n ~ cfrom
the o~isctof thc last n ~ c r ~ s t r tpcriod,~ i ~ l as is commonly
the ciisc, thcn, mc:~surcd fro111 tlic nlonicnt of ovulation, tbcsc fctuscs wcrc 14-15 and 20 wccks of dcvclopmcnt at the timc of cxposurc. Howcvcr, doscresponse extrapolations to thc situation among theprenatally cxposcd survivors of the atomic bombings
must bc guarded. The doscs were three to eight timcs
higher than the highest rcccivcd by any one of thesurvivors of the atomic bombings, and well above theprcsumcd wholc body fctal LD.jO. Moreover, theJapanese studics arc based upon live-born children
surviving at least to an agc whcrc a clinical diagnosisof mental retardation could be made. Givcn the
cxtcnsivcness of the damagc in the cases described by
Driscoll ct al., it is qucstionablc whether these fetuses
would havc survived gestation and parturition.
98. Second, although migrational cnors arc often
seen associated with wcll-rccognizcd, oftcn inherited,
syndroiiics in which nicntal rctardation occurs (forspecific instances, scc [D9, H19, M201, and for areview [B16]), Uicy appcar rclativcly uncommon in
idiopathic (unclassificd) ri~cntal rctardation. Crome(ClO], for example, dcscribcs thc findings at autopsy
on 282 institutionalized nicntally dcfcctivc individuals.
He points out rather carcfillly the liniitations of thesamplc of individuals he studicd and docs not argue
that his findings arc rcprcscntativc of "the large
number of mentally rctardcd individuals in the community or special hospitalsn. Among 191 individuals
with unclassificd nicntal rctardation, he identified
about 500 main abnormalilics (cach individual wascounted as many times as main diagnoscs occurred).
About half of thcsc abnormalilies involvcd either
dilalion of the vcntriclcs or a small brain (based on
wcight). Howcvcr, smallricss was dcfined as anything
undcr 90% of thc avcragc, which inlplics that some
40% or so of a random samplc of individuals would
be diagnosed as having an abnormally small brain. Of
morc inlnlcdiatc intcrcst iind rclcvar~cc 10 thc prcuatally cxposcd is thc frcqucncy of manogyria (orpachygyria) and ectopic grcy niattcr, since thcsc arc
the prir~laryfindings rcportcd in the Japanese studics.
Cromc idcntificd only two cascs (among 500-odd diagnoses) of pacliygyria and two of "ectopic nodules ofgrcy matter". AnoU~cr,smaller scrics of autopsies ofmentally rcu~rdcdi~idividualsin Finland rcvci~lcdthreecases of pachygyriil or agyria among 80 individuals[P3]. Finally, a study of rclardcd individuals in
Denn~arkrcportcd 34 cases of microgyria or pachy-gyria among 175 ar~topsicsIC1I].T l ~ u sthc
, abnorrn;~lilics sccn anlong t l ~ cprcnatally cxposcd survivors of
thc atomic bombings of Hirosl~irna and Nagasaki
would not appear to bc common tindings anlong thc
mentally rctardcd.

99. Strmrnary. A variety of anato~nical ahnormalitics of thc brain havc bccn sccn among thc prcnatally cxposcd, mcntally retardcd survivors of t l ~ catomic bombings of Hiroshima and Nagasaki and in
othcr c~nbryos or fctuscs also cxposcd to ionizing
radiation. Although the data arc li~nitcd,thcsc grossanatomical cffects have thus far bccn sccn only at
doscs in cxccss of 0.5 Gy. Sonic of thcsc abnormalitics havc bccn obscrvcd among ~ncntally rctardcd
individuals who wcrc not cxposcd to radiation, but
thcy appcar to bc lcss common. Thc abnornialitics
commonly corrclatc well with ~ h cembryologicalevcnts occurring at thc timc of cxposurc, suggesting a
causal rclationship. However, the observations arc
csscntially descriptive and subjcct to diffcrcnt
intcrprctations; thcy suggest but cannot establish thenature of the ccllular or molccular events that arc
inipaircd. Further similar studies arc obviously nccdcd.

I$.

OTHER HUMAN STUDIES

p;~rticuiarlywhcn cxposurc occurrcd in lhc sccond or
third trirncstcr [GR].
Subscqucr~lstudies l ~ a v cindicatcd
that this incrcasc was duc prinlarily to flamc ncvi, andthc investigators arc inclincd to attribute no biologicalsignificance to thcir finding [OR].Although thc samplc
asccrt;~incd by Oppcnhcinl ct al. [03,0 8 , 091 is
rclativcly largc (about 1,000 first-born childrcn) andt l ~ c irradiation occurred routinely rather than for~ncdicallyindicatcd diagnostic purposcs, thc doscs aregc~~crallysmall, 0.01-0.03Gy, and as previously
indicatcd, rhc bulk of the childrcn wcrc exposed in thethird trimcstcr. Unlikc thosc studies of individuals
wl~crcirradiation had occurrcd on a selective basis(c.g. [D4]),thcsc authors find no cvidcncc of aradiation-rclatcd cSfcct on morbidity or mortality, savc
thc one dcscribcd above, but the analyscs usually
poolcd all ages at exposure, and the power of the tests,
in thc statistical scnse, is small in light of the expectcd
cffcct at these doscs, based on the Japancsc studits.

101. Granroth [G2]has exaniined the association ofdiag~~ostic
x-ray cxaminations in Finland with theoccurrence of dcfccts of the ccntral nervous system.
Thc data, drawn from thc Finnish Rcgistry ofCongenital Malformations, rcvcal a significant increasein abnormalities of the brain, primarily anencephaly,hydrocephaly and microcephaly, among ncwborn
infaats prenatally exposed, when contrasted withc o ~ ~ t r osubjccts
lmatched by time and arca. No
estimate is given of the fctal absorbed dose. Moreovcr,
as the author notes, the majority of these infants wcre
cxposcd bccausc of the clinical suspicion of eithcr
maternal pelvic anomaly or fctal anomaly, so the
exposures wcrc u~llikelyto have occurrcd at a time
when abnormalities such as anencephaly arc induced[Mll].Accordingly, it seems unlikely that the results
rcflcct a tcratogcnic effect of radiation.

100. Numerous studies and a varicty of casc rcports(sce, e.g. [ B l , D5],and [MI91for a rcvicw) havc bccn
published that further the understanding of the possiblc
role of ionizing radiation in thc origin of brain abnormalities [GI,Ml]. Howcvcr, fcw of these studies
or reports provide a rcliable basis for risk estimation.
Generally, thcre is little information on the exposuresor on thc dcvclopmcntal ages aftcr fcrtilization at the102. Neumcistcr (Nl] has dcscribcd the findings ontinic of exposure, and the sample sizcs are often small.
19 childrcn prcnatally exposed to doses estimated to
An exccption to this is the study of some 998 childrcn
bc betwecn 0.015 and 0.1 Gy. No instances of severeborn at the Chicago Lying-In Hospital to women who
arc rccordcd, but post-ovulatory age
n i c ~ ~ tretardationai
had pclvi~nctryduring the course of thcir prcgnancy
at
thc
timc
of
cxposure
was not taken into considera[03,08,09].
Thc pclvimctric proccdurc was standard
tion and no suitablc comparison group was found. A
and resultcd in an estimated dose of 0.005 Gy lo thc
subsequent report, on 73 childrcn, mcrely statcs that
fetus. Since the date at which pclvimctry occurrcd was
nicntal dcvclopmc~itfollowed a normal coursc [N7].
rccordcd, the age of thc fctus at cxposurc could bc
Mcycr ct al. [MS]failed to find cvidcncc of an incstimatcd. While thc bulk (87%) wlcrc cxposcd in t l ~ ccreased frequency of scvcre nicntal retardation among
second half of prcgnancy, 120 or so wcrc cxposcd
1,455women who were prenatally exposed to small
prior to the day 140 aftcr the onsct of thc lastdoses of radiation as a result of diagnostic pelvic
menstrual cycle. A variety of cnd-points wcre examcxaminations of thcir mothers. 11 seems uncertain,
ined in this group of childrcn, rclativc to two control
I~owcvcr,whcthcr thcir case-finding mcchanisni would
groups (born beforc or aficr the pclvimctry scrics washave idcntificd women who were scvcrcly m c n ~ ~ lrely
coniplctcd), including tile occurrcr~ce of ma lignar~t
lardcd. An increased probability of premature death
neoplasms and congenital malforniatio~a,and the preamong such individuals leads to underrcprcscntation of
sencc of mental dcficicncy. Only one statisticallythc nlcntally rctardcd later in lifc. In addition, cxposignificant diffcrcncc bctwecn thc exposed and thc
y occurrcd late i n pregnancy,
corn1)arison g o u p s was observed: the S ~ C ~ U C IofI C Y surc ~ r ~ ucsot m m o ~ ~ lhavc
a f c r the most vulnerable period.
hacmangiomas was inncased in the pelvimctry group,103. Othcr studics, such as tl~oscof Nokkcntvcd [N2],arc similarly inappropriate for the estimation ofradiation cffccts. Nokkcntvcd examined 152 children
cxposcd in the first Sour rrionths after fertilization to
doscs ranging from 0.002 to 0.07 Gy. The findings
anlong Uicsc childrcr~wcrc cclrnparcd with tllc findings
aluong tl~cirunirradiatcd siblings. Only one child, in
UIC cxposed group, was found to be niicrocephalic.
Tlicrc werc no cascs of microccphaly among thesiblings. Two childrcn in each group wcrc rcportcd tobc rctardcd. Given the purported doscs and sample
sizcs, thcse findings arc not inconsistent with thecxpcricnce in Hiroshima and Nagasaki.
104. Recently, Chincsc irivcstigators [Ha, H17]
published the rcsulL~ of a study of the long-term
cffccts of prenatal exposure to diagnostic x-radiation
on childhood physical and mental development h a t
addrcsscs some of the limitations, previously cited, ofotl~crstudies. The cxposcd group consisted of 1,026
cl~ildrenwho had bccn born in hospitals in Beijing,
Shanghai and Changchun arid werc bctwecn the agesof 4 and 7 years whcn rccmilcd. The absorbed dosc to
the fctus ranged from about 0.012-0.043 Gy; thcse
doscs were estimated using a thermoluminescentdosimeter in a human fetus phantom exposed to x raysfrom the posterior-anterior, lateral and axial vicws
with typical exposurc factors. Only one child, howcvcr, was cxposed bcfore wcck 8 followirig ovulation;
13 wcre cxposcd in wccks 8-15, 41 in wccks 16-25
and the remainder in wcck 26 or subsequently (mostof them in week 37 or thcrcafter). The comparisongroup was comprised of 1,191 children matched to the
cxposcd group by sex, agc and hospital of birth.
Hcight, weight and head circumference measurements
wcrc obtained, and intclligcnce was assessed using a
50-itcm intclligcnce arid ability scale dcvelopcd by the
Capital Institutc of Pcdiatrics of the Chincsc Academyof Medical Sciences and standardizcd nationally. No
significant difference between cxposed and controls
cnicrgcd in the nicasurcrncnts of physical develop
mcnt. The meari intelligence test score was reduced toa modest but statistically significant extent among thecxposcd group as compared to the non-exposcd group(mcan IQ: 100.35 arid 101.71, respectively), and the
distribution of individual scores was slightly shifted
towards lower valucs. However, whcn possible confounding factors wcrc taken into account, this difference was no longcr statistically significant, nor was asignificant difircncc found when attenti011was focuscd on those cascs cxposed between 8 and 15 weeks
aftcr conccption. Giver1 the small doscs and the small
sample size in tlie critical pcriod, it is not surprisingthat these authors Sound no significant effects.
105. Ragozzirio ct al. [R21] have described theoutcome of 9,970 pregnancies recorded for 2,980
W ~ I I I C I in
I the Rochester, Miasesola, metropolitar~areain tlic U~iitcd Statcs in the ycars 1935-1960. The
hcalth stalus of the children was Collowcd for morethan 20 ycars in 70% of the entire cohort. This was
possiblc 1)rcausc of thc l i ~ ~ k i ~systc~ti
gc
for nledical
rccords, which fiicilitatcd tlic rctrospcctivc dctcrof radii~tionabsorbcd dose and the coniprcrnil~i~tioa
hcnsivc, long-term tollow-up ofnioU~ersand offspring.
Absorbcd dosc to thc fetus for cxarninations in which
thc utcrus was in the primary radiation beam was estiniatcd for five intervals of gestation by multiplying
calcul;~tcd fetal dose at conccption by a scale factor
bascd on average maternal anterior-posterior dimension at different gestational agcs. Fetal absorbed dosc
was cxprcsscd as the total absorbcd dosc in the firsttrimester, as the total dosc absorbed by mid-gestation
and as Uie absorbcd dose accumulated throughout
gestation. For purposes of analysis, the doses wereclassified into thrce categories, namely, 0 Gy, 0-3
niGy, and >3 mGy. Among the 8,014 childrcn where
the data wcre complete, 63 cascs of mental retardation
were rccordcd. The relative risk in the highest doscgroup, based on the mid-gestation total absorbcd dose,
was not statistically significant; the value was 1.1(95% C1: 0.06-5.39). Data werc not reported on theoccuncricc of seizures.
106. Results are also now available from a 5-year
clinical-physiological study of children who wcre bornafter tl~cCt~crnobylaccidcnt whose mothers livcd incontaminated areas at the timc of pregnancy [T6,T7].
The critical periods for cercbro- and corticogenesis(8-15 arid 16-25 weeks) for 370 of these children
occurred in May, June and July of 1986, but the doscs
accuniulatcd in these periods are not clear. However,the findings of Ilyin et al. [I51 suggest that they wcrc
probably a few tcns of milligray at most.
107, Somc delay in myelination, accompanied byslight psychomotor disorders, was seen in 14.5% ofchildren cxposed in the critical pcriod of cerebre
genesis, but in only 7.5% of children born in the firsthalf of 1988. EEG studics of thcse children showed adelay in normal alpha rhyth~iiformation, with significant input of slow waves and later formation of zone
diffcrentiiition. This was fourid in 16%18% of childrcri cxatr~i~icd
at 2 and 5 ycars of age. For the criticalgroup of children, symptoms associated with an increase it1 intracranial pressure were seen, as rcvcalcd
by special function studies. This was found in 18%35% of cascs, more frcqucnlly among children 2-3
ycars old.
108. Thc occurrence of scizures, confirmed byrepeated EEG examinations, was observed in 14 of
342 children [T6, T7]. Howcvcr, scvcn of thcse childrcn wcrc excluded since they had other proved causesof symptomatic seizures. Far the other seven h e r ewerc 110 other apparent causcs than radiation exposure.

ANNEX I I: M I A T I O N EFFECIS 01

Seizures were observed more frequently in the group
exposed at 8-15 weeks (13.4%) than in the group
cxposed at 16-25 weeks (8.2%); in the co~nparisoe
group, thc freque~~cyof seizures was only 3.0%-3.2%.
isInsofar as the developmerltal period ofvul~~erability
concen~ed,these findings are consistent wit11 Uiose th;~thave been reported for the prenatally exposed survivors in Hiroshima and Nagasaki. No cases of microcnccphaly, Down's syndrome or any gross CNS defectwere observed in the study group.
109. Sunrmary. Aside from the observations on theprenatally exposed survivors of the atomic bombingsof Hiroshima and Nagasaki, there are few other population-bascd studies of the effects of prenatal exposureon the developing human enlbryo and fetus. Those thathave been published often provide no information on
UIC doses received by the embryo or fetus or on thedevelopmental ages after fertilization at which exposure occurred. Moreover, the sample sizes are often
small and the power of the statistical tests inadequate
in the light of the expected effect based on theJapanese experience. These caveats notwithstanding,the infornlation provided by those studies that areavailable is broadly consistent with the Japanese dataand not clearly contradictory.
2.

