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 I
Late deterministic ef'fects in children

CONTENTSPage

INTRODUCTION

I.

.......................................... 870

DETERMINISTIC EFFECTS OF RADIATION EXPOSURES ........ 871

I1 . RADIATION EFFECTS IN TISSUES AND ORGANS ............. 872
A BRAIN ........................................... 872
1 . Organic effccts .................................. 872
2. Ncuropsychologic effects ........................... 875
3. Neuroendocrine effects ............................. 877
B. THYROID GLAND .................................. 881
C OVARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .884
D. TESTIS ........................................... 886
E MUSCULOSKELETAL SYSTEM ........................ 888
F. EYE ............................................. 8%
G CARDIOVASCULAR SYSTEM ......................... 892
H. LUNG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .892
I . BREAST .......................................... 893
J . DIGESTIVE SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .894
K KIDNEY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .895
L BONE MARROW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8%

.

.
.
.

.

CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897

Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
References ............................................... 909

870

U N S C M R 1993 RI~I'OI~T

INTRODUCTION
1.
Dctcr~ninistic rffccLs of ionizing radiation inhumans arc t l ~ crcsult of whole-body or local cxposures tl~atcausc sufficicnt ccll da~nagcor ccll killingto impair function in the irradiated tissuc or organ.
Thc damagc is thc rcsult of collcctivc injury to substantial nunlbcfs or l)roportio~~sofcclls. For any givcn
dctcrministic cflcct, a givcn nu~nbcror proportion ofcclls must bc affcctcd, so that thcrc will be a thrcsholddose bclow which thc nurnbcr or proportion of cclls
affcctcd is insufficient for tile dcfincd injury or clinicalmanifestation of thc cffcct to occur [ F l , 11 1. With
incrcasing radiation dose fcwer cclls survive inlact,
and therefore the dctcr~ninistic crfccts incrcasc in
scverity and frcqucncy with the dosc [U3]. If theradiation cxposurc is scvcrc cnough, dcath may result
as a conscqucncc of the exposure. Dcath is gcncrally
the rcsult of scvcre ccll depletion in one or morc
critical organ systems of thc body.

3.
Radiation-i~~duccddctcrr~~inisticdanlagc in a
~ ~ oftcn l~avca lllorc scvcrc impact
tissuc or o r g i ~willon t l ~ cindividual during childl~ood,when tissues areactivcly growing, h n n during adulthood. Examples ofdctcr~l~ir~istic
scquclac aftcr radiation cxposurc in
cl~ildl~ood
includc cffccls on growlh and dcvclopn~cnt,
hor~nonnldcricic~lcics,organ dysfunctions and caccts
on i~~tellcctualand cognitive functions. In this Anncx,
a rcvicw is rnadc of latc, dctcnninistic d a m a g tonor~naltissucs in cl~ildrcncauscd by ionizing radiation.
Life sbortcning is not discussed due to the paucity ofdata. Othcr cffccts of radiation exposurc, such as
canccr illduction, l~crcditarycffccts and early radiationcffccts, arc not considered. One objcctivc of thisreview is to try to dctcrminc thc critical dosc lcvcls
for thc appearaacc of c l i ~ ~ i c adctcnninisticleffccts.
Such dosc lcvcls will dcpcnd on the end-points
considcrcd and on the sensitivity of the techniques formeasuring Lhc cffccLs. Pcrn~ancnlrather than transient
biocl~cniicalchaagcs are cn~phasizcdin thc attc~nptsto
dcfinc the threshold doscs.

Ionizing radiation can irnpair function i l l all
2.
tissucs and organs in the body because of cell killing;
howcvcr, tissucs vary in thcir sensitivity to ionizing
4.
Thc Comnlittcc rcvicwcd the detcrministic
radiation [Fl,11). Thc ovary, tcstis, bone marrow,cffccts of radiation in Anncx J of the UNSCEAR 1982
lymphatic tissuc and the lcns of the eye belong to the
Rcport [U3]. T l ~ cbasic conccpts of ccll survival wcrc
most radioscnsitive tissucs. In general, thc doscrcvicwcd, including the factors influencing tissue rercsponsc function for thcsc tissucs, i.c. thc plot on
sponsc to fractionated or continuous exposures tolinear axes of the probability of harm against dosc, isradiation. That rcvicw of effccts was bascd n~ainlyon
sigmoid in shape. Above thc appropriate thrcshold, thc
results of animal cxpcrimcnts and clinical obscn~ations
effect becon~esmore scvcrc as thc radiation doscof adulb who had rcccivcd radiotherapy. Its main obincrcascs, reflecting thc numbcr of cclls damagcd. Thc
jcctivc was to idcntify the naturc of cffeck in various
effect will usually also increase with dosc rate,
tissucs and thc doscs and modalities of irradiation that
because a morc prolractcd dosc causcs thc cell damage
causc tl~ceffects. I t was the Commitlee's opinion thatto be sprcad out in timc, allowing for more effcctivc
bcttcr quantitative results io man would bc rcquircd,
repair or rcpopulation [12]. This typc of cffcct, which
although it was rccognizcd that such dala wcrc diffiis charactcrizcd by a severity that incrcascs with dosc
cult to obtain. For cffcck in children, the nccd for data
above sonlc clinical thrcshold, was pr~\~iously
callcdand thc difficulties wcre considcrcd to be cvcn grcater.
"non-stochastic". The initial changes on thc ccllular
lcvcl occur csscntially at random, but thc large nunlhcr
5.
of cclls rcquired to rcsult in a clinically obscnlahlc,
The i~~for~ni~liorl
in tliis Anncx on thc possiblc
non-stochastic cffcct givcs the cffcct a dctcrmi~~istic dctcr~ninisticcffccb specific to the cxposurc of childrcn conlcs from t l ~ capplicatior~of new methods to decharactcr. For this rcason such cffccts are now callcd
rive data and Ltic continued monitoring of p a t i c ~ ~whok"detcrministic" cffeck. The dosc lcvcls that rcsult in
rcrcivcd radiot11cral)y and othcr individuals cxl)oscd tothe clinical appearancc of pathological effects arc
doscs high cnougll to causc dctcnninistic damage togenerally of the ordcr of a few gray to some tens
spccilic tissucs or to the wholc body. For practicalof gray. This clinical thrcshold or critical dose isapplications it is important that attcmpts should be
bascd on clinical cxaniination and laboratory tcsts. Thc
m;~dcto quantify this damage in tcrrns of tlic degree
timc of appearance of tissue damagc ranges lroln a~t.
to t l ~ cpaucity of datii, it is not
few hours to marly ycars aftcr the cxposurc, d c p c ~ ~ d i r ~ g ol' d c t r i ~ n c ~0wi11g
really possiblc to quantify cffec~sby agc in moston the typc of eflcct and thc charactcristicr of tllc
situirtions.
particular tissuc.

ANNEX 1: U T l i DiTERMINISTIC RADIATION EWECIS IN ClllLDRENI.

DETERMINISTIC EFFECTS OF RADIATION EXPOSURES

6. Although thc pathobiology of radiation-induced
latc deterministic effects is poorly understood, it isreasonable to believe that latc damage can result froma conibination of loss of parc~~clrymel
cclls, injury to
the fine vasculaturc and/or dysfunction of the fibrocytes and other cclls [CI]. Radiation-induced latc
tissue injury of a deterministic nature appears to havc
its origin in h e sterilization of a large proportion of
the stem-like cclls of the tissue or organ in question,although thcse cells may be only a small proportion of
the total number of cells in that tissue/organ. The
consequent injury results from the natural loss of postmitotic cells that :ire not replaced or from the loss of
cclls that arc stimulated into mitosis. The timing oftissuc injury depends on the natural proliferation
characteristics of cells and also on kinetic changes
resulting from the radiation exposure that are characteristic of the tissuc p 3 ] . In addition to the loss offunctional cclls, supporting blood vessels may bedamagcd, resulting in secondary tissue damage.
Damage to the capillary network has been implicatedin the degenerative changes that are accompanied bya progressive reduction of functional capacity [Fl 1.
Other mechanisms for latc effects include increased
vascular permeability. which causes plasma proteins tolcak into interstitial spaces, resulting in the depositionof collagen and leading to atrophy of parenchymal
cells. There may also be some replacement of functional cells by fibrous tissue, reducing organ function.
The clinical effect that ensues depends on the specificfunction of the tissue in question.
Various processes of repair and repopulation will
7.
increase the threshold level of dose when radiation is
given over a long period or when a second period of
irradiation is encountered sometime after an earlier
exposure. The exact role of repopulation, recruitment
and intracellular repair of radiation injury over long
periods is not clear [Cl]. Another aspect that is not
wcll understood is the effect of prior radiation therapy
on late injuries following a second course of radiotherapy. There is repair of sublethal damage related to
fraction sizc and fractioti number, as wcll as to dose
rate. There appears to be a wide rangc in the amountof repair that can occur betwccn radiation doses or atdecreasing dose rates, which seems to be a tissuespecific phenomenon [CI ]. Increasing tolerance occurs
as a function of time (days to weeks between fractions) in organs expressing late damage and is thought
to be based on slow cell renewal.
Late radiation effects often occur in tissucs withl i n k or very little prolifcration. The radiation effects
have been attributed to parenchymal depletion secondary to endothclial changes in small blood vessels or to
the direct depletion of parcnchynial or stromal cells

8.