Exposure of the infantile and juvenile brnir~

110. Because maturation of the human brain continues
beyond birth, possible late-stage effects of prenatal
exposure of the brain to ionizir~gradiation (especiallyin the later weeks of gestation) may be similar toeffects Gom exposures of the infantile and juvenile
brain. It is clear that ionizing radiation usedtherapeutically in the treatment of brain tumours or
acute leukaemia at these ages can have deleterious
effects, as measured by conventional intclligerlce
testing (e.g. [ E l , H3, M10, R7, S3J). Meadows el al.
[MlO] stated that "significant reductions were found in
overall intelligence score for the majority of children,
younger patients being most affected". The exposuresinvolved in these instances were high, tens of gray,and most of the individuals involved were also rcceiving chemotherapy. It is also important to bear in mind
that protracted hospitalization of the young often
denies them the opportunity to socialize with theircontemporaries and the intellectual interactions thisaffords. Ncuropsychologic and other effecLr of therapeutic irradiations of children are discussed in Annex
I, "Late deterministic radiation cffccts in children".
111. X-ray induced epilation was extensively used
between 1910 and 1959 for the treatment of tinea
capitis. It has been estimated that more than 200,000
children worldwide received this form of treatment.
Albert el al. [Al], in their study of one group ofchildren treated for tinea capitis, reported a highcr

i~~cidcnccof ~ncntal illness, including psychosis,
personality disorders and psychoneurosis, anlong 1,905
c l ~ i l d r etrcated~~for this discase by x rays than among
1,501 children with tinca capitis trcated by othermeans. I t has been estimated that, in the AdamsonKicnbock treatment regimen used in these instances,tlie brain rcceived 1.5-1.75 Gy at its surface, decreasing to 0.7 Gy at the base.
112. Subsequently, Omran et al. [ 0 7 ] described theresults of psychiatric and psychometric evaluations of
109 children with tinea capitis treated by x-ray therapy
and 65 treated with chemotherapy. They found morepatients with deviant Minnesota Multiphasic Personality Inventory scores anlong those who had been irradiated than in those chemotherapcutically treated, andthe former were judged more maladjusted by their
MMPI profiles. Hence, there is evidence that exposure
to ionizing radiation can modify personality traits, butinterpretation of these data is difficult, because x-ray
treatment and chemotherapy treatment differ in aspects
other than radiation exposure and bccause a variety ofemotional disturbances are associated with protracted
liospitalization of the young. However, Ron ct al. [R8](see also [Al, 0 7 , S51) have reported a similar finding
anlong individuals treated for tinea capitis who were
not on adjuvant therapy nor hospitalized and who received similar radiation doses, possibly 1.3 Gy, on the
average. Ron et al. [R8] have stated that "the irradiated children had lower examination scores on scholastic
aptitude, intelligencc quotient (IQ) and psychologic
tcsts, completed fewer school grades, and had an increased risk for mental hospital admissions for certain
disease categories". Apparently no estimate was madeof the diminution in intelligence test score per unit
exposure. The increased frequency of cases of corticaldysfunction reported by these authors and in thestudies described in the preceding paragraph are notknown to be associated with demonstrable anatomic
changes in the brain.
113. Studies of children exposed during the first few
months of life to absorbed doses in the brain of 1.05.2 Gy as a result of therapy for haemangionlas of tlie
head, face and neck also reveal impaired subsequent
brain development (see, e.g. [T3, T4, TS]). These
investigators assessed brain function using not only
conventional clinical and neurological exanlinations
but also electroencephalography, electroniyography,
rbeoencepl~alographyand a variety of psychologicaltests. More than half of the children cxposed to doscs
ranging from 0.46 to 1.3 Gy exhibited functional
ccntral nervous system changes. These were commonly manifested as memory and emotional defects. At
so~tiewhat higher doses (2.3-3.4 Gy), darnage wasmore pronounced and included structural-functional
asymmetries that could be demonstrated electroc~~cephalographically.
Long-term follow-up has re-

628

UNSCEARvcalcd sonlc a~ncliorationof tllcsc cffccLs in SOIIIC instances. At doscs of 4.2-5.2 Gy, ancsted physical andcndoninological growth was sccn, accompanicd by arcduction in hcad size with deformity. Mental rctardation combincd with cpilcptoid phcnomcna was also
SCCII. No aniclioralion orcurrcd with timc in thcsc
mscs. Gcncrally, it was fouad that Ihc oldcr thc childat thc timc of cxposurc, the I~ighcrthc dosc rcquircd
to producc a spccific cffcct.
114. Studics havc bccn rliadc in thc fon~icrSovict
Union of the latc conscquc~~ccsof radiation thcrapy
for brain tumours, using conccntratcd bcams in fractionatcd exposures [M25]. Observations aftcr 5-10
ycars discloscd a number of asthcnoncurotic ccrcbrasthcnic syndromes, combined with hypertension,
vestibular and atactic insufficicncy, and residuall~cmiparcsisin some childrcn. Psychological studies
havc rcvealed passive attcntion instability, activc
attcntion cxhausti-bility, rapid loss of intcrcst duc tofatigue and mcmory and intellect reduction; somc
childrcn cxhibitcd overt emotional disorders. In nearly
half of thc cases studicd, howcvcr, some amcliorationof thcse cffecls occurred, and aftcr 5-7 years thcre wasan apparently satisfactory social and school adaptation.
Scvcn individuals dcvelopcd an cpilcptoid syndrome
aftcr 10 years, and nine had a lowered convulsion
preparcdncss threshold, bascd on clcctrocr~ccphalogram(EEG) tcsts.
115. Long-tcrm obscrvations have also bccn made on
89 Soviet childrcn treated with "CO gamma rays forhacmangiornas of thc skin in thc first 6 months and thelirst 2 years after bit?h [T4, T51. Local doscs wcrc
cstin~atcdto he 15-28 Gy, but cxposurc of the brain was
non-uniforni, varying from 1 to 3 Gy. A retardation in
the devclopn~cntof nlotor and motorstatic functions, as
cvidcnced by psychomotor performance or partialspeech. was sccn in 11 childrcn. By 5-6 years of agc.
almost a quarter of thc childrcn (22 per cent) cxhihitedan enccphalopathy syndromc, oftcn with evidcncc ofminor organic damagc to the ccnlral nervous systcm.
Among thc symptoms they cxhibitcd were headache,difficulty in falling aslecp, incrcascd fatiguability of thencuromuscular systcm, vcgctativc-vestibular disorders(vcgctativc as used here and subsequently in~plicsthe
autonomic ncrvous system) and a rcduction in mcmory
and associative abilities. Eight childrcn had
psychovcgctativc disorders and lowercd 10. After
puberty, during adolcsccncc and youth, satisfactory or
good social adaptation occuncd in some instances, but
pcriods were sccn. EEG
ncuropsychir: dysadaptatio~~;iltests discloscd an cpilcptoid syndrome, as wcll as alowcring of thc convulsion prcparcdness threshold in
scvcn individuals, including two with epilcptiforn~
seizures (radiation dosc 22-26 Gy). These ncuropsychicorganic and functional changes were most pronounced
in children cxposcd at 1-6 rno~~tlls
and 1-3 years of age.

116. As noted in paragraph 2, prcvious UNSCEAR
rcporls (scc, in particular, [U2, UJ]) havc considered
UIC gc~lcraldcvclopmcatal cffccLs of prcnatal irradiation ;is rcvcalcd by cxpcrinlcntal studics. I t is not t l ~ cintcnt of this AIIIICXto rc-cxan~incthc volun~ir~ous~
findings
litcraturc, but to cornnlcnt on c e r t a i ~rcccnt
that dcal specifically with the devclopn~cnt of thebrain. Molc [MI91 rcvicwed this litcraturc and thebasis it elfords for prcdicting malforn~ations after
irradi;~tionof thc dcvclopi~~ghuman.
117. Expcrimcntal studics have demonstrated that h erclativc sensitivity ofdiffcrcnt componenLs ofthe brain
to ionizing radiation differs, and possibly substantiallyso. Rcyncrs ct al. [R17,R181, for cxanlplc, havc
shown that thc cingulurn bundlc, a myclinatcd substructure of the corpus callosum, is an especiallysensitive indicator of cxposure to x-radiation. Changes
in Ulis structure occur at doses as low as 0.1 Gy, that
is, at doscs too low for the effects to be readily
cxplicablc in tcrms of mitotic cell dcath, and suggest
a disordcrcd scqucncc of n~orphogcncticcvcnts. Morerecently, using 600 kcV nculrons from a Van dc
Graaff accelerator, Rcyncrs ct al. [R22] havc shown asignificant effcct on brain weight at doscs as low as
10 n1Gy. This diniiriishcd brain weight is accompanied
by a significant rcduction in the sizc of the cingulum
bundlc. Rcyncrs ct al. concluded from their studies
that " t l ~ cthreshold dosc for detectable effects to a
dcvcloping brain may be lower than 35 mSv, inparticular for acutc cxposurc to high energy transfer
particlcs during the pcriod of corticogcncsis." Lent etal. [Ll 1 Ilavc sllown Illat mice exposed lo 2 or 3 Gy ofganlma radiation on gcslational day 16 arc invariably
acallosal. It is not clear, however, whether lhesechangcs in the cinguluni and the corpus callosum areconspicuously dctrin~cntal to the animal nor is it
k ~ ~ o wwhy
r l the c i ~ \ g u l u nappears~
to be so radioscnsitivc, more so than thc cntirc corpus callosurn.
118. Until rclativcl y rcccntly, most cxpcrimental
studics have focuscd on changes in brain morphology
or wcight (c.g. [A3, H7, S131) following cxposure toionizi~~gradiation ratllcr than changcs in brain function. l'hcrc arc cxccptions to this statcmcnt. Studics
conductcd almost thrcc dccadcs ago havc rcvcalcd thatscizurcs occur in rodcnts following prcnatal exposure.
Sikov ct al. [S12, W l I ] , for cxamplc, rcportcd anincrcascd frcqucncy ofscizurcs among tho offspring ofa l b i ~ ~ratso cxposcd at 15 days of gestation to a doscof 0.5 or 1.9 Gy. Thcse scizurcs were dcscribcd as
focal in onsct. with rapid progression from face toforclinib and hind limbs, and then quickly becoming
gcncralizcd. They wcrr said to be equivalent to thetypical Jacksonian scizurc in man, in which the attack
usu;illy proceeds fro111 the distal to lllc proximal linib.

niusculaturc. No incrcasc in scizures was sccn whcricsl)osilrc occurred on day 10 of gcst;itiori, arid 110
rfforl was made to define a tlosc-responsc rclationslril)
at 15 days of agc. Odicr ncurological deficits wcrc
notcd, sucli as giiit dcfccts, forccd circling a ~ i dhy~crscnsitivity to somc sclrsory sti~nuli, w l ~ i c l ~nianifcstcd itsclf as cxaggcratcd niyoclonic jcrks.
Although sonic of thcsc cffccls wcrc sccn in raLs
csposcd on day 10, thcy wcrc morc comnlorl anlong
the rats cxposcd or1 day 15 illid a1 tlrc liiglier dosc.
119. Howcvcr, bchavioural studics of rodcnb
followir~gprcnatal irradiation have now rcvcalcd b a t
a varicty of bchaviours arc corrclatcd with corticalniorphology. Norton IN.5, N6], for example, hasrcportcd that cortical thinning is associatcd withchangcs in an animal's ariglc of stridc, ncgativc
gcotaxis and coritir~uouscorridor activity, as well aswith other bchavioural mcasures. Shc has further
showri that some behavioural tcsts cxhibit a clcar
dosc-rcsponsc relationship to doses as low as 0.25 Gy(thc lowcst dose used in hcr cxperirncnt), allhoughscvcral bchavioural parameters wcre not altered byradiation. Jensh ct al. [J4, J5] have described similarfindings in the Wistar rat at doses of 0.2 Gy andhighcr, but they concluded that all of thc paramelcrs
they had studicd had thresholds at or above 0.2 Gy.
Kimlcr ct al. [K6]have shown that the organ mostscnsitivc to radiation-induccd altcrations changcs: i t is
thc pituitary gland at gestational day 11 and thc
primitive cortcx of thc brain at days 13-17, with apcak of sensitivity at day 15. They furllrcr notcd thata spcctruni of rcl;ltcd functional and riiorphologicaldcficib can be produced cvcn by low-dose in liter0
irradiation (0.25 Gy), with the specific end-poilit
showing the grcatcst change bcing dctcnnined by thc
day on which cxposurc occurs. Finally, Minaniisawa
ct al. dcmonstratcd an effcct of aggressive bchaviour
in adult male mice following fetal cxposurc toganiniarays [M24]. Thcsc anatoniical arid bchaviouralcspcri-mental rcsults accord surprisingly well \vilhwhat has bccn sccn in the human (for a comparisonsee [S24]).
120. Still other ncurophysioiogic cffccts, withdiffcrcrit critical periods, havc been idcntificd. Rcccntiy, for cxamplc, it has bcen shown that micc irradiatedprenatally on day 18 (corrcsponding, roughly, to wcck
33 in thc human) suffer a significant loss in spatial
mclnory [S16]. The integrity of spatial nicmory appears to dcperid on the propcr dcvclopmc~ito r thc hippocariipus, a pri~nitive,anato~nicallydistinct part ofthe cortcx lying bcncath thc ccrcbrai hcririsphcrcs. Tliis
structure arises rclativcly late in thc dcvclopnicnt oftlie human brain, hut daniagc to it ~ C S U ~ LinF a rccog-

nizcd cognitivc dcfcct cliaractcri7cd by scvcrc ariincsia
arrd includes dcficils in learning m;i;.cs. Morcovcr,
tlicrc is cvidcrice Uiat associates a rcductiori in thc~)yramidaIcclls within thc Iiippocarnpus with nicmory
i~irpairnicnt.
121. Analogous bchavioural changcs have bccri seenin priniatcs following prcriatal csposurc [OIO]. Br~zzee'
ct al. [B12], for cxan~plc,havc rcportcd that thc
cxposurc of squirrcl nionkcys on days 8 9 and 90 ofgestation to 6 0 ~ gamma-radiationo
at doses of 0.5 or
1.0 Gy rcsults in lcss accuratc and poorly coordinatedrcncxcs and ncurornuscular coordination. The
pcrccntagc of corrcct rcsponscs in tcsts 011 visualorientation, discrimination and rcvcrsal learning wcresignificantly lower in the exposed animals than in thecontrols. At doses of 0.1 Gy, no structural orbchavioural altcrations wcrc secn: howcvcr, theauthors conjccturc that more sensitive behavioural
testing arid thc use of con~putcrizcd microscopictcch~iiqucs(and, possibly, tlrc compulcr-aided mappingoS specific ricuronal populations [K9]) will revealchanges.
122. I t is difficult to put thesc observations into a
pcrspcctive suitable to thc purposes of this Anncx: thetcsts used to measurc cortical dysfunction havc no
obvious human counterparts, the nature of the doseresponse relationship is often clouded by tlie large
inhcrcnt variability in the cnd-points measured, and soforth. Morcover, abscopal effects cither in thc
cspcrimental animal, the human or both cannot be
excluded. Slovitcr el al. [ S l l ] , for cxample, haveshown that adrcnalectomy of adult malc rats results ina ncarly complctc loss of hippocampal granule cells
3-4 months after surgcry. The hippocampus, as
previously stated, is involved in Icaniing, nicmory arid
a varicty of other bchaviours and is known to be thetargct of adrenal steroids. How widespread thisplrcnonicnon may be is not known, nor is it clcar thatradiation-rclatcd damagc to thc adrcnals would effectsiniilar ch;~ngcs. Howcvcr, damage to the adrenals
fro111 prenatal exposure has bccn sccri in thc human
IDS, Yl].

123. Sutntt~ary. Thrcc general coriclusions sccm
warranted from the expcrirnenlal evidence. First, itapl)cars clcar that low doses (that is, doscs in therange of 0.2 Gy or so) producc measurable bcha\rioural and anatomic effects. Secondly, behaviouralrlla~lgcs have their structural counlcrparls in thearcliitccturc. of the brain. Thirdly, there is ;I highdcgrcc of functional specificity in tlrc informationtransmitted over ncural systcms.

UNSCMH 1993 RIIPORT

830

Ill.

RISK ESTIMATES

124. Quantitative risk estimates for radiation damage
to the brain after prenatal exposure of human beings
arc of importance because they have practical implications for radiation protection. tlowcvcr, the 11~1niin
data on which to base such estimates arc limited andimperfect. The data on the survivors of the atomic
bonibings of Hiroshima and Nagasaki provide theprimary basis for Ulc risk cv;~luation.As described in
Chapter 11, four types of observation are available
from these data:

the frequency of severe mental retardation
recognized clinically;
the diminution of intelligence, as measured byco~lventionaltcsts;
scholastic achievemc~~t
in school;
the occurrence of unprovoked seizures.
Each has its limitations, and there must be an awareness, when interpreting the available information, of
these limitations and other difficulties. However, until
more direct measures of brain damage, such as celldcath or impaired cell migration, are available, theseobservations are the only ones on which risk estimates
can be based. Unquantified clinical descriptions arc oflittle assistance, and experimental data, though
important qualitatively, provide an uncertain basis forquantitative estimates of prenatal risks in humans.
125. One of the most important problems inestimating the risk to the developing brain from exposure to ionizing radiation is the shape of the doseresponse relationship. As stated, much of the data thathave helped to identify the tcratogenic effects ofradiation have limited applicability, for either thedoses are too poorly known or too invariant to permit
discrimination between different plausible models. The
information on the atomic bomb survivors represents
one of a very few sets of data that may be relevant.
But even here, the ~nultiplicityofways in which radiation could affect the normal development of the brain
and culminate in cortical dysfunction makes it hard toassess the reasonableness of an observed doseresponse relationship. This limitation will remain until
the different causes of a neurological deficit of anorganic nature can be distinguished one from another.

126. As stated in paragraph 84, it is presently unclear
whether the cases of mental retardation seen among
the prenatally exposed survivors of the atomic bombings of Hiroshima and Nagasaki represent malfornialions or instances of maldevclopment. Their origin canbe perceived eilher as involving a dose-related largc
effect on a small number of individuals or as a small
effecl on a largc number or, conceivably, a mixture of
UIC two. Since Ihe suggested shift of the IQ curve
towards lower values must increase Ihe frequency ofrncritally retarded individuals with increasing dose, thefall in IQ and the increase in severely mentallyrctarded individuals with dose may be interrelated.
Iodccd, the observed increase in nicnti~lrctardation in
the nilical 8-15 week period and the shift in mean IQ
in this same interval of time can be shown to beniathcn~atically compatible. This fact has led thelr~tcn~ational
Conimission on Radiological Protection(ICRP) to conclude that tlie shift in IQ "appears to bea deterministic effect, probably with a threshold
dctcmiined only by the minimum shift in TQ that can
be clinically recognized" and to assert further that "theobserved shift of 30 IQ units per SV is best suited todescribe the risk" of radiation-related mental impairment 1121. The Commission also concluded that "ifboth observations (alluded to above) are correct, themost likely interpretation is that the dose required tocause an IQ change large enough to make an otherwise normal individual mentally rctarded would behigh, while the dose that would bring an individualwith potentially low IQ over the borderline may be a
few tenths of a Svn.

127. It should be noted that ICRP interpretation of thedata stemming from the studies in Japan has not goneunchallenged, most notably by Mole [ M u ] . He argues
that the ncuroembryology a ~ plasticity~ dof the brain
do not support this interpretation, that the correlation
between the shift in IQ and the occurrence of severe
nlental retardation reflects the way in which IQ tests
arc coristructcd and is not indicative of a common
underlying biologic process, and that the data are
actually better described by a threshold model, withlhe threshold being in the neighborhood of 0.5 Gy.

128. Mole contends that the interpretation of thedamage to the developing brain depends upon the
choice between two competing proposals about themechanisni of construclio~~of the primitive ccrcbral
cortex. One of these hypotheses, the radial column
hypothesis, argues that the development of the cerebral cortex arises through the radial migration ofneurons from their sites of birth to predetcnnined
destinations in the cortex, forming, as they move,
radial colur~ins with specific functions (see, inparticular, [R12,R131). The ohcr hypothesis (see[W8, W141) asserts that tlie migration of neurons is
not limited lo outward radial movement but can occur
in other directions and over longer distances thanellvisaged by the radial colun~nhypthesis. He argues
that ICRP in favoring Ule ri~dialcolumn hypothesis has
erred in denying the plasticity of the human brain.
This argument is specious for at least two reasons.
First, the hypolheses slated briefly above arc notcompetitive but supplemcnlal; it is not a matter of the
choice of one and the rejection of the other. EvidenceA N N M I I: MDIATION EFECIS ON 1lE DEVEI-OPING t IIJMAN BKNN

clearly exists for both n~cchanismsof migration. Thisshould not be unexpected, since collectively theyafford ;In explanation for both the k r i o w ~plasticity~oftlrc hunian brain and the necessity that some corticalfu~rctionsbe rigidly encoded. This does not deny~~lasticity,
but asserts that cortical functio~r is ;rcomplex process some portion of which is conscrvalive. Secondly, ICRP, while favoring the radial c o l u n i ~ ~Irypothcsis, docs not assert that all migration of
ncurorial cells must conform to this hypothesis. They
do note, however, that the radial column hypothesis
provides a basis for presuming that some srrlall 10citl
lesions could have lasting effects on mental function.

A.

KISK FROM ACUTE EXTOSURE

129. Re-evaluation of the data on the survivors of theatomic bombings of Hiroshima and Nagasaki has provided a new perspective on the pcriods of sensitivityof the developing brain to radiation-related damage
and the possible nature of the dose-response relationship. These findings have been described in somedetail previously. The main points that specificallyconcern risk estimation are the following:
(a)

@)

(c)

to radiation
the period of maximum vul~~crability
appears to be the time between 8-15 weeks after
owlation, that is, the interval when neurons areproduccd in greatest number and when theymigrate to the cerebral cortex;
a period of lesser vulnerability occurs in the
succeeding- -period, 16-25 weeks aftcr ovulation.
This period accounts for about a quarter of theapparently radiation-related cases of severe
mcntal retardation;
the least vulnerable period is 0-7 weeks aftcr
ovulation, during which no radiation-relatedcases of severe mental retardation occur.

However, as previously stated, wilhin the 0-7 week
pcriod, a higher proportion of exposcd embryos fail tosurvive gestation, and it may be that brain-damaged
embryos are less likely to survive to an age where
their handicap can be recognized clinically. Moreover,a significant increase in the incidence of individuals
with an atypically small head, presumably due togeneralized growth retardation, docs occur in b c s e
weeks.

130. In fctuscs exposed to radiation in the period 8-15
weeks aftcr ovulation, the prevalence of severe menlal
retardation at cstiniated mean doses to the mother's
utcrus of 0, 0.05, 0.23. 0.64 and 1.38 Gy, was 0.8%,
4.5%, 1.8%, 20% arid 75% (Table 4). Within thisperiod of niaximum vulnerability, it is difficult to831

know, a priori, what the appropriate dose-respo~lse
niodel should be, since mental rctardation could arise
through a variety of different biological or genetic
events, ranging from cell killing to niismanagcd
neuronal rnigratio~ilo errors in synaptogcncsis or tosolrle combination of lhcsc cvenb. Each of theseprocesses could have its own unique, but currcritly
ulrknown dose-response rclationship. Accordingly the
Co~nmittcchas elected not to fit a specific model ornrodcls but to cite the risks as they have been
observed empirically.
131. Although the Committee docs not believe that a
linear dose-rcspo~isemodel has much, if any, biological credence, prudence suggests thc need to examinesuch a model, since presumably it would maximize thecstimatcd risk at low doses. Within the most vulnerable age group (irradiation at 8-15 weeks after
ovulation), the incidence of severe mental rctardation
at 1 Gy is 0.39, with a standard error of about
0.09 G~.'.
132. In fetuses exposed to radiation in the period 16-

25 weeks after ovulation, the prevalence of severe
mental retardation at estimated mean doses to thenlother's uterus of 0,0.05,0.23,0.64 and 1.38 Gy was
0.6%, 1.8%, 0%, 0 % and 37.5% (Table 4). Thus, theorlly demonstrably increased risk occurs at doses
estimated to be 1 Gy or more.

2.

Small head size

133. A variety of dose-response relationships, withand without a threshold, have been fitted to the dataon hcad size grouped by trimester and post-ovulatory
age (weeks) at exposure. A significant radiation-related
effect on the incidence of individuals with a smallhead was rioted only in the f i s t and second trimesters
and for the 0-7 week and 8-15 week pcriods after
ovulation. It is worth noting that these findings are
similar to those of Miller and Blot [M3], when allowance is rrrade for the difference in dosinictry (theyused the T65 maternal kernla) and some subsequent
small changes in the data. They observed "a progressive increase with dosc in the frequency of theabnormality (small head circun~ference)among persons whose mothers were exposed before the 18th
week of pregnancy". When exposure occurred in thefirst trimester, the risk of an atypically small hcadsuggests a possible linear-quadratic dose-response
relationship. Both linear and quadratic terms are
significant, but the quadratic tern] is negative. The
results of fitting a linear-quadratic model to the 0-15
wcek pcriod after ovulation suggest a linear doscresponse rclationslrip (Figure 11). No excess risk forsmall head size is seen in the third trimester or among
i~rdividualsexposed at 16 weeks or tnore iiflcr ovula-t i o ~ Tlic
~ . cstiniatcd threshold, bascd on cithcr a lincaror a linrar-quadratic dose-rcsponsc rclationship, is zcro
or ncarly so. This apparent abscncc of a thrcstiold andtlic somcwhat differc~~tperiods of dcvclopmcntal
vul~icrabilitysuggcst an crl~bryologicaldiffcrcncc in
tlic cvcnts culminating in small hcad sizc, on tllc onc
Ii;ilid, and scvcrc riicl~talrctardation, on the otl~cr.
134. The rclationship of small hcad sizc to cxposurc
wecks was cvalo ionizing radiation and gcstatio~~alluatcd using four physical rncasurcnients of growthand dcvclopmcnt: standing hcight, wcight, sitting
hcight and chcst circumfcrcncc. These variables arc
highly correlated. Accordillgl y, the four nicasurcmcnts
wcrc cvaluatcd as a set, using a multivariate analysis
with cstirnatcd DS86 dose and gestational week as covariatcs and sex and small hcad size as categoricalfactors. A retardation in growth is observcd among
with a small head, with or without severei~~dividuals
nicrital retardation, when their physical mcasurcnicrlts
arc comparcd with thosc of individuals with a "nor~ n a l "llcad sizc.
135. In order to irivcstigatc the possibility of growth
rctardation using the four physical mcasurcments
simultaneously, a niultivariatc analysis of covariancc
was attempted, using data for individuals 10-12 and
16-18 ycars old, for whom comparatively largc numbcrs of obscrvations wcrc available. The rctardation of
growth with increasing radiation dosc is observed ataln~ostall ages, as judged by the negative cstimatcs of
UIC dosc parameters associated with thc four mcasurcmcnts. Howevcr, a statistically significant rctardationof growth and dcvclopmcnt, after adjusting for confounding factors bascd on scx, small hcad and gestational age, is notcd only at 17 years of age with orwithout inclusion of scvcre nicntal rctardation and at
18 ycars of age with the severe mental retardationcascs included. At 16 ycars of age there is a suggcstivc retardation of growth among individuals withsriiall hcad size and scvcre mental rctardation (p <0.10). At all othcr agcs, no statistically significant
rctardation of growth is observed; howcvcr, as previously notcd, at thcsc agcs too, growth sccnis todilliinish as thc radiation dosc increases. It rliust be
borric in mind that whcrc a statistically significant
cffcct of radiation on growth is not scen, the pubertal
growth spurt and its variability in age of onsct could
incrcasc the gcncralizcd variancc of the measurcnicnts,
diriiinishing the sensitivity of the statistical tests. Thisco~ijccturcis not suppor~cd,howcvcr, by a tcst of thehomogeneity of the gcncralizcd varianrcs, si~icctllesc
can~lotbe shown to bc sigl~ificantlyheterogeneous.
136. Post-ovulatory agc is statistically significant andncgalive lor all cocfficicnts associated with the fourphysical measurcmcats, cxccpt for chest circumfcrcncc
at 1 0 ycars of age, with or without the inclusion oftal
in theindividuals with scvcrc ~ n c ~ ~ retardation
analysis. Individuals with small Iicads, with or without
thc inclusioa of the cascs with scvcrc mcntal rctardation, rxl~ihita liiglily significant rctardation of growthand dcvclopmcr~twith gcs1;rtional agc at cxposurc, as
judgcd by ~ h cfour physical mcasurcmcnts. Why thisshould bc tnic is not obvious. But sincc the mcasurenicnts tlcclinc as gestational agc incrcases, it suggcsts
that thcrc may havc bccn sonic selcction for body sizc
in tlic carlicr gestational agcs. Expressed in anotherway, ilidividuals who survived cxposure in thc earlystages of gestation may havc rcprcscntcd healthierprcgaancics, on avcragc, Ihat wcrc thercforc destined
to give risc to largcr childrcn and young adults. If thiswcrc truc, i t would be rcasonablc to assume that no
gestational age cffcct would bc observed if the comparisons wcrc restricted to thosc sample members who
were either not exposed or cxposcd to estimated dosesof lcss than 0.01 Gy. Whcn thc data are so restrictcd,
howcvcr, tlic cffcct of gestational age remains, and its
origin is unclcar.

3. Diniinution in intelligence
and academic performance

137. Thc obscrvations on intelligence tests and school
pcrfornial~ccsuggcst the sanlc two post-ovulatory agc
pcriods of vulncrability to radiation. The period 8-15
weeks again shows the grcatest sensitivity, althoughwith the data available so far, it has not been possible
to establish the form of the dose-response relationshipunequivocally. However, within the post-ovulatory age
group most sensitive to the occurrence of clinicallyrecognizable scvcrc mental rctardation (exposurc 8-15
wceks aftcr ovulation) the di~~iinution
in IQ undcr thelincqr rnodcl is 21-33 points at 1 Gy, based on thc
new dosinic~ry and the specific sct of observations
uscd.
138. A linear-quadratic modcl does not gencrally
provide a better fit to the ir~tclligcncetcst data (seeTablc 7), nor docs it reveal pcrsuasivc cvidence of
curvili~lcarityin thc dose rcsponsc in the most criticalpost-ovuliltory age group. Howevcr, the significance ofthe cffcct at 16-25weeks aftcr ovulation is more cquivocal with a linear-quadratic model than with a lincarone. Rcgrcssion cocfficicnts obtained in fitting lincarand lincar-quadratic models to school performancercsulb arc shown in Tablc 8.
139. Tlic cffccts of diminislicd nicntal capacity
considcrcd hcrc result fro111darnagc to thc ccrcbrum in
prcnatillly cxposcd individuals. Although cxpcrimcntal
studics IA2, C12, H20] arid case reports [ B I , D5]
havc cstablishcd that the ccrchcllunl is sensitive toradiation darnagc, no evidence has emerged from thestudics of thc prenatally cxposcd survivors in Hiro-ANNEX 11: RADlATlON EFFECTS ON THE DEVELOPING I IUMAN BRAN

shinia and Nagasaki of such damage, and for several
reasons it may be difficult to identify. First, P u r k i ~ ~ j ccells, the only efferent neurons in the ccrebelluni, arc
proliferating and migrating in the same dcvclopnicntal
period as the ncuronal cells that populate the cerebral
cortex, so damage to precursors or differentiated Purkinje cclls would occur at the same tinic and might beinseparable from damage to those cclls that give riseto the cerebral cortex [Zl]. Secondly, the granular
ncurons, the most numerous nerve cclls in the cerebellum, retain their proliferative abilities after birthand could, in theory, repopulate areas of the develop
ing cerebellum that were damaged by radiation. T o theextent that this occurs, granular cell damage might be
mitigated. Estimates of the risk of damage to the
cerebellum following prenatal cxposure, based on
f i e d or progressive neurologic deficit, are presently
not possible. No evidence of damage to the mid-brainor the brain stem following prenatal cxposure has bccn
reported; accordingly, radiation risks to these parts ofthe central nervous system cannot be estimated.

4.

Seizures140. The risk ratios for unprovoked seizurcs, following cxposure at weeks 8-15 after ovulation are as
follows: after doses of 0.1-0.49 Gy, 4.4 (90% CI: 0.540.9); after doses of 20.5 Gy, 24.9 (90% CI: 4.1-192,
mentally retarded included); 14.5 (90% CI: 0.4-200,
mentally retarded excluded). Table 9 gives the resultsof fitting a linear response model to the grouped dosc
data including and excluding the severely mentallyretarded.

141. It is not clear which of these sets of risk ratios,that based on the inclusion or that based on the exclusion of the mentally retarded, should be given thegreater weight. The answer hinges ultimately on themechanisms underlying the occurrence of seizures andmental retardation following prenatal exposure to ionizing radiation, and these are presently unknown. If
seizures can arise by two independent mechanisms,
both possibly dose-related, one of which causes seizures and the other of which causes mental retardation
in somc individuals who are then prcdisposed to develop seizures, the mentally retarded must necessarily be
excluded if one is to explore the dose-response rclationship associated with the first mechanism. If, however, mental retardation and seizurcs arise from acommon brain defect, which manifests itself in someinstances as mental rctardation and in other instances
as seizures, then the mentally retarded should not be
excluded.
142. At present the only evidence suggesting a common radiation-related developn~cntaldefect is the occurrence of ectopic grey matter in some instances of833

both disorders. However, even lllis cvidencc is difficult to put into perspective, because while it is known
Uiat ectopic grcy matter occurs among some of theradiation-related instances of nicntal rctardation, theobservation of cctopia in individuals with scizures isbased on other studies. As yet, there has bccn no investigation of the incidence of ectopic grcy matter
anlong the prenatally exposed survivors of the atomic
bo~t~bingsof Hiroshima and Nagasaki who haveseizurcs but no mct~talretardation.
143. A search for a threshold in the occurrence of
seizurcs (see Table 10) discloses the following: thecentral values of h e threshold for all seizurcs range
between 0.11 and 0.15 Gy in the most critical period,that is, 8-15 weeks after ovulation, and the estimatesarc even lower for unprovoked seizures (0.04-0.08
Gy). In all of these instances, however, the lower 95%
bound on the threshold includes zero, so Ihe data
provide no compelling evidence for a threshold.

B. RISK F R O M FRACTIONATED O RCHRONIC EXPOSURE TO NEUROTOXINS
1.

Ionizing radiation

144. Little is known about the effects on thedeveloping human embryo and fetus of fractionated or
chronic exposures to ionizing radiation. Given thecomplexity of brain development and the differing
durations of specific developmental phenomena, it isreasonable, however, to assume that reducing the dose
rate or dosc fractionation will have somc effect. The
hippocampus, for example, and the cerebellum
continue to have limited neuronal multiplication, andmigration does occur in both organs. Changes continue
in the hippocampus and cerebellum into the first andsecond years of life. Continuing events such as these
may show dose-rate effects differing from those
associated with the multiplication of the cclls of theventricular and subventricular areas of the cerebrum,or thc migration of neurons to the cerebral cortex.
145. Most of the information available on the effeclsof dose rate involves the experimental exposure ofrodents. Since thcsc findings have been summarized inprevious reviews (see, e.g. [ K l l , M19, U2. U4]),
attention here is restricted to only one or two
representative observations. Brizzee et al. IBIO] (seealso [Jl]) have examined cell recovery in the fetal
brain of rats. Pregnant rats were exposed to 6 0 ~ oradiation on gestatior~day 13 in single doses, ranging
from 0.25 to 2 Gy in incrcnicnts of 0.25 Gy, and insplit doses of 1 Gy, followed 9 hours later by asecond dose of 0.25 to 1.5 Gy, again in increments of
0.25 Gy. The animals were disected and exanii~~edonthe day 19 of gestation. The incidence and severity of834

UNSCEAR 1993 RIi1'010'

tissue alterations generally varied directly with dose
and wcre clearly greater in single dose than in split
dose groups with the same total exposure. The authors
observed chat "the presence of a threshold (shoulder)z o t ~ eon the dosc-response curve in the split-dose animals suggests that cell recovery occurred in some
dcgrce in the interval between the two exposuresn.
This reduction in damage wit11 the protraction of dose
seems greater for continuous gamma-ray exposure thanfor scrial, brief x-ray exposures, and it has beenargued that this may indicate a further sparing when
the protracted dose is evenly distributed over time
[M19]. If true, this obviously has important regulatory
implications.
146. Recently, Vidal-Pergola et al. [Vl ] reportcd
resulls of fractionated prenatal doses on poslnatal
development in Sprague-Dawlcy derived rals. Theirexperiment consisted of exposing pregnant females tosingle doses of 0.5 or 1.0 Gy, or to two doses of
0.5 Gy 6 hours apart. Ofkpring were subjected to four
behavioural tests (negative geotaxis, reflex suspension,
continuous corridor activity and gait) on postnatal days
7-28. The rats were then sacrificed, and the brains
wcre removed and processed for histology. For all
four bebavioural end-points, the fractionated dose
produced an effect that was intermediate between the
0.5 and 1.0 Gy doses and that, by linear interpolation,
could be expressed as equivalent to a single dose ofabout 0.7 Gy. Mcasurcments of the upper four layers,
the lower two layers and the total thickness of thesensorimotor cortex in the dose-fractionated grouprevealed significantly lcss damage than was seen at asingle dose of 1.0 Gy but more than that seen at asingle dose of 0.5 Gy. Reyners el al. [RU] haveexamined the effects of protracted exposures to low
doses ofgamnia rays on Wistar rats from day 12 10 16
post conception and found a significant reduction inbrain weight at an accumulated dose as low as
160 mGy.