871

[ R l , R2, R3, T I , W1 1. The dose-survival relationshipfor latc effects differs fro111 Illat of acute responses.
Injury to slowly responding tissucs is more dependent
on fraction sizc. When conventional radiotherapy Gactionatio~ischedules have been altered to fewer Gactions of larger doscs, an increase in late complications
has ensued, with little or no difference in the severityof acute effects [T2]. Studies in animals indicate thatthe dose-survival characteristics of target cclls for lateinjuries are different from those of target cclls of
acutely responding tissucs. The slopes of the isocffectcurves as a function of dose per fraction are greater
for latc effects, indicating a greater irifluence on
sparing from dose fractionation for late effects [T2,
W2]. The data for low-LET radiation in adults showa wide range of sensitivities of diffcrent tissucs P I ,RI]. Few tissues show clinically significant effects
after acute exposures of less than a few gray, with the
exception of the gonads, lens and the bone marrow,
which show higher sensitivities.

9. Thcrc is little direct correlation between acutereactions and late effects of radiation [Bl, R2, N ] . Itis, therefore, the latc radiation effccts [hat are the doselimiting factors in curative radiotherapy. Interactions
with other treatment modalities may also limit theradiation dose. For example, chemotherapy administeredduring, before or after irradiation may reduce thetolerance of the tissues exposed to ionizing radiation
IN, Wl]. In radiotherapy, normal tissues are unavoidably included in the target volume, and it is the effects
in thcse tissues that limit the dose that can be tolerated.
There is still poor understanding of the exact toleranceof a given organ or tissue and of changes in tolerance
caused by variations in fraction size, target volume,
duration of treatment, dose rate and Lhc presence ofvarious chemical compounds. For a variety of tissues ororgans, a critical radiation dose for a limited volume ofthis tissue has been established empirically, mainly inadults. This dose is usually defined as the dose that willproduce a small but detectable incidence of serious
complications resulting from the radiation effect on thenormal tissue, and often 5% of serious con~plicationsis
considered rcasonablc in radiotherapy [Cl, Rl]. This
critical dose or dose rangc is different from the tern1"tolerance dose", historically used in radiation
protection. Most clinical practice involves daily
fractionation with approxiniatcly 1.5-2 Gy four or fivedays per week. I n Ibc following paragraphs this will bercferred to as conventionally Gactionatcd radiod~crapy.
Rubin et al. [ R l ] and Molls and Stuschkc [h441] havc
published d a b on acceptable doscs in rirdiothcrapy andhave presented estimates of radiation doses fordeterministic effects ill organs and tissucs of adults andchildren. There are wide variations in the critical dose
lrom one tissue to another (Tablcs 1-2).

UNSCMR 1993 WI'OHT

872

have also bccn treated with other modalities, e.g.
surgcry, cytostatic drugs al~d/or honnoacs. Most
clinical cvaluatio~~sarc, moreover, based on small
nurnbers of paticnts, and often appropriate control
groups are lacking. Furthernlorc, the long duration ofche illness, tile need for hospitalization. tbc lack ofschool iittc~ida~~cc
and olher social factors rnay have
had a n irnpact on certain effects nleasured, such asneuropsychologic fu~~ctioning.
The fact that most data
are obtained fro111 studies of patients with pacdiatrictumours makcs i t even niorc difficult to draw
conclusior~sthat can be generalized to the general
pacdiatric population. One reason for this is thatgroups of children ueated for malignant disease may
11. Only a few large epiden~iological studies ofdeterministic effects in cl~ildrenexposed to io~iizir~g include individuals with a genetic predisposition tocancer, some of whom can perhaps have a higher
radiation have bccn published. Most data are obtained
sensitivity to other radiation-induced effects as well. In
from clinical follow-up of small groups of patients
general, there is a great variability in the ages of thesuccessfully treated for paediatric turnours. In thepatients studied, and many studies have also assessed
1950s and early 1960s the prognosis for a child withpatients at widely different ages. A sizeable portion ofa malignant turnour disease was grave, and for riiany
eligiblepatients arc often riot assessed: the children
types of turnours death would follow in a matter of
may not be available for evaluation, owing to, formonths. With the introduction of modem surgery,exaniple, their refusal or that of their parents, thehigh-voltage radiotherapy and chen~otherapy,the prodisease itself or geographical factors. These selection
gnosis has improved considerably, and today a large
criteria obviously also affect the interpretation of data.
proportion of children with paediatric tumours are
cured. The proportion of two-year survivors, which
13. Radiation therapy has been claimed to account
implies the cured fraction, in 1980 ranged fromforabout 80% of the long-tcnn sequeiae in surviving
approximately 40% for patients with neuroblastoma or
childrenwith neoplasms [MI]. Severe disabilities werebrain tumours to 80%90% for patients with Wilrns'
notedin
41% of 200 children treated for cancer who
tumour or Hodgkin's disease [Sl]. Consequenlly,
had
no
sign
of disease for at least five ycars after
many children are now surviving into adulthood,therapy [M2]. The disabilities included severe
making it possible to study the late effects of theircosmetic changes (16%), severe growth retardation
treatment. Increasing reports of late effects have Icd to(lo%), the need for special cducation (8%), gonadal
systematic investigations by groups of paediatricfailure (7%) and other apparent organ dysfunctions
cancer treatment inctitutions, such as the Childrens(12%).
Hypothyroidisni (3%), minimal scoliosis andCancer Study Group in the United States and Canada
bypoplasia(22%) were some of the mild to moderate
and the International Late Effects Study Group.
disabilities. Li and Slonc [ L l ] studicd late effects in
142 patients trcatcd for childhood cancer and observed
12. In this review of deterministic effects in children,major defects in treated organs in 52% of the patients.
the various observed effects have been grouped
Dcspite this, a large proportion of the patients had
according to the organ or tissue affected. It isfully active lives, 61 % had attended collcgc, 53% weregenerally difficult to single out thc specific effect ofmarried arid 32% had progeny.
radiation in children with paediatric tumours, as most

10. There is great variability in the latent intervals
between radiation exposure and the clinical nlanifcstation of late deterministic eKccts, which niay develop
at times varying from ~ i ~ o n t htos 10 or more ycars
after treatment. The latent interval depends on thetissue or organ affcctcd and is, for example, up to 2
years for myelitis, one to several years for nephritis,
1-5years for eye effects and 6 months to many ycars
for fibrosis in subcutar~cousand connective tissues[T2]. The rate at which radiation injury becomesmanifest in a tissue rellects the rate of turnover oftarget cells and their progeny [Fl].

11. RADIATION EFFECTS IN TISSUES AND ORGANS
A.

BRAIN
'

1. Organic elTects
14. The developing human brain is especiallysensitive to ionizing radiation. Previous UNSCEAR
Reports have considered the general developnien~aleffecls of prenatal irradiation [U2, U4]. A review of
the results of the study of survivors of the atomic

bombings in Japan, as well as reviews of other epidemiological investigations relating to prenatal
exposure to ionizing radiation and effects on the brain,arc presented in Annex H, "Radiation effccts on thedevelopil~g hurn;tn brain". The mechanisms of observed effects from exposure in fetal life are different
from the mecl~anisn~sin a nearly fully developed
brain. This S e c t i o ~reviews~d a b on late effccLs following exposure of the brain of i~~fatits
and children.

15. The rcsponsc of thc nornial brain to radiation
dcpcnds on the total and fractional doses of radiation,
the duration of exposure, tile cxposcd tissue volume
and the age of the exposed subject. The outcomc ofiatrogenic radiation da~nagc to the normal brain
depends on the nlagnirudc of the darnage and thebrain's lack of cellular repopulation. Although partial
recovery takes place bctwecn fractionated cxposurcs,
the brain has very little repair function [KI. M3j. Aftcr
birth, the pcriod of greatest radiosensitivity of thc
human brain is during the first two yean of life, before
maturation is completed. Treatment involving the wholebrain is more likely to have an adverse effect on
younger children by interfering wilh ncural devclopnient before maturation of the brain is complete.
16. There is a large body of evidence indicating thatradiotherapy to the central nervous systeni is associated with adverse late effects [B2, B3, D l , D26, F2,
K2, K3, 0 1 , P3]. This delayed type of damage isbelieved to be the effect of injury to the fine vasculalure andlor loss of parenchymal cclls, resulting in
ischaeniic necrosis and loss of parenchynlal function[ A l , C1, C2, S2]. Vascular changes may occur aftcr
relatively low radiation doses. Glial cells proliferate
during the first yean after birth and are therefore
sensitive to ionizing radiation. A decrcase in thereplacement of glial cells and the associated interfcrence with myclination have also been postulated as
causes of delayed radiation injury [M4].

17. Treatment-related sequelae of the central nervous
system have been documcntcd in children with brain
tumours and acute leukaemia, as well as in children
having other tumours h a t require treatnient of thecentral nervous system. The concept of treating thecentral nervous system of children with acute lymphoblastic leukaemia was developed in the 1960s in order
to avoid leukaemic relapse of the central nervous
system [A2, MI. Most patients with leukaemia or
solid tumours other than of the brain do not haveprimary disease of the central ncrvous system, and theeffects of treatment can therefore be better distinguished from the effects of disease. In addition, theradiotherapy in these patients generally involves
relatively low radiation doses in the brain. Analysis ofradiation effects in brain tunlour patients is moredifficult because of the much highcr radiation doses
and the possible effect of the tumour on brain function. In a follow-up study of 102 subjects treated forbrain tumour in childhood [L2], 40% of the subjects
had mild to moderate disabilities but were living
independently, 9% were capable of self-care and 4%
required ir~stitutior~alization.Moderate or severe
disabilities were reported in 13 of 30 (43%) irradiatedpatients and in 11 of 72 (15%) who did not receive
radiotherapy. Functional deficits were more cornmon
anlong those treated before two years of age.

18. Five distinctive forms of late effects in thecentral ~lcrvoussystem have bccn dcscribcd: necrotizing Icukomyelopathy, Ieukoencephalopathy, mineralizing microangiopathy, cortical atrophy and necrosis.
Necrotiziag leukomyelopathy is a spinal cord lesionthat does not appear to be related to radiotherapy,
since the majority of cases have bcen observcd in nonirradiated patients [P2]. Lcukocncephalopathy is a
syndromc caused by dcmyclination; it develops inpatients who have rcceivcd cranial irradiation withintrathecal andlor systc~nicniethotrexate treatment [ P I ,P2, R4]. I-listopathologically, leukoencephalopathy ischaractcrizcd by dcmyclination, beginning with axonal
swelling and fragmentation and progressing to necrosis
and gliosis [MI. Leukocncepl~alopathypresents as
multifocal coalescing areas of necrosis in the deep
white mattcr, and in the late stage white matter is
rcduccd to a relatively thin gliotic calcified laycr.
Cortical grey mattcr and basal ganglia are not affected.
Clinical findings range from poor school performanceand mild confusion to lethargy, dysarthria, ataxia,
spasticity, progressive dementia and even death.
19. Both intrathecal methotrexate and cranialradiotherapy affcct endothelial pinocytosis, anddamage to the endothelial barrier could be involved inlate effects following such treatments [L3]. Theinteractions between nletholrexate and radiation within
the central nervous system may be due to the overlapping neurocytotoxicity of the two treatment modalities or to mcthotrcxate acting as a radiosensitizer.
Irradiation of the central nervous system niay also
increase the pernleability of the blood-brain barrier or
may slow the turnover of cerebrospinal fluid andclearance of methotrexate from the central nervous
system. This would alter the distribution of methotrexate in the cel~tralnervous system so that someareas accumulate higher amounts of the agent [B4].
Significant levels of methotrexate can also bc found in
the spinal fluid aftcr it has been administcrcd
systea~ically.The risk and severity of Ieukoencephalopathy are dircclly proportional to the total radiationdose, the cumulative dose of systemic methotrexate
and tt~enumber of therapeutic modalities used (Figure
1) [B2, B4].The highest incidence of Ieukoencephalopathy is found ill patients receiving radiothcrapy andmethotrexate administered both intravenously andintrathecally. The least neurotoxic combination appears
to be intrathecal plus intravenous mclhotrcxate. If
radiotherapy to the central nervous system must beeneurocombined with methotrexate thcrapy, d ~ least
toxic approach appears to be to administer thesemodalities in sequence [B2].
20. Leukocncephalopathy has been reported after
20 Gy or riiore ill cornbinatio~~
wit11 intrathecal methotrexate [M6, P3, R4j. No evidence of leukocncephalopathy has bcen found in children for whom intra-

vcnous or i~~trathccal~l~ctllotrcxatc
was discontinued
beforc radiothcrapy. Lc~~kocnccpl~i~lol~atl~yhas not
been rcportcd aftcr fractionated radiothcrapy of thecentral ncrvous systcrli with 18-24 Gy alone and rarcly
with intrathccal mcthotrcxatc alo~lc184, K4].Leukocnccphalopathy can illso occur aftcr a single dnsc of
10 Gy whole-body irradiation prior to bo~lcmarrowtransplanlation [A4, D2, Jl]. Almost all such rcportcd
cascs havc occurrcd in childrcn, suggesting that thematuring brain is nlorc susccptihlc. Thcse paticnts
wcrc usually givcn intensive chcmotl~crapyand cranialradiothcrapy with 20-24 Gy ovcr a fcw wccks prior to
the whole-body irradiation. Lcukocnccphalopathy
occurrcd within a fcw ycars of whole-body irradiationin thcsc paticnts and has usually rcsultcd in scvcrc
neurologic deterioration.
21. Mineralizing niicroangiopathy affects prcdominantly ccrcbral grcy nlattcr and somctimcs ccrebcllar grcy mattcr and is charactcrizcd by focal calcifications in the central ncrvous system. This dcgcncrativc and mineralizing disorder is believed to rcsult
from radiation-induccd damage to thc sn~allvcsscls[B4,P2, P4]. Histopathologically, calcifications arc
found in small blood vesscls occluding the lunlcn withmineralized necrotic brain tissue around the vcsscls.
Neurological abnormalities, such as poor muscular
control, ataxia, hcadachcs and scizurcs, havc bccn
obscrvcd in patients with this complication. Mincralizing microaryiopathy is not fatal, and its cffcct onncuropsychologic functioning may bc minimal, although permanent destruction of specific regions of
the brain may occur. Mirlcralizi~~g
microangiopathy
has not bccn found in childrcn who did not rcccive
cranial radiothcrapy [P4]. It occurs predominantly inchildrcn who rcccivcd 20 Gy or morc. Bctwccn 25%
and 30% of p a t i c n ~who survivc more than ninemonths alter intraU~ccal mcthotrcxatc and cranial
irradiation with 24 Gy havc evidcncc of mincralizing
microangiopalhy. The lesion occurs more oftcn inyoung childrcn [B4,DS].Whcn mineralizing microangiopalhy arid lcukocnccphalopathy coexist, theclinical manifcstatioris oftllc Icukocnccphalopathy will
prcdon~inatc.
22. Cortical atrophy is perhaps the niost conimon
manifestation after lrcat~ncntof thc ccntral ncrvous
system. It is thc rcsult of multiplc arcas of radiationinduced focal necrosis causing loss of cortical tissue
and production of ventricular and subarachnoid space
dilatation [C3, D3, D4, D5]. The cortcx of atrophic
brains is microscopically charactcrizcd by an irrcgular.
neuronal loss from a l l six layers. Astrogl ial proliferation is son~ctimesprcscnt, usually confined to the marginal layer. Ccrcbral atrophy occurs alter fractionatedcranial radiotherapy in nearly half of the patients
receiving >30 Gy to UIC entire brain. The latcnt pcriod
between radiothcrapy and thc onset of atrophic than-gcs dclcclablc wit11 roa~putcdto~nographyis 1-4 ycars
or CVCII lol~gcrID31.
with 25-65 Gy to thc
23. Aftcr cranial rirdiod~cral~ywl~olcbrain (dclivcrcd at s 2 Gy pcr day) to trcat brain
tuniours, cortical alrol)hy has bccn found in half of thecllildrr~~
ID.51, abnornlalilics of the whitc niatter in
26% and calcifications in 8% of the patients. Cortical
atropl~yhas also bccn dcmo~lstratedin one third ofchildrc~~
with acutc lyn~phoblasticlcukacmia rcccivir~g
24 Gy ~)rophylacticcranial irradiation and iatrathccal
mcdiotrcxatc IU].Crosley ct al. [C3] found cvidcnceof abnormality of thc central ncrvous systcnl at autopsy ill 93% of 91 cl~ildrcntrcatcd for acute Icukacmia.
Modcralc to scvcrc atrophy was observed in 13% of
paticnLs rccciving no prophylactic treatment of thc
central ncrvous systcm, in 19% of patients receiving
radiothcrapy given in 1-2 Gy fractions over 2-15 days
(the total brain dose was not stated), in 43% of
patic~~Ls
givcn intrall~ccalmethotrcxate and in 47% of
paticnts who reccivcd both chc~notherapyand radiotherapy. Atrophy did not conelatc with lcukacmic
infiltrations or vascular or i~~fcctiousprocesscs.
Childrcn with thc most scvcrc atrophy wcre thc ones
who wcrc youngcst at onset (mcan age: 2.5 ycars).
24. Ccrcbral necrosis is a serious sequclac and isusually diagnosed 1-5 ycars after treatment but may
dcvclop morc than a decade Iatcr. It is characterizedby all insidious onset of clinical features [ U ] . Postirradiation myclopathy occurs with rapidly increasing
incidence at doses above 45-50 Gy with conventional
fractionation. Tllc dose per fraction is critical, andalmost a11 cascs of llccrosis following total doscs of
c60 Gy had fractions of >2.5-3.0 Gy [ K l , M7, S 2 ] .
An interaction betwccn chcrnotherapy and radiothcrapy
has bccn obscrvcd for methotrcxate in childrcn but has
bccu difficult to show for othcr agents. A total dose o f
50 Gy with 2 Gy pcr fraction or 55 Gy in 1.8 Gy fractions over six wccks, five daily fractions per wcck, isconsidered to bc tolcrablc in adults [As, 1(2,S561. A
morc rcccnt cstimatc has been givcn by Bloom [B35],
who assu~ncdth;~t thc maxiniu~n tolcrahlc radiation~ to 3 yciirs old is 33% lowcr thari
dosc for c h i l d r c ~up
in adults, and for childrcn 3-5 ycars old the dose has
to hc reduced by 20%.
25. Vcry few data arc available on the cffccts of
hypcrliactionatcd radiothcrapy. Frecman et al. [F3]studicd 34 paticnk 3-18 years old (mean: 7 ycars) who
wcrc irradiiitcd for brain SICIII turnours with 1.1 Gy
twicc daily with a minimum intcrval o f 4 - 6 hours, toa total dosc of 66 Gy given in 60 frac~ionsover 6
wccks. In thc 16 patients who were alive at one year
(only 7 wcrc free o f progressive disease), d~crcwas noof radiation-relatcd injury. Microclinical suspicio~~scopical examination of thc I1rai11in 8 patic~lLsfailed
to show any injury altributal~lclo the radiothcrapy.