147. Newly developed techniques for the culturing of
ncuronal cells in virro make such cell studies morepractical now than in the past. For example, the nlcans
cxist to culture cells from a snippet of the embryonic
forcbrain of the mouse (see, e.g. [F2, H15, H161).
These cells, when dissociated and plated in amonolayer, will form structures with a well-defined
lumen and dispose themselves radially around thelatter much like the proliferative zones seen in the
fetal brain. The cells will divide, become post-mitotic,
as cvidenced by UIC presence of neural filament
protein, and actually migrate to the periphery of theglobular aggrcgalc. At about 5-7 days after theformation of the aggregates, they collapse, presumably
for want of a supporting structure, and although thecclls will continue to divide and migrate, they nolonger have a well-defined architecture. No studies

have been published describing U I cl'fcct~of exposure
to ionizing radiation on this sequence of evcnts inthese cultures. However, even a week could be longenougl~to determine whether radiation docs alter, eventransitorily, UIC surface properties of these neuronalcells, muc11 as Feinendcgcn ct a]. reported forhaematopoictic stem cclls [F3,F4]. The measurements
oil tlic l~acmatopoietic stem cells are essentiallyindirect, but given the existence of specificmonoclonal antibodies to a variety of the neuronal celladhesion molecules and cytoskeletal proteins, a more
direct test of alterations in the neuronal or glial cell
membrane or the cytoskcleton of the neuronal cell ispossible. If such studies arc to be informative,
however, it will be necessary to demonstrate that thechanges seen in vilro parallel changes in vivo and are
not merely the consequence of the experimental
manipulatiot~s.

2.

Neurotoxic cheniicals

148. Sotnc insight into the nature of the developmental effects to be anticipated from chronic radiation
exposure may come from toxicological effects inembryos and fetuses exposed to toxic chemicals [W3,
W4, W5].In Minamata, Japan, where the bay and its
marine life were contaminated by methylmercury, 23
of 359 children born between 1955 and 1959 showed
symptoms of cerebral palsy, a proportion 10 to 60
times higher than normally expected. Fetal exposure
reduced brain weight in severely poisoned children to
one half or less of normal, and abnormal cells could
be seen distributed throughout the brain. Severe,
permanent central nervous system damage leading tobehavioural and other neurological disorders was also
seen in Iraq, where seed grain contaminated with~nethyln~ercury
was used as food. These incapacitatingconsequences were often observed in children of
mothers whose most comrnon symptom of methylmercury poisoning during pregnancy was a mild,transient paraesthesia. Such observations suggest thatthe cnlbryo and fetus are much more sensitive tomethylrt~ercurythan the mother, but it should also be
noted that methylmercury accumulates to higher
concentrations in the blood and tissues of the enibryoand fetus than in those of the mother [I3, W6).
149. The fetal alcohol syndron~e offers anotherpossible paradigm. Abnormalities of the central
nervous system, particularly mental retardation andsniall head size, are also the nlost pronounced eflectsof heavy inlra-uterine exposure to alcoliol [S6]. The
averagc IQ of individuals with fctal alcohol syndronie
is about 65, although scores niay vary from 1 6 to 105
IS7]; also, the severity of the mental retardation
correlates with the severity of the dysmorphic featuresin the iedividual. Clarren et al. [C3,C4] (see also[H4])have noted that areas of ectopic grey mattcr inthc frontal and temporal white regions of Ihc ccrrhral
hcmisphercs and leptomcningeal ncuroglial hctcrolopias, both evidences of abnormal ccll migration, arc
common among infants with fetal alcohol syndrome.
This appears truc not only aniong thosc infants born tochronically alcoholic mothers, but also those born towonlcn who dcscribe thcmsclves as infrequent drinkcrs
who have occasional cpisodcs of intensive drinking.
150. It is generally assumed that the tcratogenic effectof alcohol, insofar as abnormalities of the central
nervous system arc conccn~ed,is initiated during tbc
first trimester, but this has not been well cstablishcd.
Given the commonly chronic naturc of the exposure,
it is not surprising that the sensitive period is
impcrfcctly known. Rcnwick et al. [R9],using anargument based upon seasoriality in the prevalence of
fetal alcohol syndrome, on the one hand, and ethanoluse, on the othcr, suggested that thc damage may
occur as late as weeks 18-20 of gestation. Since they
apparently measured gestation from thc last menstrual
period [Rg], this corresponds to 16-18 weeks after
ovulation and suggests that the vulnerable periods foralcohol use and cxposurc to ionizing radiation niay bc
similar. It should be noted, however, that leptomeningeal hctcrotopias of the kind observed in fetal
alcohol syndrome have not been reported in either
humans or other primates exposed to ionizing radiation, although heterotopic grcy matter has been seen,
as previously described. Thcse leptomcningeal neuroglial heterotopias are seen as a shcet of neural andglial tissue that covers a part of thc brain surfacc arid
may partially incorporate the pia matcr. They areapparenuy continuous with the molecular layer of thecortex and may represent a persistence of its subpial
granular layer [B8]. If so, thcy arise somewhat latcr,
probably after wcck 24 [B8, 221. Thc aberration in
migration that occurs appears less a failure of theneurons to move from the pcriventricular proliferative
areas than an inability to rccognize whcn to stop; thecells commonly migrate beyond their normal sites offinal differentiation.
151. Furthcr insight into the effects of ionizing
radiation on thc developing human brain is to befound in the neurotoxic effects of prenatal expwurc tolead (see, c.g. [M22, S19, S201). Although the toxic
effects of this metal are many and varied, four findings appear especially pertinent to this Annex. First,
the effects of prenatal exposurc to lead on the dcvelopnient of the ccntral nervous system nppear to belincar over a widc rangc of doses. For example, thedccline in performance on the Bayley Mental Dcvelop
mcnt Index, which has a mean of 100 and a standard
deviation of 16, is 2-8 points per 10 p g of lead pcr
decilitcr of blood IM22]. But the epidemiological data
do not allow a threshold to be established with con-lidcncc. Lincarity docs not seem to be truc for all
r~curotoxiceffects, howcvcr. The lead-rclated impairlrlcnt of peripheral ncrvc conductance, for cxaniple,
appcars to follow a quadratic dose-response cunre,suggesting that a threshold may exist for this effect[S21]. In this instance ncurotoxicity apparently
requires the recruitment of scvcral nerve fibcrs if adysfunctional state is to obtain. This suggests that theshape of thc dose-rcsponsc rclationship is intimately
rclated to thc dcvelopmental biology of the end effectmeasured. Sccondly, since there are no absolutely
lead-free societies, it is not possible to compare leadfree situations with those involving vcry low levcls of
lcad cxposurc in ordcr to dcterniine whether there arc
non-monotonic regions in the empirical dose-response
relationship. This situation is similar to that involving
exposure to ionizing radiation. Thirdly, there issubstantial evidence supporting the notion that leadtoxicity involves molecular interactions of this metal
with calcium and sodium [S19]. Given the ubiquity of
cxposurc to lead, its effect on the transmembranal
influx of calcium and the possible role of N-type
calcium channels in neuronal migration, this suggests
the need, in the case of ionizing radiation, to explore
carefully thc molecular and cellular mechanisms that
may subtcnd radiation damage. Finally, in s o far as
lcad provides a paradigm for the potentiation of radiation-related effects on the central nervous system
Lhrough other toxic exposures, it is important torecognize that evaluation of the mother at the time of
pregnancy may not predict the actual exposurc of theembryo or fetus to a neurotoxin. In the case of lead,thcrc is cviderice that bone stores of h i s metal can bemobilized during pregnancy and cause rapid changes
in internal exposure.
152. Brock ct al. [ B l l ] , as well as others, havc shownthat chemically induced injury to the postnatal mammalian brain is often manifested by alterations in .thecytoarchitecture of specific neuroanatomical regions.
More importantly, they havc shown that these anatomic changes are accompanied by quantitative changes
in the protcins associated with specific ccll typcs.
Thus, for example, thc organometallic compound trimethyltin, which preferentially destroys the ncurons of
the limbic system, depresses the concentration of thesynaptic vesicle protcins synapsin I and p38 but
increases that of glial fibrillary acid protcin (GFAP) ina dose-related manner. This suggcsts a widespreadastrocytic response to the chemical, since GFAP is the
major protein of intcrmcdiate filaments in astrocytes.
Presumably trimethyltin stimulates aslrocyte division
and, possibly, othcr glial elcmcnts as well. Whether
this also occurs in the prenatal brain is not clear;
however, it is known that the radial glial cclls thatprovide guidance during migration of the immatureneurons to h e cortex will ultimatcly devclop into
astrocytes and, possibly, oligodendroglial cclls [CS]

once their guidance functiol~ceases. Astrocytes have
many neuronal characteristics, such as neurotransmitter
receptors, ion channels and neurotransniittcr uptake
systems. Moreover, it has been shown that cultured
astrocytes express certain ricilropcptide gel~espreferentially and specifically for the brain region fromwhich the cultured cells were derived, suggesting thatthe pcptides synthcsizcd in astrocytes niay play a rolein the development of the central nervous system[SIO].
153. Summary. The information available on exposureof the developing human brain to protracted doses ofionizing radiation is still too limited to perrnit estimates of risk at low dose rates; however, the animal
data that are available suggest that the risk is lower
but the degree of attenuation is uncertain. Moreover,
it is difficult to extrapolate this infomiation to thehuman case because of the differences in duration of
the relevant neuroembryologic events. Data on exposure to neurotoxic chemicals have provided someinsight into the molecular and cellular events associated with such exposures, which may be pertinent toradiation-related brain damage.

C. UNCERTAINTIES
154. Estimates of risks from prenatal radiation
exposure of h e developing human brain have been
derived only from the high-dose-rate, acute exposuresof survivors of the atomic bombings of Hiroshima andNagasaki. Many uncertainties are associated with theserisk estimates. They include the limited nature of thedata, especially on mental retardation and seizures, theappropriateness of the comparison group, errors in theestimates of the tissue absorbed doses arid in the
cstimates of prenatal ages at exposure. Moreover, there
are other confounding factors that would play a role.
Socio-economic circumstances in the final year of the
war and immediately thereafter were stringent, affecting both the availability of food and the resources totreat diseasc. Thus, maternal nutrition and hcallh status
and the possibility of i~rtercurrent disease could
contribute to higher risks than might be seen otherwise.

155. Sample size and comparison group. Only 21 of
the 30 severely mentally retarded individuals in theClinical Sample received fctal absorbed doses estiniated to be 0.01 Gy or more, and three of these had
health problems that could account for their retardation, making it unrelated to radiation (two cases of
Down's syndrome and one case of Japanese encephalitis in infancy). With their removal, there are only 18
cases in the critical period without known cause andmight be attributable to exposure to ionizing radiationor other factors.

156. As to t l ~ rcomparisor~group, the atomic hombings rcsulted in cxceptiol~alcircun~stancesthat couldl a v e altered the normal frequency of severe mental
retardation or have iritcracted non-additively with
exposure. However, compi~risonof the frequency of~iiental rctilrdation among cl~ildrenwhose mothcrs
were present in the city at the time of the bombing but
received an estiniated dose of lcss than 0.01 Gy withh e frequency of severe mental retardation aniong
children whose mothers migrated into these cities after
the bombing reveals no difference.
157. Estirnafion oJprenala1 age. The apparent timingof vul~~erable
events in dcvcloprnent can be affectedby errors ill the dctcrmination of prenatal age, possibly
seriously so in specific cases. Gestational age isusually estimated from the onset of the last m e n s t ~ a lperiod, assuming that 280 days, on average, intervene
between the beginning of menstruation and parturition.
Post-ovulatory age is then calculated by subtracting
two weeks. This method is sensitive to at least two
types of errors, namely, miscstilnation of the onset of
menstruation and that associated with the tacit assumption that all pregnancies proceed to term. If any
terminated prematurely, as must surely have been true
for sonic of the sample of prenatally exposed survivors
in Hiroshima and Nagasaki, the estimated age of thechild at exposure would be incorrect Prematurity is
generally dctcrmined by an infant's size and weight atbirth, but U~esemeasureme~itswere not routinely madeand recorded in the months irnniediately following thebombings. At the initial physical examination of thesesurvivors the mother was asked about the child's
weight at birth. The trustworthiness of her recollections is uncertain, however, since a subsequent mailsurvey often revealed large discrepancies between theweight obtained at interview and that given in thesurvey. Wol~lenwith irregular nicnslrual cycles or wlloniiss a menstrual period for any of several reasons,notably laclational amenorrhea, illness or malnutrition,
could erroneously identify the onset of their last cycle.
Japanese women formerly nursed their infants loager,so lactational amenorrhea may have been more common. Sorne were undernourished due to the econoniic
strir~ge~rcies
that obtained during and following thewar, and infectious diseases were more frequent in thesurviving populations. Another possible source of error
may arise from variations between individuals in theprenatal age at which specific developmental eventsoccur [M7, N4, S171. This does not seem likely to bea major lilnitation of the data, but little or no
inforn~ationis available on the probable magnitude ofthis source of variability.
158. Doshefry. All estimates of doses in the studyof survivors of the atomic bombings in Japan are subject to at least three sourccs of error: (a) determinations of dose in air with distance from the epicentre,-

A N N M 11: RADlAIlON EFFECT3 ON TllE DEVEI-OI'ING HUMAN BRAIN

U37@) the attenuation factors for building materials andtissues and (c) the locations and positions of thesurvivors. Some of these, noli~hly(c), ran never be
evaluated rigorously for all of the individuals
concerned. Errors of this nature can affect inferenceson the overall shape of the dose-rcsponse relationshipas well as parameter values defining that shape [G3,G4, J3, P2]. Pierce ct al. p 2 ] have shown that random
dosimctric errors can lead to a 10%-15% undercstimalion of the cancer risk among the survivors, andpresumably a similar error could obtain in the cstimales described here. Nevertheless, there reniain
troublesome inconsistencies in the DS86 system,
notably with regard to neutrons in Hiroshima. Straume
ct al. [S22], for example, using all of the available
lncasuremerll data on thermal neutron activatio~~
including new measurements for %I, suggest that
thermal neutron activation at about 1 km in Hiroshima
was 2 to 10 or more times higher than that calculated
based on DS86. The implications of this discrepancy
with regard to risk estimates is not wholly clear, since
it must be noted that low-energy neutron activation
contributed little to the dose in Hiroshima. It is notpresently known whether the fast neutrons, those withenergies in the range 4.1 to 1 MeV, which comprised
the bulk of the neutron dosc in Hiroshima, have been
similarly underestimated. However, Preston et al. [PSIand Sasaki et al. [S23] have attempted to determine
the possible impact of this discrepancy on risk estimates. Preston et al., based on several different
assumptions regarding the neutron RBE, found that thecancer risk estimates might be in error by 2% to 20%;
whereas Sasaki and his colleagues, using a series of invitro experiments, found that the difference in chromosome aberration frequencies between the two cities is
explicable if the neutron dose in Hiroshima was aslarge as 5 % of the total dose in Gy rather than theestimate of 2% or less provided by the DS86
dosin~etry.

160. First, the experimental data arc often contradictory. S ~ I IofI ~the disparity in results may reflectt l ~ cchoice of experimental animal: sornc investigators
have used inbred strains of niice or rats and others
outbrcd lines. Sonic may reflect the choice of the endpoint mc;lsurcd. Howcver, Hoshino ct al. [H6] havercportcd the frequency of pycnotic cells to bc linearwith dosc, even at doses below 0.24 Gy, and Wannerct ;]I. [W9] reported a measurable, but not statisticallysignificant, diminution in brain weight in guinea pigs
at exposures as low as 0.04 Gy. More recently,
Wagner ct al. [W12] demonstrated a statisticallysignificant diminution in the brain wcight of guinea
pigs exposed to 0.075 Gy on day 21 following
conception (this corresponds to approximately week 5
or 6 following ovulation in the human). The loss inbrain weight was approximately 1 mg m ~ ~ -Studiesl .
of beagles exposed on the day 26 post-ovulation haveshown a similar linear decrease in brain weight overa range of doses extending from 0.16 Gy to 3.6 Gy[H7]. Koncrmann [K7] has argued that the lowest dosc
in animals causing overt brain damage is generally
0.1 Gy or higher. This is consonant with other experimental studies. However, he noted that more subtle
changes, such as the alignment of the small andmedium-sized pyramidal neurons in the inner pyramidal ccll layer of the mouse cortex, can be seen atdoses as low as 0.025 Gy and that errors in alignmentarc marginally significant at 0.05 Gy (p < 0.10). It is
not obvious what the occurrence of pycnotic cells or
malaligned neurons is measuring in s o far as functional brain damage is concerned. Nor is it clear whata loss in brain wcight implies if the numericaldensities of brain cells are increased, as has beenreported [R14]. An increased cell density can, ofcourse, mean less neuropil (fewer axons, dendrites andglial processes between the nerve cclls), and it isreasonable to assume that fewer interccllular conncctions could reduce the quality of brain function.