ANNEX I: MIX DETERMlNlSTlC RADIATION IiITECIS IN CllllDREN

26. Abnormalities are frequently obscrvcd bycomputcd tonlographic scannir~gin long-term survivorsof cl~ildhood acute leukacmia treated with cranialradiothcrapy and intrathccal ~ncthotrcxate (B5, B6,
C14, D24, El, M5, 02, 03, 013, 014, PS, P7, R5,

S55]. Abriornial brain scan Iiridings rliay not hccomc
apparerlt until many ycars have elapsed since thcrapy.
The type of brain abnormalities dctcctcd include
intraccrcbral calcifications, white matter hypodensity
and cortical atrophy (Table 3). Patients who received
24 Gy in 2 Gy fractions with ietrathecal chemotherapy
appear to have a higher incidence of each of thevarious abnormalities detected by computcd tomography than those who did not receive radiotherapy.
On average, there is a 40% incidence of brain
abnormalities after 24 Gy in 12 fractions over 2.5
weeks combined with intrathccal methotrexate,
although the incidence varies from study to study,
depending on the number of patients arid length offollow-up. At brain doses of 18-20 Gy combined withintrathecal methotrexate or after intrathecal plus
il~travenousmethotrexate, the average prevalence ofbrain abnormalities detected is 10%-15%.
27. Magnetic resonance imaging appears to be moresensitive than computcd tomography in demonstratilig
treatment-related neurologic damage in irradiatedchildren. The types of changes observed by magnetic
rcsonance correlate well with the type and severity of
the neurologic dysfunctions [A6, C4, K5, P6). Constine et al. [C4] observed radiation-induced changes in
the white matter in 90% of the patients by magnetic
resonance imaging, and 68% of these changes were
not visible by computcd tomography. Enlargement of
the sulci was demonstrated in 76% by magnetic resonance imaging and in 52% by computed tomography.
Patients treated on a hypcrfractionatcd schedule(1.2 Gy per fraction) had less severe changes, despite
the fact that some received over 70 Gy.
28. Summary. The available clinical data on
deterministic radiation effects on the brain in children
are based on small and often heterogenous groups ofpatients with varying age at exposure and varying
lengths of follow-up. Well-designed epidemiologicalstudies of late effects are lacking, and it is therefore
not possible to draw any firni conclusions about theradiation effects on the brain and the exact criticaldose levels for the appearance of various clinicalpathological entities. There is evidence that theincidence of late brain effects will increase as thenumber of fractions is decreased and the fraction size
is increased. l'he most important effects in the brain
following radiotherapy to the central nervous system
are leukoencephalopathy, miricralizing microangiopathy, cortical atrophy and cerebral necrosis. Radiolherapy involving the whole brain is more likely tohave more severe adverse effects in young children by875

iritcrferir~gwith ~icuraldeveloprncnt bcforc maturationof the brain is complete. Brairi changes have beendcmo~istratcdwith coniputed tomography and magnetic resonance iniaging after 18 Gy of fractionatedradiothcrapy to the brain. Leukoenccphalopathy has
been observed after >20 Gy in 1.8-2 Gy daily fractions to the whole brain together with systemic
mcthotrexate and has rarely becn reported after 1&
24 Gy without niethotrcxatc (Table 4). Leukoencephalopathy has been found in children who were givena single dose of 9-10 Gy whole-body irradiation, butthey bad generally received cranial radiotherapy prior
to the whole-body treatment. Mineralizing microangiopathy has rarely been reported following radiation
doses below 20 Gy in 1.8-2 Gy fractions in combination with methotrexatc. Cortical atrophy has been
observed after 18 Gy in 1.8-2 Gy daily fractions combined with intrachecal methotrexate. A whole-brain
dose of 50 Gy in 2 Gy fractions over 6 weeks is
generally considered to be a critical dose in adults forradiation-induced necrosis. For children up to 3 years
old, the dose should be reduced by 33% and for children 3-5 ycars old the dose has to be reduced by 20%.

2.

Neumpsychologic effects

29. Individuals vary in personality characteristics andmental abilities, and tests have becn designed tomeasure such differences. Ability tests are among themost widely used tools in psychology. They can bedivided into achievement tests (designed to measureaccomplished skills and indicate what the person can
do at present) and aptitude tests (designed to predict
what the person can accomplish with training),
although the distinction between these two types oftests is not clear-cut. The intelligence quotient (IQ)isan index of mental development and expresses
intelligence as a ratio of mental age to chronologicalage. Heredity plays a role in intelligence, and cnvironmental factors such as nutrition, intellectual stimulation and the eniotional climate of the home will
influence where within the reaction range determinedby heredity a person's IQ will fall. Ability tests are,despite their limitations, still the most objective method
available for assessing individual capabilities [A7].
30. Intelligence and academic achievement testingsof long-tcrm survivors of childhood cancer reveal ahigh incidence of memory deficits, visual-spatial skill
impairment and attentional deficit disorders. Available
data identify radiothcrapy to the central nervous
system and the synergism with intrathccal chemotherapy as primary etiologic factors in the ncuropsychologic sequelae of survivors o r childhood cancer[ G l , Ma]. The brain is particularly sensitive to biologic insults during periods of rapid growth and development, which after birth comprise tbe first four years

876

UNSCFAR 1993 REPORT

when glial cells proliferate and myelination occurs.
Therefore the age at which the child receives cranial
irradiation is of importance, and the younger the ageof the child at the time of exposure the more serious
the intellectual dcficit will be. The effect of age a twhich brain damage occurs depends heavily on thetype of psychological ability n~casuredand the instruments for that measurement as on well as tbe location,
extcnt and pcrmancnce of the damage. Multiple factors
may be involved in the causation of intellectual
deterioration, and the interpretation of IQ may be
confounded by the type, location, extcnt and permanence of lesion, hydrocephalus, age of the child at
the time of diagnosis, the aggressiveness of the surgery, radiotherapy and chemotherapy, lack of school
attendance, and by anxieties and fears experienced byh e child at the time P I , E3, M8]. Parental social
class or parental education level havc in some studis
been found to be strong predictors of IQ in the survivors of acute childhood lcukaemia In, W3]. Thisemphasizes the importance of controlling for social
class differences.
31. Neuropsychologic dysfunction with behaviourial
or intellectual impairment may occur in up to 50% ofchildren with brain tumours IB6,B7, B8,D6, D7, D8,
D9, D10, D11, E2,H2, K6, L2,M9, M10, R6, S3,
S4]. These children have received high radiation doses
to the brain, and the direct cffects of tumour andlor
increased intracranial pressure may havc contributed tothe development of the intellectual problems. Radiotherapy is the most important factor for cognitive
sequelac in long-term survivors of pacdiatric brain
tumours who rcceived brain doses of 40 Gy or morein 1.8-2 Gy daily fractions [D8, D9, E2, J2. K6, LA,
S3]. In some studies a strong correlation has been
observed between IQ and radiotherapy, and young
childrcn have generally shown the greatest IQ losses.

32

Radiotherapy to the central nervous system inacute childhood leukaemia (usually 24 Gy fractionatedover 2 5 weeks) has been associated with subsequent
adverse neuropsychologic effects [C4, C5, C7, E3,E4,
E5, H3, 13, K5,L22, M2, M5, M6, M I 1, M12, 0 3 ,017, P5, R7, R8, R9, S5, T4, T14]. The mostcommon finding is decrements in general intelligence.
Otbcr documented cffects include general memory
impairment, difficulties with short-term memory,
distractibility, deficits in abstract reasoning,quantitative skills, visual-motor and visual-spatial
skills [C6, D9, E3, E4, J3, M4, M6, M11, M131.
Neuropsychological dysfuriction has been reported in
up to 30% in children with acute leukaemia, although
the deficiencies have been mild, and the children haveusually functioned well within the wide normal range.
Some studies suggest that adverse effects on intellectare not noted until 2-5 years after treatment. Prophylactic radiotherapy with 24 Gy is associated withpoorer intellectual function than is intrathccal
chemotherapy (Figure II), Mean overall intelligence
scores in irradiated children are, in general, 10-15
points lower than niean scores in non-irradiated childrcn. Perfomlance skills arc usually more affected thanverbal skills, irradiated patients scori~iga n average of
15-25 points lower than the mean performance IQ of
non-irradiated children [B2, B7]. The younger thechild is at the time of irradiation, the greater thencuropsychologic dcficit [C7, H4,J3]. Children treatedwith 24 Gy plus cytotoxic agents for acute leukaemia
generally display greater neuropsychological disabilities in a variety of ncuropsychologic tests [B9,C5, E3, E5, L5, M11, M12, R8, R9], although somestudies have failed to detect such deficits [H4, M8, S6,
V2]. Overall, data show that radiolherapy in conjunctior~with n~cthotrexatchas a deleterious effect onlater cognitive dcvelopment. Intrathccal methotrexate
as the only prophylactic therapy does not appear to be
associated with any global or specific neuropsychologic impairment [PS,T5]. There is some evidence
that chemotherapy combined with radiotherapy impairs
intellectual functions to a greater extent in children
with acute leukaemia who are less than 5 years of age
than in older ones (E3, E4, E5, J3, M12].
33. Neuropsychologic late effects can also be seen
after doses to the brain of 18 Gy from fractionatedradiotherapy [M13, 0 1 , 0 4 , 0 1 7 , R7, T4, T6]. Studies
by Tamaroff et al. [T4, T6] suggest that a dose to thebrain of 18 Gy or 24 Gy in children with acute leukacmia in combination with intrathecal methotrcxate
may have similar delcterious sequelae for neuropsychologic functions. Patients receiving radiotherapy
had significantly lower mean full-scale IQ scorcs andperformance IQ scores than non-irradiated children.
Ochs ct al. [Ol, 0 4 , 0171, on the other hand, did notobserve any significant difference in initial or final
full-scale IQ scores between long-term survivors of
acute leukaemia having rcceived 18 Gy cranial fractionated radiotherapy plus intrathecal methotrexate andthose having received methotrexate only. However,statistically significant decreases in overall and verbal
IQ and arithmetic achievement were found in bothgroups. Thus, 18 Gy of cranial radiotherapy and intrathccal methotrcxate may be associated with comparable decreases in neuropsychologic function.
34. A clear dose-response relationship for impaired
neuropsychologic functions has, however, not yet been
established. Ron et al. [RlO, R30) studied a cohort of
10,842 Israeli children who were irradiated for tinea
capitis a t a mean age of 7 years, receiving a mean
brain dose of 1.5 Gy (range: 1-0-6.0 Gy), a control
group of ethsicity-, sex- and age-matched subjects
from the generiil population and another control groupof siblings. For a subgroup taking scholastic aptitude
tests between 1%6 and 1970, the irradiated children

ANNEX I: L4nl DETERMlNlSTlC RADIATION EFFECTS IN Cl+tLDREN

achieved lower examination scores. For males born
between 1949 and 1955, irradiatcd subjects achieved
lower examination scores on 1Q and psychologic tests,
completed fewer scl~oolgrades and had ;I sligl~tcxcess
of mental hospital admissions. Malcs with multiple
irradiations had twice the ~ncr~tal
hospital admission
rate of males with a single irradiation (34.0 versus
17.4 per 1,000); there was no such difference amongfemales. The standardized risk ratio for mental
hospital admissiorls was 1.0 for non-irradiated males,
1.1 for rrialcs having one treatment, 2.4 for twotreatments and 4.8 for 23 treatments (test for linear
trend, p c 0.01). Therc were also cliangcs in tlie
electroencephalogram anlong the irradiated subjccts
and significant diffcrenccs betwccn the irradiated andcontrol subjccts in visual-evoke-respo~~sc
averages,
providing further evidence of inipaircd brain function
following the radiotlierapy. Children irradiated at lessthan six years had a relative risk of 1.7 (95% CI: 1.12.8) for mental hospital admissions, whereas for older
children that relative risk did 1101differ significantly
from 1 [RlO].

35.

An indication of an cxcess of admissions tomental institutions was also obsewed in a survey of
American children with tinea capitis after similarradiation doses ( 0 5 , S7]. Shore et al. IS71 studied
2,215 patients givcn radiotherapy for tinea capitis inchildhood. The brain received 1.5-1.8 Gy at thesurface and 0.7 Gy at the base. Therc was a 30%
excess of psychiatric disorders in the irradiatcd groupoverall when controlling for race, sex, socio-economic
status, age at therapy and interval from treatment todisease. Oniran el al. [ 0 5 ] made a psychometric andpsychiatric evaluation of 177 subjects treated 10-29
years earlier for ringworm of the scalp. Radiotherapy
was given to 109 subjects, and 6 8 received topical
medications. Average age at treatment was eight years
in both groups. The irradiated group manifested more
psychiatric problems and were judged more maladjusted in the testings when controllil~gfor educational level and family psychiatric disorders. However,the psychiatrist's overall rating of current psychiatricstatus showed only a borderline difference between thetwo groups.
36. The Israeli and America11 studies of children
irradiatcd for tinea capitis suggest that doses to thebrain of 1-2 Gy would be associated with late neuropsychologic effects. The dose givcn to these patienls
is the lowest that has becn reported to lead to functional ncuropsychologic disturbances after radiotherapy
in childhood. However, it is difficult to identify
mechanisn~s that could explain these functionalchanges after such relatively low radiation doses.
Furthermore, the observations are not supported byclinical follow-up of patients treated for childhood
tumours, and the possibility that confoundi~lgfactors

8-77

are responsible for this observed association cannot be
ruled out. The trauma of baldness and of having had
trcatnicllt for tinea capitis may have caused sorne ofthe psychological problenis. Also, at least in the Israeli
cohort, parts of the brain received higher doscs thanthe meall doscs of 1-2 Gy.
37. Summary. The incidence and extent of ncuropsychologic dysfunction anlong children given radiotherapy to the central nervous system arc difficult todefine. A variety of factors complicate the study of a
possible association between effect and dose, including
the underlying disease and associatcd clinical findings,
other treatment modalities, the impact of illness on
body image and school attendance, and perhaps also
parental social class. Most studies contain a small
number of patients of varying ages, who received avariety of treatment modalides and had varying
follow-ups. Several studies, however, indicate thatradiotherapy increases the risk of adverse neuropsychologic effects. Younger children, particularly
those less than five years of age at time of treatment,
are more severely affected. Clinical follow-ups ofsunlivors of paediatric cancers have demonstrated adecline in IQ after doses to the brain of 18 Gy withconventional fractionation. In general, performanceskills are more affected than verbal skills. It isdifficult to distinguish the impact of radiotherapy fromthat of metliotrexate. It is possible that intrathccal
methotrexatc administered prior to radiotherapy inchildren with acute lcukaemia may be associatcd withless intellectual in~pairmentthan its administration
during and after radiotherapy. TWOepidemiologicalstudies of children irradiated for tinca capitis of thescalp suggest adverse ncuropsychologic effects after
1-2 Gy to the brain, with parts of the brain having
received more than the mean doses in at least one of
the studies. It is likely that these observations can beat least partially explained by confounding factors. The
available data on neuropsychologic effects after radiotherapy in childhood do not allow an analysis of thepossible effect of the fraction size on neuropsycbologic functions, s i ~ ~ cmostestudies deal with conventional fractionation schedules.

3.