159. Dose-response Junction. Within the period of
maximum vulnerability, all the data on t11c prenatally
exposed survivors of the atomic bombings of Hiroshima and Nagasaki can be satisfactorily approximatedby more than one dose-response function. Given thatncuronal death, mismanaged migration arid faulty synaptogenesis could all play a role in the occurrence ofmental retardation or other cortical dysfunction andthat each could have its own different dose-response
relationship, there is little or no prior basis forpresuming that one or the other of these rnodcls better
describes the fundamental biological evcnLs involved.
The most appropriate model, therefore, remains amatter of conjecture, and it seems unlikely thatepidemiological studies will ever be able lo determine
this. This means necessarily that the estimation of risk
must rest on a series of considerations not all of which
are biological.

161. Secondly, Muller et al. [M14], in a study of
x-ray irradiation of prein~plantation stages in themouse, have shown that exposure at the single-cellstage can produce malformed fetuses, although the riskof death of the fetus is greater. They not only notedthat the single-cell stage is characterized by a highradiation sensitivity but also asserted that theirobservations are best desaibcd by a linear-quadratic
dose-response function without a threshold in this(their) special case. This conclusion, they contended,
is consistent with theoretical considerations, since tlle
exposure of a single cell differs from tlic exposure ofpolycytic stages in development, where the high capacity of enibryonic cells to replace damaged cells andthe need for a number of cells to be affected if a~nalformationis to ensue argues for a threshold. However, the fact that they found teratogenic effects
following the exposure of a single cell, wt~creasnlost

otlrer expcrimerrlal studies lravc focused on later
critical stages in development and have commonly
found no evidence of a radiation-related effect,suggests that the niechanis~lrs involved in theirfindings niay be quite different from those of others.
Indeed, Pa~npfcr and Strcfl'cr [P4], in a study offemale mice irradiated wit11 neutrons (7 MeV) or
x rays when the embryos were at an early zygote
stage, interpreted their results as suggesting that thereactions of preimplantation embryos to irradiation
could be more complex thae the simple all-or-none
response generally considered. In these experiments,
the most commonly encountered malformation was
gastroschisis, but omphaloceles and anencephalies
were also observed [M21]. The proportion of
rnalformcd fetuses increased with dose in a linearquadratic nlanner f o r both radiation qualities. These
investigators estimated the relative biologicaleffectiveness of neutrons in tlle induction of externalmalformations to lie between 2 and 3 , increasing
somewhat as the reference x-ray dose increased.
162. Exfraneous variations. Alternative, non-radiation-related explanations can be found to cause or confound the effects to the developing human brain
observed in the study of survivors of the atomic
bombings in Japan. These include (a) genetic variation, @) nutritional deprivation, (c) bacterial and viral
infections in the course of pregnancy, and (d) embryonic or fetal hypoxemia, since there is substantial
evidence to suggest that the cerebrum and its adnexa
are especially sensitive to oxygen deprivation. There
were also exposures to other potentially noxious
physical or chemical agents, including the blast wave,
tlie fumes associated with the extensive conflagrationthat followed the bombing, and the volatilization ofchemicals, such as lead, the fires produced. The
possible roles some of these may play in the present
context have been explored elsewhere m 6 , M 1 6 , 0 1 ] ,but the roles of others can only be a source ofspeculation, since no relevant data are available.

163. Mole [M 181, in particular, has contended that theradiation-related depression of fetal haematopoiesis
may have played an important role in the occurrenceof severe mentill retardation among the prenatally
exposed survivors in Hiroshima and Nagasaki by
reducing oxygen transport to the fetal brain. M i l e theabscopal effect to which he alludes cannot be established unequivocally, it remains a contention to bearin mind in interpreting the human data. However, theissue of thc oxygenation of the developing embryonicand fetal brain is a complex one, involving not only
blood volume and concentration of haemoglobin, as
Mole suggests, but also the specific haemoglobinpresent, since this afrects the binding and unloading ofoxygen. The earliest l~acmoglobins present in thedeveloping individual, the embryonic ones, areproduced in the yolk sac, but from about week 8tlrrough week 28 after fertilization, the major site ofery~hropoicsisin the fclus is the liver and not the bone
Inarrow (8141. If a depression in erythropoiesis
occurred at this time, it would have to entail damage
to l l ~ ehaematopoietic cells in the liver or, to a lesser
extent, perhaps, the spleen. The single case of fetal
marrow irradiation at 21 weeks to which Mole alluded
has litdc relevance, therefore, despite the fact that themarrow was apparently normal. The site of erythropoicsis does gradually shift from the liver and spleen
to the bone marrow in the last half of gestation,
making bone marrow depression a more important
threat to the fetus at this later stage of development.
This is not the time when the brain appears especiallyvulnerable. It is, of course, not known whether significant damage to the liver does or does not occur atthe doses and times of relevance in the human case;however, studies of prenatal exposure of rats at
comparable stages of development, 10 and 15 days ofgestation, failed to show an alteration in liver weight
as a percentage of body weight, although spleen
weight did decrease [S13]. It would be reasonable topresume, nonetheless, that haematopoietic cells in theliver have the same sensitivity to radiation as those in
the marrow itself and that a diminution in their
number might not be reflected in liver weight. At
about 9 weeks of gestation, the bulk (90%) of thehaemoglobin to be found in fetal red cells is fetal
haemoglobin, and even at birth this haemoglobin stillaccounts for 80% of the haemoglobin present. Fetal
haemoglobin has a substantially enhanced alkaline
Bohr effect, which in concert with the fall in pH ofmaternal blood as it passes through the placenta
facilitating maternal oxygen unloading, maximizes
oxygen transport to the fetus. Finally, the incidence ofhypoxia-producing complications of late pregnancy
docs not appear to be significantly different among
pregnancies terminating in a menially handicappedchild from that seen in general [DlO].
164. No fully satisfactory assessment of the contribution ofthe sources of variation alluded to above canbe made so many years after the event. It is only possible to speculate on their importance. Given thepresent uncertainties (since most of these extraneous
sources of variation would have a greater impact at
high than at low doses, and thus produce a concave
upwards dose-response function), the careful course
would be to assume that the dose-response relationshipis not mi~teriallyaltered other than addilively by thesepotential confounders. This would have the effect ofoverestiniatirrg the risk at low doses, which are ofgreatest concern in radiation protection.

ANNEX 11: RADIATION EFlTCIS ON T I E DEVELOPING IiUMAN 13FtAlN

IV.

839

FUTURE PERSPECTIVES

165. Numcrous events are involved in the proccsscs
that bring forth a functional brain, any one of whichis potentially susceptible to radiation damagc. Thcre isclearly a nccd to confirm and extend thc findings on
cercbral cortical impairnient following prenatal exposure to ionizing radiation described in the carlicr
paragraphs. To do so, howevcr, will ent;~il not only
more neurologically focused clinical examinations,
including the various non-invasive techniques now
available to image the living brain, but a concerted
effort, national and intcmational, to identify groups ofindividuals prenatally exposed to ionizing radiationthat might be able to contribute information. Suchstudies will have value well beyond the immediate
assessment of the risk of prenatal exposure to radiation; they can contribure to a deeper understanding of
human embryonic and fetal development, to a clearer
appreciation of the diversity among individuals in theage at which specific embryonic or fetal landmarks areachieved, and to a sharper definition of the developmental ages most vulnerable to exposure to chemicalor physical teratogens. Some methods of investigation
which might be profitably exploited in future researchstudies are considered in this Chapter.

166. Epidemiological studies. The prenatally exposed
survivors of the atomic bombing of Hiroshima andNagasaki are unusual in many respects, not the leastof which is the fact that they are the only group of
survivors whose life experience subsequent to exposure can be followed literally from birth to death andwho can thus providc unique insights into the effect of
the exposure on central nervous system aging. As yet,howevcr, there have bcen no studies directcd at detcrmining the effect of radiation on specific cortical
functions. Nevertheless, many of these functions canbe investigated with a surprising degree of precision,and the time at which cortical neurogenesis is initiatedand its duration, are often reasonably well known.
Particularly appealing as subjects of study are thevarious aspects of visual function. Some 30% or so of
the human cortex appears to be involved in the processing of visual stimuli, and the mechanisms lhroughwhich this processing occurs are better understoodthan for any other cortical arca. Similarly, it has longbcen known that the brain exhibits weak electricalactivity, which can be measured. Its recording is not
painful or invasive, and other studies have revealed
measurable radiation-related alterations in the normal
record of these electrical potentials.
167. Future investigations of central nervous system
impairment should look for damage not only to the
cerebrum but also to the cerebellum and brain stem, tothe extent that effects on the latter can be dissociatedfrom effects on the former. Methods of visualizing theliving brain such as magnetic resonance imaging(MRI) or positron eniission tomography (PET)might
give subclinical evidence of radiation-related centralr~crvoussystem damage. If thcrc are nietabolic diffcrenccs bctwcen neuronal and non-ncuronal cells, PET
scans, since they can measure. some metabolic funclions, could give evidence of impaired migration or o fsitcs in the brain that are non-functional but seem tobe histologically nomial. Individuals with intractableseizures, for example, often have regions of the brainthat show no functional activity yet appear grossly
normal. Similarly, recent advances in MRI, which
does not involve exposure to ionizing radiation, havemade possible some functional measurcnients of brain
activity, and further developnicnts can be anticipated.
Singly and collectively, these techniques hold great
pronlise for furthering the understanding of thefunction and physiology of the brain in the healthy aswell as the diseased state.
168. Of particular import have bcen the recent
developments in MRI that allow functional parameters
to be added to the information content of the images
themselves (see, e.g. [M17]). Although these newer
uses of MRI have not been applied to the study offunctional damage to the brain following prenatal
exposure to ionizing radiation, their promise seems
great. High-resolution MRI, togcther with neurologicalfindings has demonstrated, for example, that selective
bilateral darnage to the hippocampal formation is sufficient to cause significant, permanent memory impairment [S14]. Also, neuropsyctiological studies ofpatients with confirmed hippocampal damage suggestthat the hippocampus is essential in thc establishmentof long-term memory. This role of the hippocampus
appears to be a time-limited one, however, and ultimately the role is transferred to the neocortex [Z3].
Where practical, the use of these non-invasive but
highly infomiative techniques should be encouraged inclinical as well as experimental studies. They could be
the means not only of determining the functional
impairment associated with grossly visible changes in~ i braincbut also of identifying damagc that cannot be
related to gross morphological changes.
169. Radiation-related damage to the brain could also
be evaluated by simpler means. Cognitive tests, suchas those measuring word association, learning ability,
Inemory and intelligence, could be informative. Moreover, in die light of experinienlal findings on otherprimates, careful studies of auditory and visual acuity
and olfaction and taste should be useful. These might
include the audiometric assessment of thc left andright ears and the conventional appraisal of visualacuity. Smell and taste could be evaluated througb
exposure to a battery of tastes or aromas at diffcrcnt

840

UNSCEAR 1993 REPORT

concentrations. Evidence of premature loss of hearingor vision should be sought, since a l a s e r initial number of neuronal cells could lead to earlier manifestation of an aging central nervous system.
170. Still other neurophysiologic effects, with different critical periods, can be envisaged. Recently, forexamplc, it has been shown that niicc irradiated prenatally on day 18 (corresponding to about week 35 in
the human) suffer a significant loss in spatial memory.
The integrity of spatial memory appears to depend on
the proper development of the hippocampus. This
structure arises relatively late in the development of
the human brain, but damage to it results in a rccognized cognitive defect characterized by severe amnesia
and evidenced by deficits in learning mazes. There isevidence that associates a reduction in the pyramidalcells within the hippocampus with memory impairment. Here even simple pencil-and-paper mazes might
be informative.
171. Prenatal exposure to a nuclear accident might
give rise to a dysfunctional child, either because oforganic damage to the developing brain or because of
the disturbed psychosocial milieu into which the childis born. The frequency, severity and pathogenesis ofthese psychosocial disorders have been poorly studied.
If thcir origins are to bc understood, the children
found to be abnormal need to be studied to ascertain
ways in wliich the children, families, and communityand culture interact to cause psychosocial dysfunction
and to form perceptions of risk. A child's perceptionof risk is not independenlly formed, but is inculcated,
at least in part, by the attitudes of his or her age peers

R I I ~fa~iiily,and thcir attitudes are shaped, in turn, bycommul~ityand culture. Thus, to understand the originof psychosocial disorders arising out of a nuclear
accident, it is essential to understand the workings ofthe larger milieu. Without this understanding, purely
p r i ~ g ~ ~ ~ameliorativei~ticor prevc~itiveefforts are likely
to be ulrproductive and ultiniately self-defeating because they arouse expectations than cannot bc fulfilled.
172. Experimental studies. Although no animal
species is an ideal model for human brain develop
meat, experimental studies will and must continue toplay an important role in understanding the effects ofprenatal exposure on the developing human brain.
Such studies can serve to confirm epidemiologicalfindings in humans, to provide data on possible doseresponse relationships and to afford insight into molecular and cellular mechanisms that is not easily available from hutnan investigations. It warrants noting, aswell, that extrapolations to the human being ofmolecular and cellular mechanisms revealed by animal
experimentation are likely to be better than extrapolations based upon gross, phenotypic end-points,
although the latter arc often a necessary first step inthe detection of radiation-related effects. Numerous
questions of a mechanistic nature exist for whichanswers are not now available. For example, what
initiates migration? How does the migrating neuron
know that it has reached its destination, which is thepoillt at which it disengages from its radial glial
pathway? Recent advances in neuromolecular biology
and the ability to culture specific neuronal cells invirro hold promise for providing answers to thesefundamental questions.

CONCLUSIONS
173. The human brain is relatively sensitive toionizing radiation at certain stages in its prenatal
development. Data from Hiroshima and Nagasaki, as
well as from a few other studies, indicate that there
can be consequences to the central nervous systemfrom exposure to radiation at these stages. The
abnormalities that have been observed correlate wellwith animal experiments and with current knowledgeof the developmental embryology of the brain. Itshould be noted, however, that these findings do not
represent a major public health problem. There wereabout 100,000 deaths at Hiroshima and Nagasaki, andsomewhat more than 285,000 survivors. Among thesesurvivors there were possibly as many as 10.000
pregnant women whose greatest immediate risk was
the loss of their pregnancy. Although the observations
on loss of pregnancy arc limited, this risk appears tohave been markedly elevated among those women in
the first eight weeks of pregnancy, but it was also
greater than normal among women in the 8-15 week
interval [CIS]. Nonetheless, the epidemiological data
do indicate substantial risk of abnormalities in thecentral l~ervoussystem following high doses at certain
periods ofpregnancy. The risk is highest for exposuresoccurring during post-ovulatory weeks 8-15, that is,when the greatest number of neurons are produced andwhen they migrate to their functional sites in the
cercbral cortex. During weeks 16-25 after ovulation, alesser vulnerability is observed, with little apparent
risk for exposures before week 8 or after week 25.

174. Among the prenatally exposed survivors of theatomic bombings of Hiroshima and Nagi~sakiwho
have been under clinical scrutiny, there are 30 cases ofANNEX 11: RADIATION ElTECE ON V I E DEVELOPING H U M A N B R N N

scverc mcntal rctardation, some of which are probably
not radiation-related, 30 with small head size without
apparcnt nicrital retardation, 5 2 with seizures, of w l ~ i c l ~24 appear to be unprovoked (those wid1 no clinically
identifiable precipitating cause) and sonic with reduced
intelligence quoticrit scores or with lower scholastic
achicvcment in school.
175. Both severe mcntal retardation and lower intelligcnce test scores arc obscrvcd to occur following prcnatal exposures during the two sensitive periods of
dcvclopment previously describcd. Thcsc effects aremutually consistent if radiation is seen as operating on
a continuum of qualities of brain function. The
damage caused by exposure to 1 Gy within thc mostvulnerable pcriod, namely 8-15 weeks aficr ovulation,
increases the frequency of mental retardation to about
40% (background frequency: 0.8%), and lowers IQ by
25-30 points, which is consistent with the obscrvcd
increase in mental rctardation. The specific value ofthe IQ decrement depends on the sample used to estimate the risk and on whethcr the mentally retarded
individuals are included in that sample. Prenatal
exposure to 1 Gy in the most critical period appears tocause a decrement in average school performance
score equivalent to the shifting of an average individual from the 50th percentile to the lower 10th
percentile and increases the risk of unprovoked seiz-84 1

ures by a factor of approximately 25. For the pcriod
16-25 weeks, no cases of scverc mental rctardation
were obscrved at cxposurcs of less U~an0.5 Gy. Thus,
albeit with some uncertainty, a threshold could beassumcd for that pcriod. As to unprovoked seizures, atestimated doses in die range of 0.1 to 0.49 Gy therclativc risk is 4.4; whercas at doses of 0 5 Gy or
grcatcr the relative risk is 14.5 when the cases ofmental retardation are excluded from the data.
176. Thc risks cited in the preceding paragraphs assume the dose to have been an acute onc. It is reasonable to assume, however, dial these risks would besmaller for chronic exposure over the same critical
periods, and this assumption is supported by thecxperimcntal animal information that is available.
However, there are numerous potential confounding
factors, and the human data are still far too limited toprovide quantitative estimates ofthe possible reduction
in risk at low doses.
177. The limitations in the data prcsently available
arid the uncertainties in the risk estimates have been
pointed o u t Definite risk estimates cannot be obtained
at doses lower than 0.5 Gy or at low dose rates. The
above estimates are therefore obviously provisional
until additional evidence from further investigations
can be obtained.

UNSCEAR 1993 REPORT

8-42

Tahle 1
Temporal pollern or hreln dcvclopment
P"01
lmprtanr dc~rlopmormdelurusI 1 a t r - o w l n r o ~agc

3 wccklNcural folds clorc to l a m neural tube
O r v i a l i c l j m begins lo l a m
Cranial and ccr%ialflcxura appur
Ganial and spinal molor nudci dcvclop

4 wcckr

Paired optic v c r i d a cvcn; oanial m d spinal n c w u cmcrgc
Spin.1 ganglia dcvdcp and 1x0~7smlcr m a r l navuus syrtcrn
aorurc of ncural tube

S wc+hDicaccphalic nudci devdcp
F i n d and hypophyrir cvat
ivcruon of ccrcbal vaida
OTGI md lcnr indued by the optic primotdia
Olaoid p l u u r devclcp and cutborpinal fluid fills neural lube
B a d ganglia and amygdala develop
Maja ccrchal a r ~ n i alam
O n l l i u t i o n and dcvclcpnmt ofaudal spinal ox& p a l e r i a mrnissurc devdqrs
Dcgjnninp of the cncbcllurn and m c b d l u nudd aFpar
lhinning of the roof ofthe 4h vcnvidc d l w cnebrospiaal fluid to flow oul

6 werlu

Neural rctiru develops
Olfaaay ncrva grow to base d train; tccTaay vcsicla appear in chaoid plexus
Beginnings of hippoampw and dfactory apparatus appur

7 weeks

Ncocortial primadia appears
Olfactay bulb c m l r
Formalion of pipenled rctiml cpithcliurn and aliary body

8-11 wccka

Coniul plnlc appears in neocortu
Rrst rynapsca i n the molecular and subplate rcljms o f lhc ncocalcx
Ncurons rnigate fran thc prolifcrativc zmu; op~icncrvc pathways form
Prdifnativc zone of 3rd venlridc is cxhaustd
Cortical plalc of mcbellurn a p p r r
Antcrior comrnirrure dcvclops
Conical plnlc of the hippoampus appan
Sylnn and hippaampal firrura form
Skdctal rnusdc innernled ud pint ca~iliesappear
Ilasd foramina and rubarnchnoidr p m opcn

12-15 wcckl

Corpus callmum lams
G~vnseptum pelliddurn formed
Migration of n c u r w to ncomtcx io full r w n g
Cortical wall lripla in h d m o s
Chlccrpinal fiberr darualc
Purhnjc ccll migndoa m p l a c . invard m i p t l o a aC enanal granulc cclls bcgm

16-20 wccks

Gamlnal zones d l a l a d vcntridcs arc dcplacd
h s t wavc of ncccorlicll mlpallm
Pranincnce d rubvcn~riculargermnal m c and 8rs1uavc d dial rnigatim
Thalamocortical affnenlr invade thc dcphs of Ihe catical plalc. syrwpscs appear and largc pyramidal ncuronr k g j n to drffercn~iateCacbaI rutarachnoid spa- arc open lo Ihc sapttal srna
Activc pharc of nalural n m c dl dcah

20-24 w e b

Ncwonal m~grationto neomtcx wmplctc
Chmulc ccllr d ccrcbcllum and dmtale gnu of hippocampus cmtinuc lo prdilera~cand migale
RadtaI dial ccllr rclesx ventricular at~achmcntsand migatc into maex nr protoplasmic nrtrocylcs
l'rinury gyri and rulci f a m
Myclination begins
Rctinogcniculstc, brain rlcm auditory and Grual mola, and sensory lernnircal palhways are lwnong thc firrt lo dcvclop

25 wccla
to end of tcrm

Gtanulc ccll migratim continues
Glial proliferation wntinua
Appcarnncc d dial fibrilr and acidrc glial fibillsry protein signal inncasing capacily for glinl rcsponsc lo injury
Sccmdary gyri and rulci lam
Maluration of supragranular nmortical layers k p s
Myclinatior~of intnnal a p u l r bcginr
R t h d g o w h d dcndrila and axms and syn~ptopnesir

A N N M El: XADIATION EFFECJS ON T)IE DEW:l.OI'INGIILJMAN IiRAIN

M3

Table 2
Sltn nnd levels of neumn~ilvarintion[E2]
Gencric wniu andd d o p n m r o l pimrrry procwes\'wiarions in ccll dit.tiuq migrorioq
dhrrinn, diflncnriarim, dcmh

GI1rnaphology

Varintim in dl shape and rim; variation i n dcndritic and axonal artutilatims (spatial distrilxticm. bandung
adcr, lcndh oibranchu, r~umbcrd spines)

Conncclion panems

Variatims in n u m b o i inpub and aulpr~s;connection adcr uib mhcr ncurons; lccal varur long-range
connccrimr; dcgcs of ovcrlap d arbors

Cytcarchit~mia

Varia~imin number or dewily of cells; thicknus d individual m t i u l layers; relative hidrnur o isuprapnular. infngranular and grandu layas; position of sanata; vrrialiw i n cdurnns; variatim in strips
a patches of tminations; mriation in anismropy d fibers

Tnnsmittcrr

Variatimr between 4 1 s in a population; bawcen cells at diNcrcat t i m u

Dynamic raponse

Variations i n synaptic chcrnistry and u'zr or synapse; i n electrical properties; in cxcitatoryfinhihtory rstior andlocatims d synapses: in ahat- and lmg-term symptic altcrnlion: in rnclabolic stateN w d transpon
Inlcradion.. uilh $inaTnhle 3
Severely mcntnlly retarded lndlvldunls exposed in ulero to the atomlc bon~blngsIn Japanloll

File n u m b

Dnrc cf btrh

Dore of dcah

Crmsc of dcdh

Sex

Post-awlatory
age at exposure(wmw

Absorhcd dmc in uterus (Gy)

Totrl

Neutroa

1.4
0.14
0.87
1.36
0.69
1.02
2.22
0.05
0.56
1.39
1.64
0.29
0.6 I
0.06
0
1.23
0
0.03
1.O
0
0
0

0.01
0
0
0.0 1
0
0
0.01
0
0
0.01
0.0 1
0
0
0
0
0.0 1
0
0
0
0
0
0

Kogn IQ score
1955-1956

Smnll head
S~ZC

Significant
clinical finding

IIiroshima

245971404239246116400590471693401 141
4002 10
R.S72m40lOLl4445224010814040322457632417283120214007162x683
433800460463450056400 13340303

5.3.1946
1.3.1946
28.21946
25.2 1946
24.21946
I 2 2 1946
15.21046
11.21946
6.2.1946
4.2.1946
27.1.1946
23.1.1946
15.1.1946
11.1.1946
5.1.1946
1 2 12.1945
1 2 12.1945
8.121945
2211.1945
29.10.1945
229.1945
18.8.1945

14.1.1953

Malieant ocoplasm of lim

F
M

.U
M
M

21.1.1952

Ill d c f i n d unkovm

MF

28.6.1952

Acddcntal drowning

M
F

I:
F
F
30.8.19S8

18.21970
19.9.1956

Tutcrdosis

Renal failure
Heart failure. epilepsy

M
F
F
M
M

F
M
M

26.3.1966

Hcart failure, epilepsy

F
M

8
8
8
9
9
10
11
11
I2
I2
13
13
I5
I5
16
19
20
20
22
26
31
36

64

Ya
Ya
Ya
Ya
Ya
Ya
Ya

Nm-natal jauadicc

No

56

64

59
60

Ya
Ya
Yea
Ya
Yn
Ya
Yes
No
No
No

D m ' s syndrome

Down's r y n d r c n ~Rdardtd sibling
Encephalitis at age 4

Ya
Yo
No

Ya

b n ' s spbomc--

SagesskiOS096R
07848714262..
1523061438 18151845078481257021

224.1946
27.2 1946
6.2.1946
26.1.1946
15.1.1946
15.1.1946
2.1 1.1945
25.9.1945

F
M
14.3.1962(jencral symptans, mcningitir

M
M

.U
F
F
F

1
9
12
13
IS
15
25
31

0
1.16
1.18
0
1.46
0
1.79
0

0
0
0
0
0
0
0
0

62

So
No

PosiMe birth trauma
N~r~brornalcsis

Ycs
No

Yn
56
60

No
No

No

Cmgrnilol l u a

ANNEX I I: RADIA'IION EFFECTS ON DIE DEVELOI'INCi I IUMAN BRAIN

845

Tahlc 4
Severe mental rehrdatlon In indivldunls cxposcd in rrlem Lo the tlton~lcb o n l h l n g in ,111pnn"
1011

Pm-o~ulaory

Evaluarion

age

cnregoriec

Dmc c o r c g a i e (Gy)

< 0.010.01-0.09

0.10-0.49

0.50-0.90

a 1.0

Told

Ilirnahin~n
Number of subjccts
Number rclarded

145
0

35
0 (w@)

24
0 (05%)

50 (0%)1
0 (0%)

210
08-15weeks

Number of subjects
Number retarded

209
0 (m)

4I
2 (4.9%)50
1 (2.0%)13
3 (23.15)

96 (66.7%)322
12 (3.7%)

16-25 weeks

Number of subjects
Number rctardcd

243
2 (0.8%)47l(212)

46
0 (0%)

14
0 ('=I

7

2 (3.6%)357
5 (14.0%)

r 26 wccks

Number of subjects
Number retarded

227
2 (0.9%)

57
0 (w)

47
0 (0%)

4
0 (0%)

20 (c"w

337
2 (0.6%)

All agcs

Number of s u b j m
Number retarded824
4 (0.5%)180
3 (1.7%)167
1 (0.6%)36
3 (8.3%)19
8 (421%)1226
19 (1.5%)

1074
1 (1.4%)0-7weeks

N~aanki

0-7w&

6-15weeks16-25 wccks

2

26 w&

All a g a

Number oC subjects
Number retarded60l(1.74)

0

7
0 (m)

0
0 (0%)

Number of subjeas
Number retarded46
2 (4.3%)

3
0 (%)

7
0 (0%)0 (m)3
3 (100%)61
5 (8.2%)h'umber of subjects
Number rctnrdcd

65
0 (Ww)

8
0 (0%)

11
0 ('3")

20 (m)1
1 (100%)1 (1.1%)

Number of subjects
Number retarded

4

0

14
0 (OR)1
0 (0%)2

1 (1.42)093
1 (1.14)

Number of subjects
Number rctardcd

243
4 (1.6%)21
0 (0%)39
0 (0%)

50

7
4 (57.1%)315
8 (25%)

2
0 (070)284
1 (0.4%)

12

6

72

2

87

Hoih cities

0-7w&

8-15wccks

16-25weeks

r 26 weeks

All a g u

Number of subjecu
Number retarded

1 (0.5%)

41
0 (m)

31
0 (0%)

50 (0%)

Number of subjects
Number relarded

255
2 (0.8%)44
2 (4.5%)57
1 (1.8%)30

9 (75.0%)383
17 (4.4%)

Number of s u b j d s
Number retarded308
2 (0.6%)55
1 (1.8%)90 (0%)

160 (&)

8
3 (37.5%)

6 (1.4%)

Number of subjcns
Number retarded299

3 ( 1.090)61
0 (0%)

61
0 (OT.)

50 (0%)

4
0 (c"w

430
3 (0.72)

Number of subjccu
Number retarded

8 (0.79;)

2D 1
3 (IS%,)206
1 (0.5%)41
3 (7.3%)2b
12 (46.2%)

1541
27 (1.8%)

205

1067

15

" Three caser d D m ' s syndranc have becn cxdudcd.
DS86 ulcrinc ahsabcd dose; mean dceea within d m catcgaics fa total ranplc arc 0, 0.05, 0.23.0.64 and 1.38 Gy,respectively.

444

UNSCMR 1993 REPORT

846

1'1iblc 5
Srnlill haid s l m in cliildrc~icxpos~din ltlero lo the atomic bombings In Jiipnn
I0131

Part-o~ylolory

K~~~tJuolim

OXccnre~oriuL)me c o r c p r i u (Cy)I'
c 0.010.01-0.09

O.lO.O.JP

0.50-0.00

r 1.0

Toral

nimrhims
Rrsl trimcsicr

Scmtd trimalcr

Third Irimmcr

Numbcr d subjccts
Numhcr wilh small head size
Number mentally retarded

7 (3.2%)40

57
3 (5.3%)41

52
12 (23.1%)0, 1

95 (55.7%)
20

3
2 (66.7%)
20343
29 (8.5%)
4,2

Numbcr d rubjeas
Numbcr with small head rite
Number mentally retarded317
3 (0.955)
91

62
3 (4.8%)1, 1

57
4 (7.0%)1. 0

17
2 (11.8%)
1, 0

10
3 (30.0%)3, 1

463
I5 (3.2%)
6. 3

Number d subjects
Numbcr with small head size
N u m b mentally retarded229
5 (22%)2 1

61
2 (3.3%)90

46
1 (22%)0. 0

70 (0.096)40

20 (0.0%)40345
8 (23%)2 1

116
5 (4.3%)
41

222

Npg.ukiNumbcr d subjeds
Numbcr with snull head size
Number mentally retarded

88
0 (0.0%)91

90 (0.0%)0. 0

15
1 (6.7%)0,0I (100%)0, 0

33 (100%)1. 0

Scmnd Lrimcstcr

Numbcr d suhjcas
Numbu with small head size
Number mentally retarded80
2 (25%)92

90 (0.0%)0. 0

120 (O.%)0,03
0 (0.0%)0,022 (100%)20

106
4 (3.6%)
22

Third trimutcr

Numbcr d subjects
Numbu with small head size
Numbcr mentally retarded

74
O(0.W)
41

7
O(O.osb)0, 0

15
1(6.7%)
0,01
O(0.m)
0,03
O(0.W)
91

100
l(l.m)
0,2First v i m m a

1

Rolh cities
Erst aimester

Number d subjects
Numbcr with small h a d size
N u m b menially retarded310
7 (23%)
41

66
3 (4.6%)41

67
13 (19.4%)0, 1

106 (60.0%)20

65 (83.3%)
3,0459
34 (7.4%)
5,3

Second trimcaterN u m b d subjects
Number with small head size
Number rncntally relarded397
5 (1.3%)43

71
3 (4.2%)
1. 1

69
4 (5.8%)1, 0

20
2 (10.0%)40

12
5 (41.7%)
5, 1

569
19 (3.3%)b5

Third trim&er

N u m k d subjects
N u m b with small head sire
Numba mentally retarded303
5 (1.72)f 2

68
2 (29%)
0. 061
2 (3.32)0. 0

60 (0.0%)0,050 (0.0%)0. 1

445
9 (20%)
23

25
5 (20.0%)
0. 0

42 (50.0%)0. 0

10 (0.0%)0, 0201
15 (75%)40

48
1 1 (22.9%)
1, 1

12
5 (41.7%)
3. 0

74 ((n.l%)4, 0295
24 (8.1%)
9,2

13

5
1(20.0%)1. 1

333~(1.5%)
1. 3

4

2
0 (O.m)Uimshima

0 7 wcch

6-15wech

16-25w v h

a 26 w v k s

Number d subjects
Numba with small head size
Numbcr mentally retardedUS
5 (3.7%)4 0

36
3 (8.3%)90

Numbcr d rubjects
Numbcr wilh small head size
Numbcr mentally retarded167
3 (1.6%)0. 0

41
1 (24%)

N u m b d rubjeas
Number with small head size
Numbcr ment~llyretarded

2322(0.9%)
41

45
2(4.4%)
0,1

0

N u m b d suhjectr
N u m b uilh small head sireN u m b mentally rclnrded

214
5 (23%)
2 1

58
2 (3.54)0,044
1 (2.3%)
0, 0

00
0, 0

0. 0

322
8 (25%)
2 1

1, 1

38
0
0. 0

O O ~ )
0,0

Nqs~uki

0-7w c c h

Number d ruhjects
Numhcr wilh rmnll head size
N u m k mentally retarded60
0 (Om)
41

7
0 (0.0%)0,07
I (4.3)
0, 0

0
00
0,0

1
1 (100%)0. 075
2 (272)0, 1

8-15wccks

Numhcr d suhjcctr
N u m b with small head size
Numbcr rnenlally retarded

46
0 (O.w)
Q2

4
0(
0
Q0

9
0 (0.0%)0,02
1 (50.0%)0,04
4 (100%)3,065
5 (7.7%)
3. 2

ANNEX 11: MDIATION EFFECTS ON 111E DEVELOPING IIUMAN BRAIN

I'ar~.odnrory

16-25 weeks

r 2f1w e e h847

D a r c cnfrgories (Gy)'

Evaluation
rnrcxoriu< 0.010.01-0.09

0.10-0.40

0.50-0.99

r 1.0

Told

Number d nubjccta
Number with s m l l head size
~ m b e mmtallyrraardcd65
2 (3.1%)0. 0

80 (0.lW)90

120 (OW)
40

20 (0.0%)90

10 (0.0%)0, 1

2 (23%)
a1

Numba d subjects
Number with small head rizc
~ ~ m mcntal~yb araardcd

O(O.m)

6
O(0.W)
40

141(7.I%)
40

1
O(0.W)0

2
O(O.Fm)0. 094l(l.l%)
1

4

2

2 (50.01)
0, 0

1 (50.0%)0, 0

276
17 (6.2%)
91

71

*

41

a

68

a

Dolh cilicr

N u m b d subjects
N u m b uith s m l l h a d s i x
Number mcntnlly rclnrded

195
5 (26%)
0. 1

43
3 (7B%)0, 0

32
6 (18.8%)
0. 0

N u m b d subjcas
Numbcr with s m l l h a d size
Number mentally rctardcd

233
3 (1.3%)0. 2

45
1 (22%)
1. 1

11 (19.3%)
1, 1

14
6 (42.9%)3, 0

11
8 ((727%)7, 0

360
29 (8.1%)
12 4

16-25 wcckr

Number d subjects
Number uith small h a d rizc
Number mentally retarded297
4(1.4%)
0, 1

53
2(3.8%)
0, 1

50
O(O.m)
40

15
O(0.Wm)0. 0

61(16.7%)
1, 2

421
7(1.7%)
1. 4

26 weeks

N u m b d rubjcar
N u m b uith small h a d size
Number nlcntally rctarded285
5 (1.8%)2,264
2 (3.1%)0, 0

58
2 (3.5%)0, 0

50 (O.m)0,04
0 (0.6)0, 0416
9 (22%)
22

Number d subjects
Number wilh small head size
Number mmtnlly rctrrdcd

1010
17 (1.7%)
2 6

205
B (3.9%)
1. 2

197
19 (9.6%)
1. 1

38

23

8 (21.1%)
3, 0

10 (43.5%)
8. 2

1473
62 (4.2%)
15, 110 7 weeks8-15 u&

1

agm

57

DS86 utcn'ne atsabcd dose; m a n dcscs uithin dose c a t c g u i a fa taal ssmplc arc 0. 0.05, 0.23. 0.63 and 1.30 Gy. rapcaivcly.
N m b m of mcntdly rcludcd uith small head size fdlowcd by numba >f mentally rnardcd wilh normal hcad size.