Neumendocrine effects

38. Growth depends on a delicate interplay of endomine and nictabolic factors, and secretior~of growth
hormone from the pituiury gland is necessary forriornial growth [S31, W4]. Growth horlnol~cdeficiency
is usually defined as an impaired response of serum
growth honnone to various provocative tcsts. The
cornmonly used tcsts include slimulation with arginine,omithine, insulin-induced hypoglycemia, Ldopa,
growth-homioae-relcasir~g hormone or exercise.
Neuroe~~docrinc
ab~lormalitieshave becn observed in

A N N I X I: ] A T E L)ITL~UVIINIS~ICRADIATION EI:I:ECTS

Shalct ct al. [Sl I ] foul~d normal growth hormone
rcsponsc to hypoglycacmia in 14 childrcn with brain
tunlours prior to trcatnlcnt, and growth hormonc
dcficicncy occurrcd ancr a br;iin.dosc of 25-29 Gy in
7 paticnts within two ycars of radiothcrapy. Of 13
childrcn in whom growtli could be asscsscd, 12 hadpoor growth.
4 2 Cranial irradiation with 24 Gy in 12-16 fractions
ovcr 2-2.5 weeks for acutc Icukacmia has also bccn
associatcd with a measurable reduction in growth
hormonc responsc, although growth remains rclativcly
unaffected at this dose [M14, M15, M16, M17, 0 9 ,P2, S19, S201. OLhcrs havc claimcd wholc-brain irradiation to be an important cause of short stature insurvivors of childhood acute lcukaemia [D15, K 7 , 0 7 ,P8, WS]. Some data suggcst that a significant numbcr
of childrcn less than 4 ycars of agc with acutelyniphoblastic leukacmia are short before the onsct ofthcrapy [Bll]. Some data suggcst that thc effect ofradiation on growth hormone secretion can be reduced
by decreasing the dose per fraction. Shalct ct al. [S19,S21] studicd growth hormone levels and growth in 17
leukaemic children who rcccivcd 25 Gy in 10 fractions
ovcr 2.5 weeks and in 9 childrcn who rcccived 24 Gy
in 20 fractions ovcr 4 weeks. Of the 17 children who
rcceivcd 25 Gy in 10 fractions, 1 4 had subnormal
growth hormone rcsponse to insulin, compared to 1 of
9 patients who rcccivcd 24 Gy in 20 rractions (p <0.002). Arginine stimulation tcst was carricd out in 16
children givcn 25 Gy and in 7 childrcn receiving
24 Gy, and impaired rcsponsc was seen in 6 and 1
patients, respcctivcly. The grcatcr impairment ofgrowth hormone rcsponse to insulin hypoglycaemia
followil~girradiation with 25 Gy in 10 Gactions to thc
hypothalamic-pituitary axis suggests that the hypothalamus rathcr than UIC pituit;iry gland was the site ofdamage. 'Iberc was no differcncc in mcan standing
hcight standard dcviation score bctwccn the two
irradiated groups, but thcy bob differed significantlyin this respect from nonnal childrc~~.

43. Griffin and Wadswortl~ [G2] colnparcd UIC
growth of 66 children with acute lcukacmia to thc
growth of nonnal childrcn matchcd for agc and scx by
calculation of the standard dcviation scorc. All paticnts
had cranial radiotherapy with 24-25 Gy in 15-20
fractions ovcr 21-28 days, and 24 of thcrn also had
spinal radiothcrapy with 10-24 Gy in 5-20 fractions
ovcr 7-28 days. The standard deviation scorc forheight [calculated as (x-x)/SD whcrc x = mean of thenormal population: x = [tic mcasurcrnent; SD = standard dcviation] of the paticnts fell significantly in thefirst ycar of treatment (Figurc IV), This was spccifia l l y related to craniospinal radiotherapy but not to
agc or chemotherapy. Robison ct al. [R13] studicd I87
children (mean age: 5 ycars) with acutc lcukaemia
who reccived cithcr cranial irradiation with a median

IN CIIII-DRIIN

879

of 24 Gy (range: 14-28 Gy) in 1.2-2 Gy fractions fivetinlcs a wcck plus intratliccal ~ncthotrcxatc;c r a ~ ~ i o spinal irradiation alonc (24 Gy); or craniospinal
irradiation plus a b d o ~ ~ ~ i nirradiational(12 Gy). At
diagnosis no sig~rificantdiffcrcncc was obscwcd in the
hciglit distribution comparcd to cxpcctcd population
standards. Aftcr trcatnlcnt, an cxccss was obscrvcd in
Ihc proportion of paticnts ir dtc lowcr pcrcc~~tilcs
inconjunction wit11 a dccreasc in the proportion ofpatict~ts in thc l~igtlcstpcrccntilcs. The o111y factor
found to have a significa~~t
impact on attaincd heightpcrccntilc was radiothcrapy.
44. Childrcn with acutc lcukacmia havc a highGcqucncy of biochemically abnormal growth hormonc
response to stimuli, but growth liormone deficiency is
unconlnlon. Impaired rcsponse to stimuli, suggesting
abnormality in thc hypothalamic-pituiey axis, does
not necessarily indicatc absolutc growth honnone
deficiency. Thc prcscncc of growlh hormone abnormalities is not ncccssarily corrclatcd with clinicalfindings of short stature [07, S19]. Most of theadverse ccntral nervous system sequclac in paticnts
with acutc lcukacmia have been observcd among those
who rcceivcd 24 Gy of cranial radiation and intrathccal chcniothcrapy.
45. The dose rcquircd to prevent lcukaen~ic
infiltration into the central ncwous systcnl can now besafely lowered from 24 Gy to 18 Gy [Nl]. Few datacxist on UIC cffcct on growth of radiation doses bclow
24 Gy. In some studies, growth impairment has been
similar aftcr 24 Gy and after 18 Gy [R13, S22, W5].
Others havc observed that growth impairment in childrcn wilh acutc lcukacmia has bcen less frequent andgencrally ~nildcrbelow 24 Gy [B12, C11, C23, G2,
S19, V1, V2]. Cicognani ct al. [C23] found thatchildren who had reccived I 8 Gy in 10 fractions hadcomplete growth recovery and normal growth homione
responses to pharmacological tesL5. Childrcn who had
rcccived 24 Gy in 1 2 fractions showcd significantly
lowcr standard deviation scorcs for height than at
diagnosis and had irnpaircd growth honnonc rcsponse.
46. Aftcr a single whole-body dose of 10 Gy, scvcrc
growth retardation appear ia most childrcn ID2, S23].
Many if not most of thcse children also rcccivcd
cranial radiotherapy prior to thc wholc-body irradiation. The majority of paedialric patients trcated withhave dccrcascd growth ratcs onwhole-body irradiatio~~
longitudinal growth velocity curves, and growth
hormonc lcvcls havc bcen subnormal in ahout OIIC
third of thc paticnL~ID14. S24. S25). Sandcrs IS241
rcportcd suhnoni~allcvcls of growth h o r ~ n o ~in~87%
cof children who rcccivcd both cranial radiothcrapy a ~ i dwholc-body irradiation, c o ~ ~ ~ p a rtoc d42% of those
who received wholc-body irradiation only. Dceg ct al.
velocily curves in
ID21 obscrvcd ~ ~ o r l n agrowthltransplant-treated children who did not receive wholebody irradiation, whereas irradiated childre11 had
impaired growth and dccreascd growtl~ velocity.
Growth hornlone levels wcre sub~~ornlal
in about one
third of the irradiated patients.
47. Some data suggest that fractionation will reduce
the adverse effects of whole-body irradiation. Barrett
et al. (B13j rcported growth lior~nonedeficie~~cyin 6of 8 children after a single whole-body dose of 10 Gy
and in 3 of 8 children who had a fractionated wholebody dose of 12-14 Gy in 6 fractions given twice
daily for 3 days. Sanders et al. IS231 evaluated growthin 144 patients following marrow transplantation forchildhood leukaemia at a median age of 10 years. All
children had received nlultiagcnt chemotherapy, and55 had received a median of 24 Gy (range: 18-29 Gy)
to the central nervous system, 5 of whoni had also
received a median of 12 Gy to the spine. A wholebody dose of 9.2-10 Gy in a single exposure wasgiven to 79 patients, and 63 patients had a fractionatedregimen of 2.0-2.3 Gy per day for 6-7 days for cumulative doses of 12-16 Gy. Growth hormone levels were
measured in 43 patients 1-8 years afier transplant. andgrowth hormone deficiency was present in 27 subjects(63%). Of these, 21 patients had received pre-transplant cranial irradiation. By three or more years after
transplant, boys who received single whole-body
exposure were 8.0 i: 2.3 cm shorter than boys who
received fractionated whole-body exposure (p c 0.03).
Among boys who had not received cranial irradiation,
those given single whole-body exposure were 15.2 i:
3.2 cm shorter than thosc given fractionated wholebody exposure (p c 0.04). Girls showed similar trends
that were not statistically significant
48. Hiroshima survivors exposed to >I Gy at ages
0-19 years were shorter and weighed less than theoverall population. Those who were less than 6 years
old and who also received >1 Gy [B14] at the tinle ofthe bombings were shorter still, on average. The
analyses were based on the T65 dosimetry. Exposure
to high radiation doses markedly reduced mean height
for those who were very young at the time of thebombings, but this e f i c t diminished with increasingage. Average height for those agcd 0-5 years at thetime of the bombings was significantly smaller for the>1.0 Gy dose group than for the groups 0 Gy (not incity), 0-0.09 Gy and 0.10-0.99 Gy for both males andfemales: smaller by 4.4 cm or more for males and by
2.5 cm or more for females (Table 5). For those aged
6-11 years at the time of the bombings, sn~allerheights were again found for the >1 Gy dose group,
allhough to a lesser degree. For subjects aged 12-17
years at the tirile of the bombings, no apparent differences between the four dose groups were found. Whenthe high dose group was further divided into 1.002.49 Gy and 22.50 Gy groups, the mean heights wereless for hot11 n~alesand fe'crtialcs aged 0-5 years at the
tinlc of the bombings ill d ~ 22.50
e
Gy group. The diffcrcnce froni tlrc 1.00-2.49 Gy group was statisticallysignificant for ~nalcs.Average hcigbls of fen~alesaged
6-1 1 years at t l ~ etime of the bonibings and for malcs
a l ~ dfernales agcd 12-17 years at the time of the b o n ~ hings were al~proxin~atcly
the siime for UIC two dosegroups (Table 6). 111 Nagasaki, the effect of dose onheight was not statistically significant, although thenlcan heigl~tof Nagasaki fcmalcs aged 0-5 years at thetime of the bombings was least for those who were
exposed to >I Gy (Table 5). Among males, those exposed to 0-0.09 Gy at agcs 0-5 years at the time of thebombings showed the smallcst mean height. For boththe 6-11 year and 12-17 year groups, however, themean height for boys in the high dose exposure group
was the smallest. A reanalysis based on the same T65
dosimetry was undertaken of the relationship between
attained adult height and radiation dose of 628 survivors of the atomic bombings in Hiroshima andNagasaki aged less than 10 years at the time of thebombings [14]. Average height tended to be lower as
exposure increased, except among Nagasaki males(Table 7). Two-way analysis of variance of height inrelation to sex and dose by city showed that height
was significantly different by sex and total kerma in
Hiroshima. In Nagasaki, however, it was significantly
different by sex but not kernla total dose. Growth anddcvclopnle~~tof stature depends on nutrition, socioeco~~oniic
conditions, the quality and quantity ofradiation received and, possibly, other factors.
Contrary to the report by Bclsky and Blot [Bl4], theresults of Ishimaru el a]. [I41 suggested that diminished stature was not significantly related to age at
the time of the bombings for individuals exposed
before the adolescent growth spurt, something which
was probably due to the small sample size. The observed difference between the two cities may changewith new aa;~lysesbased on the new DS86 dosirnctry.
49. Children on the Marshall Islands exposed toradioactive fallout in 1954 wcre also found to have asignificant reduction in height, which was probably
mainly due to radiation-induced hypothyroidism [R14,S261 (see Section 1I.B).
50. Children with radiation-induced growth hormone
deficiency can now be treated with growth hormone,
although thcre are as yet no long-term studies of theeffccts of such a therapy in a large number of children.
Some data suggest a significant growlb response to
therijpy in children who receivcd cranial irradiation
alone, wl~ercasthe response in patients rcceivirig cranie
has beer1 less satisfactory IG3, S20].
s p i ~ ~ irradiational
51. Sunlrrrary. Irradiation of the central nervous
system nlay produce damage to the hypothalarnicpituitary axis, resulting most c o ~ n ~ n o ~in~impairedlygrowth hormone secretion. The hypothalaniic cells
producing the powth-hor~nonc-relcasitlghormone are
the most sensitive endocrinological target. Growth
hormone deficiency can be expected in approximately
75% of children treated for brain tumours, and a
growth velocity or height below the 10111 percentile
can bc expected in 70%. The growth hannone deficiency is permanent. Patients with acute leukaemia
have in general received lower doses to the central
nervous system but growth hormone secretion is stillaffectcd. After 25-30 Gy, the growth l~ormoneresponse to insulin-induced hypoglycaen~ia is impaired
within two years of irradiation. After 24 Gy in 12-16
fractions, there is also a rueasurable reduction in
growth hormone response to stimuli. Growth has beenless affected after 24 Gy than afier higher radiation
doses in the brain, suggesting that the normal physiologic requirements of growth hormone secretion havebecn m e t No effect on growth hormone secretion has
been observed below 18 Gy. A 1 0 Gy whole-bodydose in a single fraction results in severe growth
retardation in the majority of children, who generally
have been pretreated with chemotherapy and cranialradiotherapy. Fractionation appears to be of importance for the effect on growth hormone secretion andgrowth, and increasing fiaction size will result in ahigher proportion of patients with subnormal growth
hormone response. Growth impairment is seen more
often after a single-dose whole-body irradiation with
10 Gy than after a fractio~~atedregimen of 12-16 Gy
in 2 Gy fractions over a weck. It is not possible todefine the lowest dose capable of impairing growth
hormone secretion, since available data are obtained
from small studies with varying ages at exposure andlengths of follow-up, as well as different methods forassessing the growth hormone level. Such a dose
appears to be lower than 18 Gy from fractionatedexposure. G~owthhas been affected in the survivors of
the atomic bombings in Japan at acute doses of >1
Gy, especially among children less than 6 years ofage. This effect may be due to a combination of brain
damage, damage to the spine, nutritional factors etc.

13.

THYROID GLAND

52 Hypothyroidism is the most common late detcrministic effect of the thyroid gland following exposure
to ionizing radiation. Thyroid nodularity is considered
to be a stochastic phenomenon and is therefore notdiscussed in this Section. Clinical damage to the pituitary and thyroid glands is usually manifested several
years after exposure and is preceded by a subclinicalphase [F4]. Direct damage to the thyroid gland byradiation can cause primary hypothyroidism, whereas
damage to the hypothalamic-pituitary axis may produce secondary hypothyroidism. Primary hypothyroidism has been demonstrated in 4094~90%of

patients with pacdiatric tunlours given 15-70 Gy to thethyroid gland and followed for up to six years [BlO,
C5, C13, D16, F4, G4, K8, 08. P9, S9, S23, S27,
S281. The onset of hypothyroidism may be several
months to years following the radiotherapy. Administration of oral thyroxine during radiotherapy does notappear to prevent later thyroid hypofunction IBIS].
Radiotherapy alone and with chernothcrapy have becn
associated with similar high incidences of hypothyroidism. Paticntq treated with chemotherapy only
have generally not had any significant thyroid hypofunction, although transient thyroid dysfunction has
been reported IG4, G5, H7, L7, S27, S28, S29].
53. The incidence of overt [low serum T 4 andelevated thyroid-stimulating hormone (TSH)] and compensated (norn~alserum T4 and elevated TSH) hypothyroidism varies with the radiation dose in the thyroid
gland, the length of follow-up and the way in which
the thyroid function was determined. Thyroid surgery,iodine-containing contrast material and age of thepatient at the time of radiotherapy may contribute to
the development of hypothyroidism. The effect of age
at the time of radiotherapy on the development ofhypothyroidism is a matter of controversy. In one
study, 48% of patients with Hodgkin's disease who
were younger than 20 years of age at the time oftreatment had elevated TSH levels compared to 33%
of older patients [G4]. Green et al. [GS], observed that
7 of 15 children with Hodgkin's disease and irradiatedat the age of less than 13 years developed hypothyroidism, compared to 3 of 12 among those who had
been older than 1 3 years. In a study by Tarbell et al.
IT91 of patients irradiated for Hodgkin's disease, the15-year actuarial risk for hypothyroidism was 64%
among patients aged 16 years or less, as comparcd to29% among those older than 16 years. Others have not
identified age as a contributory factor [D16, K8, N2,
S28, S29]. The possibility that the thyroid is moresensitive in childhood is also supported by the highincidence of increased TSH levels in children irradiated for Hodgkin's disease [D16, S27].
54. Elevated TSH levels have been observed inchildren who received radiotherapy for brain tumours
after 25-30 Gy to the hypothalamic-pituitary axis or
24 Gy to the thyroid gland [C26, D6, H6, 0 6 , SlS].
Various studies show that hypothyroidism is dosedependent. In a study by Glatstein et al. [G4], nopatient had an elevated TSH level afier 15 Gy to thethyroid, as compared to 44% of the paticnts receiving
40 Gy or Inore. Kaplal~ct al. [KS] round elevated
TSH levels in 15% of patients who received <30 Gy
and in 68% of those who received higher doses. Logistic regression analysis showed &at both higher
radiation dose (230 Gy) and lymphangiography increased the risk of having an elevated serum TSH
level. Constine el al. [ClS] measured thyroid function

in 119 childrc~r irradialcd for Hodgkin's discasc.
Radiotherapy was dclivcrcd ovcr 4-5 wceks: 24 childrcn rcceivcd a neck dosc of 26 Gy or less (rncan:
22 Gy) and 95 rcccivcd >26 Gy (nlcan: 44 Gy). Morc
rccciving >26 Gy had clcUran 75% of tl~ccl~ildrc~rcoml)i~rcrlto 17% of ~ ~ O StreilIcd
C
vatcd TSH ICVCIS,
with lower doscs. A weak correlation wit11 age (p c0.05) was found, and thc doubling dosc for thc nrcan
peak TSH valuc was 11 Gy (Figure V).