Table 6
Expected a n d observed incldcnce or small hcad size In IndivlduaLs exposed in u e r o tn the atomic bombings In
Japan
[0131
Number with snurll hcad s k c

Pnn-ovulmory ogc

0-7 w c c h
8-15 weeks
16-25 weeks
a 26 weeks
All agu;*

Number of d j a u

276
360
421
416
1473

Ertlrnatcd f r a n assumed 25% dmiance in lhc normal Bstnbution.
Number uith and without scvcrc mental raardation bvcn in parcnthesea

Expected *O b s d7

17 (0,17)
29 (12 If)
7 (1. 6)9 (2 7)62 (15. 47)

9

11
10
37

Table 7
Hegrcsslon cotlTlclcnlr obhlned In fllllng nlodels lo lnlclllgence lest scores e11d ulcrlnc ahsorbcd dose lor
lndlvldunls expcaed in ufem Lo the atornlc bonlblng In Japanis41

Pan-ovulnroryaKc

R e p u s i o n cwficunr "Hcgrcrswn
male1

I

a

S ~ n i j i i m c cl o r 1 u/
c

b

b

c

Clinical r u b u m p k , all c u e s included
0-7 w&
8-15 waks
16-25 weeks

Linearr26w+ck.
All 1 p0-7 w&
8-15 weeks
16-25 waks

Linearquadra~ic

26 w&

L

All r p106 : 1.2
108 r 0.99
111 :0.89
107 :
0.80
108 r 0.47

-27 r 5 3-29.0 :4.2
-20.4 :4.4
4.2 2 5.0
-15.8 :2 4

107 r 1.2
108 I 1.0
0.91
111 :
107 :0.82
109 r 0.48

-34.0 2 135-25.8 2 11.1
9.3
-3.6 :-10.1 z 12.8
-20.7 2 4.8

p c 0.01
p c 0.01
p c 0.01
16.4 :6.5-2.9 9.2-16.8 :8.2
7.1 2 14.2
4.2 r 3.6

p c 0.05
p < 0.05

p c 0.05
p c 0.05

p c 0.01

PE-86 nubaunplc, all m u n included
0-7 w&
8-15 w&
16-25 w u &Lineara 26wrckr

All 8

p

0-7 wcch
8-15 waks
16-25 w a l a-Linearquadrntic

106 r 0.94
110 :0.92
110 r 0.76
108 r 0.68
109 Z 0.40

-1.7 r 5.1-25.3 r 4.0-21.4 :4.2
4.7 z 5.0
-15.7 2 2.2

107 r 0.97
110 :0.97
110 :0.77
108 0.71
109 :0.42-24.1 r 12.5
-33.6 z 9.7
8.8
4.9 :
-11.9 r 12.5
-20.2 t 4.6

+

26 w&
All agcr

p c 0.01
p c 0.01
p < 0.01
12.1 r 6.1
6.1 r 6.6
-14.9 r 8.0
8.8
14.0
3.7 :3.3

p c 0.10
p c 0.01

p c 0.05
p < 0.10

p < 0.01

Clinical ~ubramplc,retardelion cercr cxcludcd
0-7 wceb
8-15 weeks
16-75 wccb
1

Linear

26 wuka
All 8p

0-7 w&
8-15 weeks
16-25 weeks

Linearquadratic

a 2 6 w&
All agcr

106 r 1.2
108 r 0.98
111 z 0.89
107 r 0.79
108 :0.47-27 r 5.3
-25.0 :5.1
-9.8 r 5.7
4.4 r 5.0
-10.2 :2.6

107 + 1.2
108 r 1.0
111 :0.92
108 r 0.82
109 2 0.48

-34.0 r 13.5
-26.1 r 12.2
-5.9 :15.6-10.8 2 12.7
-19.0 r 4.8

p c 0.01
p c 0.10
p c 0.01
16.4 r 6.5
1.2 r 11.7
4.2 :23.3
7.7 r 14.0
8.1 :3.8

p c 0.05
p c 0.05

p c 0.05

p c 0.01

p c 0.05

PLS( s u b m ~ n p l ~rcL.rdation,
C ~ C excludedB
0-7 w a k t
8-15 w a b
16-25 wuwcckr

Lincar

r26&
All age4
0-7 wcckr
8-15 &
16-25 weeks
a 26 w&

All a pLinear-quadratic

106 :0.94
110 :0.91
110 r 0.76
108 r 0.68
108 r 0.40

-1.7 r 5.1-21.0 2 4.5-133 r 5.2
4.9 :5.0-11.0 r 2.5

107 r 0.97
110 r 0.94
110 r 0.79
108 r 0.70
109 r 0.41

-24.1 :125-293 r 9.9-5.1 r 15.0-125 2 124-17.8 z 4.6

p c 0.01
p c 0.01

p c 0.01
12.1 r 6.1
6.3 2 6.7
-12.8 2 22.0
9.3 r 13.9
5.9 r 3.4

p c 0.10
p c 0.01

p c 0.05

p c 0.01

p c 0.10

Shc regcsrion mfficicnt a is Ihc cstimatd IQ score at rcro dose (intcrccpl); b ir thc incrcasc in 10 scare per unit d m c (~y-I);
c is ~ h ci n n u r c in 10 r c a c
p a unit do.c squared ( ~ y . * ) .

ANNEX 11: IlrZDlATlON EI:iTCIS ON 'Il
lE DEVELOI'ING I KIMAN BRAIN

84 9

Tahle 8Regression cwfllclen(s oblalncd In fltting models to avcrege school performance and utcrlne absorbed dose forlndlvlduals exposcd in ufero to the atomic hmh lngs In Japan1021

Pm-odaruty

Regression

axe

modcl

Regression cocfliicnr 'aIb

SigniJuancc Imul of

I

c

b

c

Fin1 g n d c

0-7 weeks8-15 wceks
16-25 week

tinearz 26 weeks

All a g a
0-7 u,ccks
8-15 u.ccks
16-25 weeks

tincarquadratic

26 U - C C ~ ~All a g a

3.09 r 0.08
286 r 0.06
3.03 r 0.05
3.11 2 0.05
3.03 r 0.03

0.23 r 0.32
-1.15 r 0.22
-0.97 :0.24
0.23 + 0.36
-0.70 r 0.14

3.18 2 0.08
287 r 0.06
3.05 2 0.05
3.10 :0.05
3.05 r 0.03

-2.66 :
0.89
-1.21 r 0.58
-153 :
0.72
0.84 r 0.79
-151 r 0.27

p c 0.01
p < 0.01

p < 0.01'

1.38 r 0.40
0.06 r 0.48
0.67 :
0.80-0.82 r 0.95
0.70 r 0.20

p < 0.01
p c 0.05

p < 0.01

p < 0.0s

p c 0.01

p c 0.01

Second grade

0-7 weeks8-15 w c c h
16-25 weeks
a! 26 weeks
All ages

Linear

0-7 u w k s

Liocsrquadrrlic

8-15 wceks
16-25 wteb
2 26 wccks

All a g u

3.09 r 0.09
286 + 0.06
3.05 r 0.05
3.16 r 0.05
3.05 + 0.03

0.36 r 0.34
-1.27 + 0.22
-0.96 2 0.24
0.01 + 0.36
4.76 r 0.14

3.17 :0.09
286 :0.06
3.06 r 0.05
3.15 2 0.05
3.07 r 0.03

-2lc :
0.98-1.14 2 057-1.79 r 0.72
0.21 r 0.80
-1.64 0.27

p c 0.01
p c 0.01
p c 0.01
1.19 2 0.44
4.12 r 0.48
0.97 r 0.80
-0.28 r 0.97
0.76 :
0.20

p c 0.05
p c 0.05
p c 0.05

p < 0.01

p c 0.01

p c 0.01'hid grndc
0-7 w c c h
8-15 w&
16-25 a&>26uPtr
All ages

Linear

0-7 wukr
8-15 weeks
16-25 w e e kz 26 wcekr
,411
aga

Linear-quadratic

3.11 :0.10
286 :
0.06
3.02 ? 0.06
3.10 z 0.05
3.02 + 0.03

0.12 r 0.38
-1.17 :
0.25
-1.01 :
0.25
4.06 r 0.37
4.74 :0.15

3.21 :0.10
286 r 0.06
3.02 r 0.06
3.10 r 0.05
3.05 + 0.03

1.08
-3.04 :
-0.90 r 0.62
-1.17 + 0.77
-0.13 r 0.81
-15 7 r 0.29

p c 0.01
p < 0.01
p < 0.01
1.S :0.48-0.25 r 0.54
0.19 2 0.85
0.10 r 0.98
o.n :0.21

p c 0.01

p < 0.01

p c 0.01

p c 0.01

Fourth p r d c

0-7 v;cckr
8-15 a-eclr
16-25 wccb

Linurx 26 weeks

All ages

0-7 urclu
8-15 weeks
16-25w&
I

26 weeks

All a p

Lincarquadratic

278 :
0.11
288 :
0.06
0.05
3.03 :
3.13 :0.05
3.02 z 0.03

-1.72 r 0.84
4.95 z 0.42
-1.09 2 0.26
-0.35 r 0.32
-0.89 r 0.18

282 r 0.11
289 r 0.07
3.05 r 0.06
3.13 r 0.05
3.03 r 0.03

4.42 + 2.88
-1.5? 2 0.98
-1.88 r 0.75
4.44 r 0.78
-1.52 0.45

p c 0.05
p c 0.05
p c 0.01
p c 0.01
5.78
5.66 :
0.90 z 1.39
0.95 2 0.84
0.11 z 0.88
0.82 :
0.54

p < 0.05
p c 0.01

The regicaricn coeflicicnl r is the m a n rchmi s m c at zero dou (inlcrccpl); b is the i n a u r c in mean rchool r c a c pa unil dou (Ciyel)mean school r c u c pn unit dcsc squared ( G ~ ~ ' ) .

c is the i n n u ' c in

T ~ ~ h 9l c
Hcgrcx~lonc o c ~ c l c n t sobhincd In flttlng a llncur nlodcl to sclzurcs und uicrlnc nbsorbtvl dmc for lndlvidunls
cvposcd in rrlero Lo ihc ntorriic haml)ings In Jupnn
1031

I'asr-o~ularor).
age

Rcpersion
modcl

Regression rocficicnrbaSignific~rc
lnrl ofb

All l e i m r t ~0-7 w c c h
8-15 weeks
8-15 wcekr I,
16-75 wccks
a 26 uccks
NI n g u

linear

0.7 wccks
8-15 wccks
8-15 u+ceL
16-25 weeks
2 26 weeks
A l ager

Linear

4.55
2 51
3.87
4.73
3.89
3.97

-0.046 2 0.34
0.18 2 0.087
0.15 2 0.084
0.001 2 0.052
0.024 2 0.064
0.054 2 0.037

4.62
261
3.70
4.39
3.62
3.88

0.058 2 0.12
0.11 2 0.11
0.083 2 0.10
0.016 0.067
0.029 +. 0.071
0.026 1: 0.040

p c 0.05
p c 0.10

p c 0.10+

Febrile ~ r i z u r t s
0-7 weeks8-15 wccks
8-15 u*ccks '16-25 w c d u
s26wcelrsb
All ages

Lincar

0-7 wcckr
8-15 weeks
8-15 wceks
16-25 wccks
r 26 u-ceks
All ages

Linear

*

+

1.81
246

-0.041 0.34
-0.018 % 0.071
4.023 + 0.073-0.030 2 0.048
0.033 ? 0.052
4.012 2 0.015

4.10
1.96
221
283
1.84
261

-0.050 0.30
-0.018 2 0.081-0.028 2 0.017-0.036 0.11
0.033 2 0.056-0.013 2 0.021

4.06
1.80
221
279

=
+

p < 0.10

Unprovoked s e i m n
0-7 weeks
8-15
8-15 wceks
16-25 weeks
i26wceksb
NI a*Linear

0-7 weeks
8- 15 weeks
8-15 weeks
16-25 wccks
a 26 wccks
All sgu

Linear

*

0.89
1.71
1.98
1.89
1.45

0.20 2 0.084
0.18 2 0.083
0.042 2 0.054-0.019 2 0.070
0.074 0.033

p < 0.01
p c 0.05+

p c 0.05

0.92 1
1.50
1.58
1.69
1.30

0.15 % 0.10
0.13 2 0.099
0.067 0.065-0.018 z 0.065
0.052 2 0.035

p c 0.10+

p c 0.10

7hc rcgrasion codlicirnl a is thc nurnhcr of scizurcr per 100 indrvidualr a1 zero dcsc (inmcepl); h is the innensc in frqucncy dsdzurca per unit done (G~.').

*' G r r s d revcrc mcnlal retardation includcd in ~3mplc.

P d c d mnlrols. Data fa cmrrds (> 0.01 Gy) over all gestalional ages u w c used.
Cares of sevcrc martal rclarda~ioncxcludcd f r a n mmple.

ANNEX 11: RADIATION ISI:lW33 ON TIE DEVELOIIING IIUMAN B W N

85 1

T11h1e10Hcgrcsslon cocMcicnts and n l l m s l r d thresholds o h b i n d In llltlng 14 l i n c ~ rmcdcl lo s c l z u m and uterinet~hsnrhcddose for indlvidunls cxposcd in rtrero to the ntonilc homhinys in . l t ~ p i ~ nlC)lIPasf-obularory
age

Regressiun
model

Thresholdb

Jiknifimce
1n.cl ofb

0.26 t 0.13
0.25 :0.14
0.10 ? O.M

p c 0.05
p < 0.10
p < 0.10

0.15
0.20
0.23

Re~rcrsioncoeficicnf a
0

ICY)

N I rrizurn

8-15w c c h '6-15wccks

linear uith rhruhdd

271
3.94
4.08

All ages

8-13w c c h '8-15wccks 'Linear uirh lhrcshdd

270
3.72
3.93

All ngcs

0.17 ? 0.16
0.17 2: 0.20
0.M :0.07

0.11
0.17
0.23

Unprovoked scizurrs

8-15w c e k '8-15wccks'

Linear with thrcshdd

0.90
1.72
1.4-1

0.26 :0.11
0.25 :0.11
0.09 r 0.04

p c 0.01
p < 0.05
p c 0.05

0.08
0.11
0.00

8-15w c c k '8-15w e b

lincar with thrcrhdd

0.91
1.49
1.28

0.19 :0.13
0.17 r 0.12
0.07 t 0.04

p c 0.10

0.04
0.04
0.W

All ages 'All agesp c 0.10* The r c g r w o n cosf~cicnta is the numtcr of scizurcs per 100 individuals at w o dose (intercept); b is thc inncarc in Crcqurncy of scizurcs per unit dose (Gy-').
95% a in parcnrh-.
' C I s c s d ~ v o rncntdcretardation included in rarnplc.
Podcd controls.
Csscs d lcvcrc mcntal rciardation cxcludcd l r a n larnplc.

*

UNSCWR 1993 REPORT

852

DOSE GROUP (Gy)

16-25 w e e k

0

0.2

0.4

0.6

0.8

UTERINE -ORBED

1.0

1 .?

1.4

DOSE (Gy)

F i ~ u mI.
Incidence of severe menlnl mtardation in lndlviduals exposed in irfero lo the alomlc bombingsin Japan. Numbcr of cases Indlcaled in upper figure. Tobl numbcr of cases Is 27; one case In controls
exposed 111 0-7 wecks not shown; thme cnses of Down's syndrun~cexcluded.
1011

ANN]:% I I: WDIAnON E F m m ON n l l r DEVELOPING I IIJMAN BRAIN

100-

853

First trirncs~cr

0 Second ~rirna~cr
Third trimesteriE

tr: 60 5
a 405

0

0.5

1.O

1.5

2.0

1.5

2.0

I
1.5

1
2.0

W R I N E ABSORBED DOSE (Gy)

0 8-15 weeks

0.5

1.O

UTERINE ABSORBED DOSE (Gy)00

>16 wecks

0.5

1.O

UTERINE ABSORBED DOSE (Gy)Figure 11.
Incidence of s n ~ u l lhead s i x In lndlviduals exposcd in ukro to U-IC e b m i c bombings in Jupt~n10131

110 -

20:looE!

3H

9080

-

70

-

60

1

I

0-7 wccks

8-15 w c e hI

16-25 wecks

I > 26 w w hI

Nl agesI

NI agcs

POST-OVUIATIRYAGE

I
I

0-7 wcckr

8-15 wecks I 16-25 weeks

I > 26 weeks

POST-OVUUTOIIY AGE
Figurn 111.
Change In ln(cll1gence scorn and school performnnce
in lndividuuls exposed in trfero (o (he abrnlc bombings In Jnpun
lor, S j l

IANNEX 11: RN)It\'nON E F E m ON YIE DEVELOPING IIUMAN BRAIN

855

Glossary
abscopalthe effect on non-irradiated tissue of the irradiation of other tissues of an organism

acallosalin the context used here, implying without a corpus callosum

anencephalya mngenilal anomaly of the brain with the abscncc of the bones of the cranial vault;
usually the cerebral and cerebellar hemispheres are lacking and the brain stem isrudimentary.

anosmia

the inability to smell

apoptosis

a particular form of cell death, apparently progtdmmed, in which death occurs relatively
rapidly without mnspicuous damage to the cell membranedevelopment of the tree-like network of nerve processes
a star-shaped neuroglia cell; the final differentiated form of the radial glial cells thatprovide guidance to the neurons as they migrate from the proliferative zones
surrounding the ventricles to the cortex

axon

a nerve fibre that is continuous with the body of a nerve cell and is the essential
stimulus conducting portion of the cell. It consists of a series of neurofibrils surrounded
by a well-defined sheath, known as the axolcmma; the latter is in turn encased inmyelin, a mixture of lipids, and a final sheath, the neurolemma.

brain

the mass of nervous matter that lies within the cranium or skull and consists of anumber of discrete parts, such as the brain stem, the cerebrum and the cerebellum

brain mantle

the distinctively laminated layering of grey matter covering the cerebral hemispheres

brain slem

the portion of the brain that connects the cerebrum with the spinal column

Broca's area

the region in the left hemisphere involved in language. It lies in the frontal lobe above
the lateral sulcus (the Sylvian fissure) behveen the two anterior limbs of this fissure.
It is also known as thc parolfactory area or the area subcallosa.

bulb, oIJactory

the greyish expanded forward extremity of the olfactory tract, lying on a sieve-like plate
above the ethmoid bonc and receiving the olfactory nerves
an abbreviation of the words cell adhesion molecule; a number of surface molecules are
known, such as N-CAM, a molecule that allows one neuron to recognize another, or
Ng-CAIvl, that is involved in neuron-glial recognition. N-CAM exists in at least two
forms, an embryonic (E-N-CAM) and an adult, which differ in the degree of sialylation.

caudate nucleus

a long h o n e shoe-shapcd mass of grey matter that is closely related to the lateral
ventricle throughout ils entire length. It consists of a head, a body and a tail.

cerebellum

the posterior portion of the brain, consisting of two hemispheres connected by a narrow
mass of tissue known as the vermis

cerebrumthe largest portion of the brain including the ccrcbral hemispheres. In its earlier stagesof development, the ccrebrum is characterized by four major layers, namely, the mantle,
the outermost margin of the brain; the cortical plate; the intermediate or migratory
zone; and the matrix or proliferative zone.

cinguluma well-marked band of nerve fibres lying immediately above the corpus callosum that
relate the cingulate to the hippocampal gyricisrerna magna

the largest of the cisterns lying in the space between the pia mater and the arachnoid
membrane of the brain; i t lies between the under surface of the cerebellum and theposterior surface of the medulla oblongata. The term mega cisterna magna implies anabnormal enlargement of this cistern.

colobomaa mutilation of a structure, generally of the eye. For example, coloboma iridis is acongenital cleft of the iris.

commissurea bundle of nerve fibres passing from one side to the other of the brain

corpus callosum

the great transverse cnmmissure between the two cerebral hemispheres; i t lies beneaththe longitudinal fissure and is covered on each side by the cingulatc gyrus.

856

UNSCEAR 1993 REPORT

the outer layers of the cerebral hemispheres and the cerebellum wherc most of theneurons in the brain arc located. The cells of the cortex are arrangcd in extensive,
stacked layers that are distinguishable histologically. Six layers arc recognized, namely,
the molecular or plcxiform laycr (layer I), the outer granule cell layer (II), the outerpyramidal cell layer (Ill), the inner granule cell layer (IV), the inner pyr~midalcell
layer (V) and the plymorphous layer (VI). Layer V, the inner pyramidal cell layer, isoften further subdivided into two sublayen, known as V, and Vb.V, consists of small
and medium-sized pyramidal neurons, whereas Vb is made up of large pyramidal
neurons. The spheres of projection of thcse two suhlayers arc also different.
cortico-corrical cells

the most superficial of the cells of the mrtcx

cytoarchitectonics

the cytoarchitecture of a structure, particularly the cerebral cortex, where different areas
may be mapped according to the manner in which various cells are distributed in thecell layers

dendriteone of the branching pmtoplasmic processes of the nerve cell

diencephalon

the part of the brain h a t includes the thalamus and related structures. It is derived fromthe posterior part of the prosencephalon.
the revised system of computing the gamma and neutron doses rcceived by thesunivors of the atomic bombing of lliroshima and Nagasaki; this system wasintroduced in 1986, hence the acronym DS86 (dosimetry system 1986).

dysleria (severe)an uncorrectable inability to read understandably, now attributed to a specific lesion in
the language centre of the brain located in the left temporal lobe

ectopia

as used in the present context, the displacement or malpositioning of ncuronal cells;
synonymous with heterotopia

encephalomeningocele

a protrusion of the brain and its membranes through a bony defect in the skull

cnolase, neuron-specifica form of the glycolytic enzyme cnolase, or phosphopyruvate hydratase, which appears
to be restricted to neuronal and neuroendocrine tissues and can be a useful marker forneuronal damage

cpendymal layer

the layer of cells that line the venlriclcs; the term subependymal implies the region
beneath h e cpendymal layer.

folia cerebelli

the narrow, leaf-like gyri of the ccrcbellar cortex/rogile X syndrome

an inherited. X-linked form of mcnlal retardation associated with a characteristic
secondary constridion (often called a fragile site) of the X-chromosome. The extent of
the mental retardation can vary substantially.

ganglia (ganglion)a term generally used to describe a knot or knot-like coliedion of nerve cell bodies
outside the central nervous system

gap junction

the cells of a multicellular organism arc able to influence the activities of one anotherthrough a variety of processes. Collectively, thcse processes are refencd to as intercellular communication. Adjaccnt cells, for example, can transport small molecules
back and forth through their cell walls by means of a specific channel, known as thegap junction. Their capacity to do this, however, is influenaed or modulated by anumber of factors, such as the calcium levels within the cells. Regulation of thiscommunication through gap junctions is presumed to play a role in the occurrence ofcancer and in the development of the brain.

gastroschisis

a congenital &fed in the abdominal wall, usually with protrusion of the viscera

GFAP

dial fibrillary acid protein, a biochemical marker of glial cells

glomerulus, ol/adorya rounded body in the olfadory bulb formed by the synapses of dendrites of one classof olfactory cclls, known as mitral cells, with the axons of the olfactory cells of thenasal mucous membrane

granular neurons

one of the five discrcte types of neuronal e l l s found in the cerebellum; these cells arisein the outer granular layer of the cerebellar cortex and migrate inwards to their sites offundion. They make synaptic connedions with the spiny processes on the Purkinje cell.
the specialized end of a growing axon (or dendrite) that provides the motive force for
iu elongation

ANNEX 11: RADIATION EFFECTS ON THE DEVELOPING HUMAN BRAIN

857

gyrus

one of the prominent rounded elevations of the surlace of the hemispheres of the brain;
the cingulate gyrus or the callosal gyrus, a synonym, is a long, curved convolution thatarches over the corpus callosum.

hem ianopsia, ltomonomous

defective vision or blindness affecting the right halves or the left halves of the visual
fields of the two eyesa direrence in coloration of the iris of the two eyes, or different parts of the iris of thesame eyeheterotopia

see ectopia

hippocampus

a deeply infolded portion of the cerebral cortex, lying on the floor of the inferior hornof the lateral ventricle. It is a submerged elevation that forms the largest part of theolfactory cortex. It is now thought to bc involved in learning and memory since damage
to it results in a recognized cognitive defect characterized by severe amnesia andincludes defiats in learning mazes.

Iwloprosencephnly

a failure of the forebrain to divide into hemispheres

horseradish peroxidase

an enzyme derived from horseradish that catalyzes the oxidation of certain compounds
by peroxidehydrocephaly

a condition marked by the excessive accumulation of fluid in the cerebral ventricles,
resulting in a thinning of the brain and causing a separation of the cranial bones

hypergonadotrophism

the overproduction or excretion of the gonadotrophic hormones, the hormones of
pituitary origin

hypogonadism

inadequate gonadal function, represented either by deficiencies in gametogenesis or thesecretion of gonadal hormones

leptomeninges

the combined pia mater and the middle layer of membranes covering the brain andspinal cord known as the arachnoid

UIRH cells (luteinizing hormone

these are speaalized ciliated neurons that arise in the olfactory placode and migrate into
the cerebrum. Their function is to release the hormone that stimulates the productionof the luteinizing hormone, which in turn is involved in the elaboration of the sex
hormones.

releasing hormone cells)

limbic systema group of subcortical structures of the brain (the hippocampus, hypothalamus,
amygdala) that are concerned with emotions and motivations

macrogyria (also called pachygyria)

a developmental abnormality of the brain in which the gyri are fewer in number than
expected and relatively broad, and the sulci are short, shallow and straighter thannormal. In its most extreme form, known as argyria or lissencephaly, there may be a
total or almost total absence of gyri. Maaogyria is an abnormality in neuronalmigration.

mamillary bodies

two protuberances on the under surface of the brain beneath the corpus callosum; they
are a part of the brain known as the hypothalamus.

medulla oblongata

the portion of the brain that is continuous above with the pons and below with thespinal cord

mmencephalon (or midbrain)

the part of the central nervous system that arises from the middle portion of the initialdivisions of the embryonic neural tube

micrencephaly (microencephaly)

abnormal smallness of the brain

motonruron (motor neuron)a neuron that enervate. muscle fibres

motor corter

the region of the cortex lying in front of the central furrow, or sulcus, that divides the
cerebral hemispheres into anterior and posterior portions. I t is the site of the processingof motor impulses.
a mixture of lipids arranged around the axons of nerve fibres. Myelination refers to thedevelopment or formation of the myelin sheath around a nerve fibre.
the laminated, evolutionarily younger portion or the ccrebral cortex in humans andhigher vertebrates

neuritesee axon

858

UNSCEAR 1993 REPORT

ncrtmblas~sembryonic cells that develop into neurons

neumfibroma~osir,m u l ~ i p l e

an inherited neurological disorder ct~aractcrizcdgenerally by the appearance early inchildhood of discrete, small, pigmented lesions in the skin, followed by the
dcvclopmcnt of multiple subcutaneous neurofibro~na.The latter can develop along
almost any nerve trunk. Two different types of Illis disorder have k e n identilied, eachassociated with a dimercnt genetic locus.

(von Recklinghurrsen 's disease)ne~troglia(or oJtcn jusr, g l i a )the non-nervous cellular components of the nervous system; they providc support to thedeveloping structures of the nervous system and pcrform important melabolic functions.
There are a variety of diffcrcnt glial cells, distinguishable by their morphology andfunction. One especially important group is the transitory set, known as radial glia cells,
that providc guidance to the neurons as they migrate from the prolifcrativc zones totheir sites of function.

neurona nerve cell, consisting of the ccll body and its various processes, the dendrites, axonsand ending. Neurons do not normally divide.
a collective term describing the network of neuroglia, axons and dendrites and theirsynapses in the brain

nucleus accumhens sepli

an area of the brain immediately txncnth the h a d of the caudate nucleus and medial
to the putamcn

oligodendroglia

a class of neuroglial cells having few process= that form a sheath around nerve fibres
or a capsule around nerve cell bodies

o l j a c ~ o t ybulb

a specialized arca on the ventral aspect of the cerebral hemispheres, distinguishable
about mid-gestation; related to the development of olfactionomphalocele

congenital protrusion of the abdominal visccra at the umbilicus

oplic Iecfum

the first central station in the visual pathway of many vertebrates. It is located in the
midbrain and is analogous in mammals to the superior colliculus, a rounded eminenceon the dorsal aspect of the meserlcephalon concerned with visual reflexes.

arycephaly

a condition in which the top of the head is pointed

pachygyria

see macrogyria

paleocortcr

the cortex of the primate brain is often divided on the basis of the antiquity of originof specific segments; [he paleocortcx is the evolutionarily older part (the ncocortex in
the younger) and includes the olfactory cortex.

p a r a h i p p c a m p a l gyrus

a convolution of the interior surface of each cerebral hemisphere, lying between the
hippocampal and collateral sulci (or furrows)

PE-86 sample

the sample of prenatally exposcd survivors in Iiiroshima and Nagasaki. It wasconstructed. beginning i n 1955, based upon birth registrations, ad hoc censuses by thea t y authorities and the Atomic Bomb Casualty Commission, and interviews of women
who were enrolled in the gcnctia programme in these cities in 1948-1954 and werepossibly pregnant at the time of the bombing.

perivenlricular (or circumwntricular) meaning around the ventricles of the brain
p i a marer

the innermost of the three membranes (or meninges) that cover thc brain spinal cord.
The other two membranes are known as the dura mater, the outermosl of the thrce, andthe arachnoid that lies between thc pia and dura malcrs. ' R e arachnoid membrane isseparated from the pia mater by Ihc subarachnoid space.

placode, ol/ocroty

a thickening of embryonic cells lying in the bottom of the olfactory pit as the pits are
deepened by the growth of the surrounding nasal processes

plasmalemma

the plasma membrane

premolor corlcx

the region of the cortex of the bri~inlying just I d o r c the motor corlcx, where complex
motor movements arc organizcd

prosencephalon (or Jorebrain)

the most forward part of the three primary division of the neural tube: i t gives rise to
the dienacphalon and tclcncephalon.

Purkinje cella large nerve acll of the ccrchcllar cortex; these cells are the only ones in thc
cerchcllum that carry nerve impulses out of the cerchcllum itself.

ANNW H: W I A f l O N WTWTS ON TIIE DEVELOPING IIUMAN BRAIN

859

pyknosis (also spelled pycnosis)

a degeneration of a cell in which the nucleus shrinks in size and [he chromatincondenses into a solid, structurcless massradial glia

a specialized group of neuroglia cells that assist immature neurons in their migration
to the cortical plate; later in the development of the brain these cclls will differentiate
into astrocytes.

Ratlrke's pouch

a pouch of embryonic cctodcrm that gives rise to the anterior lobe of the pituitary bodyrhinencephalon

one of the portions of the telencephalon, specifically that part comprising the slrudures
toward the centre of the furrow separating the forward part of the parahippocampal
gyrus from the remainder of the temporal lobc of the brain

rhombencephalon (or hindbrain)

the most posterior of the three initial divisions of the neural tube; it subsequently gives
rise to the metencephalon and the mylencephalon.

schizencephaly

an abnormality of the development of the brain in which there are abnormal divisions
or clefts of the brain substancesomalosensory corterthat portion of the cortex of the brain that is involved in the processing of sensory
stimuli that arise in the body outside of the brain

subarachnoid

implying bcncath the arachnoidea, a delicate membrane interposed between the duraand pia matcn; the subarachnoid space lies between the arachnoidea and the pia mater.

subplate neurons

a special group of early arising neurons that appear to be instrumental in the laying
down of the first axonal pathways; also known as transient pioneer neurons

sulcusone of the grooves or furrows on the surface of the brain that bounds or delimits the
convolutions, the gyri. The sulcus that separates the corpus callosum from the gyrus
cin yli is called the sulcus corporis callosi.

syncytium

a multinudeated protoplasmic mass formed by the secondary union of originallyseparate cells

synaplogenesis

the process or processes that culminate in the formation of synapses, that is, the places
where a nerve impulse is transmitted from one neuron to anothertelencephalon

the part of the brain that includes the cerebral hemispheres and is derived from theforemost part of the neural tube

rinea capiris

infection of the skin of the scalp with one or several different genera of fungi

ulerine myomatosis

the occurrence of benign neoplasms in the musculature of the uterus

ventricles

as used here, the cavities within the brain derived from the lumen, or open canal, of theprimitive neural tube. The term ventricular is used to describe the layer in the brain
immediately adjacent to the ventricles.

w n Recklinghausen's disease

see neurofibromatosis, multiple

860

UNSCEAR 1993 REPORT

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