55. Most of the cxpericr~ccin radiation-rclatcd lateeffects in the thyroid has bccn gained from the trcatmen1 of Hodgkin's discasc. Cornpc~rsatcdhypotl~yroidism occurs in up to 75% of thc trcatcd clrildrc~r,and
uncompcnsatcd bypothyroidisrn has been obscrvcd inless than 30% of the children [C14, D16, D17, F4, F5,
G4, G5, M18, S17, S27, S28, S29, T8). Paticnts irradiated for lymphonias or head and neck carlccrs havegenerally rcceivcd 24-60 Gy fractionated ovcr sevcral
wceks. In some studics lymphangiography prior toradiotherapy has bccn shown to increase thc risk ofhypothyroidism [G4, G5, K8, S27, S28, S291; inothers, it has not [C14. G5, N2, T8]. Lymphangiography may incrcasc thyroid damage from subscqucnt
irradiation for the following reason: the iodine released
from the contrast material could inhibit thyroid
hormone synthesis and secretion within a fcw days,
thcrcby causing increased tbyrotropin sccrction andconsequent stimulation of thyroid cells at the time ofirradiation [Kg]. An expanded extrathyroidal pool ofiodine may increase susccptibility to hypothyroidism
in irradiated subjects.
56. Lower radiation doses may also incrcasc the riskof hypothyroidism. In children with acute lcukacmia
receiving cranial irradiation with 1 8 Gy, the thyroid
dose is 3%8% of the cranial dose IRIS]. Hypothyroidism has bccn observed in up to 20% of longterm survivors of childhood acute leukacmia aftcr 1825 Gy of cranial or craniospinal radiotherapy withconventional fractionation [N3, R16. R18. S12j; others
have failcd to observe such an effect aftcr cranial
doses of 8.5-24 Gy in 2 Gy fractions ( 0 7 , V1 1. Mcan
thyroid doses of 4 1 0 Gy in infancy or childhood fromfractionated radiollrcrapy for bcnign discasc has notbccn associated with clinical hypothyroidism, although
fo1lou~-uplasted as long as 25 years IH8, R19]. In
conlrast, hypothyroidisrn has been reported in 7 of 9
'loma
Russian children after radiolberapy for skin an&.
with thyroid doses of >l.l Gy [T15].
57. Thyroid hypolunctio~~
can occur aftcr wholcbody irradiation. Children w11o rcccivcd a rcgi~iicnof
chc~nolherapyin preparation for a transpla~~thave anincidence of Uryroid dysfunction that is not greaterthan normally observed among non-transplant childrcn[S24, S2.51. Radio~hcrapyappears to be thc major, if
no1 the sole, causc ofsubscqucnt thyroid hypofuectionin thcsc ~)aticnts.111 1cr111sof its cffccts OII Ulyroid
hypofr~~~clioa
IT1 71, single-dosc radiotherapy has bcc~rclai~rlcdto be cquivalcnt to a total radiation dose 4-5
tinrcs Iargcr w l ~ c ~it ris dclivcrcd ill convc~~tional
kactions. Si~ndcrsct ill. IS23, S24I studicd 142 palic~rls
1-17 ycilrs old i~ftcr~ O I I CIrliirrow transpla~~tatio~r
totrca t hi~c~ni~lologicalnii~ligr~;~rrcics.
All patie~rtshad
rcccivcd ~r~ultiagcnt
chc~nothcrapy.55 had been prctrcatcd witlr 24 Gy fractionated cranial radiotherapy
and 12 hiid rcccivcd 1 2 Gy spinal inadialion. Wholcbody irradiation was dclivcrcd as a single dose of 9.210 Gy (n = 79) or 2-2.2 Gy daily for 6-7 days to 12.015.8 Gy (11 = 63). A ~ n o ~ rclrildrcrig
who rcccived 10
Gy si~rglcwlrolc-body exposure, 56% had conipcnsatcd I~ypo~hyroidismand 13% had ovcrt hypothyroidism, a~rdthe figurcs for c h i l d r c ~who
~ rcceivcd fractionatcd whole-body irradiation were 21% and 3%. respectively. These diffcrcnccs most likely reflect the
shorter observation tinles after fractionated exposure(mcdian nine years versus five years). Longer followd dctcrmine whether there is any rcal
up is ~ ~ c e d cto
diffccrcncc bctwecn the two typcs of whole-body exposure. Ka~sanisct at. [K9] evaluated thyroid function in
80 patients aftcr bone rnarrow transplantation foraplas~icanacmia or acute Icukacniia. Median age at
the tinre of trar~splanlalionwas 10 years (range: 2-21
years). Patients with aplastic anaemia received hi@dose chcmothcrapy and total lymphoid irradiation witha si~rgle dose of 7.5 Gy, and leukacrnia patients
rcccivcd cidicr whole-body irradiation as a single
fraction of 7.5-8.5 Gy (n = 33) or fractionated wholebody irradiation with 13.2 Gy (n = 20) in 1.7 Gyfrac~ionstwice daily for four days. 0 1 2 7 patienls withlirradiation, 11aplastic anaemia plus t o ~ lymphoid
showcd thyroid hypofunction, as compared with 9 of
5 3 patients with acute lcukacmia plus whole-body
irradiiition. The five-year actuarial risk estimate ofhypothyroidism aftcr total lymphoid irradiation was
42% (95% Cl: 23%-61%), wl~icllwas significantly different from 10% after fractionated whole-body irradiation (95% C1: 0%-23%) (p c 0.05), but not dirfcrent
fro111 21 % after singlc-dosc whole-body irradiation(95% CI: 7%-35%).
58. Thc tllyroid gland 11as t l ~ ccapacity to i~ctivcly
corrccnlratc iodinc, and ri~dioiodinc can U~crcforc
dclivcr co~rsidcrablcradiation doses to the gland, a factthat has bcerr and is still uscd in diagnostic andthcrapcutic medical proccdurcs D18, G6). The mostc o m n ~ o ~ ~usedl y radioiodi~rcis ' I , which has a halflife of ciglrt days. Most d i ~ l i011
~ hypotl~yroidismafter
13'1 cxposurc cn~alratefro111studics on paticnts wid1
hypcrll~yroidisni, and tl~cir cxpcricecc rnay not bc
dircc~lytriit~sferahlcto a r~orn~alcuthyroid population.
r t s hypcrthyroidis~n,hypothyroidism is
In ~ ~ a t i c ~witlr
common cvcn after surgcry or trcallncnt with antithyroid drugs [B17, HlO]. The thyroid uptake of 13'1
is Irighcr ill Irypcrthyroid patic~rls,but the turnover of'1

ANNW I: IAlT DEI-ERMINISTIC RADIATION EFFEC7S IN ClllLDREN
chc nuclidc is morc rapid. I t may thcrcforc bc possiblc
to approximalc the cxpcricnce of hyperthyroid paticills
to that of cuthyroid subjects [M19, M20, N4j. In adulth crthyroid palicnk trcatcd wit11 a sii~glcdosc of
the cun~ulativcprobability of lrypotl~yroidis~~lisrclatcd to tl~c l 3 I l activity ad~nioistcrcd pcr ui~itthyroid weight IB16j. Holm ct al. 11-191 obscntcd ana~lnualhypothyroidisrn of 3% t l ~ cfirst 24 ycars aftcr
I3'l thcrapy for hypcrthyroidism. Thcrc arc only "crylimikd data on thc cffccts of thyroid absorbcd doscs
from 1 3 1 ~of c25 Gy and h c cffccts in childrcn.
NCRP Report No. 55 [N4] citcd unpublished datafrom Hamilton and Tompkins, who obscrvcd that8 of
443 subjccts (2%) lcss than 16 ycars old and judgcd tohave nonnal thyroids bccame hypothyroid aftcr diagnostic l % tcsts. Thc incidence of hypothyroidism
was 0% pcr ycar in 146 subjects who rcceivcd ~ 0 . 3
Gy in thc thyroid, 0.15% per ycar in 146 subjects who
received 0.3-0.8 Gy and 0.23% per ycar in 151 subjccts aftcr thyroid doscs of >0.8 Gy. A linear modcl
with a thrcshold was postulated for hypothyroidism;
owing to the largc functional capacity of the thyroid
gland, a largc nu~i~bcr
of cells would havc to bc
affectcd lo result i n hypothyroidis~n. I-Iayck ct al.
[ H l l ] obscrvcd hypothyroidism in 8 of 30 (26%)
patients bctwccn the ages of 8 and 18 ycars who
rcccivcd I3l1 therapy for hyperthyroidism. Thc meanamount of l3'l adniinistcrcd was 240 MBq, and themean follow-up was nine years. Frcitas ct al. IF61
found a 92% prevalcncc of hypothyroidism in 51
patients aged 6-18 ycars aftcr 1 3 1 ~therapy for~
520 MBq).
hypcrthyroidism (~ncan1 3 1 activity,"6,

59. In 1954, following dctonatiol~of a megatonne
nuclear dcvicc at Bikini, 250 inhabitants of the Rongclap, Ailingnae and Utirik atolls of thc Marshall Islands
were cxposed to radioactive fallout IC16, L8, R14].
This consisted ofwhole-body gamma-irradiation, bctairradiation of the skin from fallout dcpositcd on theskin, and internal absorption of radionuclides from theingestion of contaminated food and watcr. The mostserious internal exposurc was that to the thyroid gland,
from radioiodines in thc fallout. Thc cstiniatcd thyroid
dose varied from 0.3 to 3.4 Gy among those agcd 18
years or more to 0.6-20 Gy among thosc lcss than 10
ycan of age. Many uncertainties wcrc involvcd in thedose calculations. and particularly in the thyroid
dosimetry. The most widcsprcad late cffccts of fallout
cxposurc arnong thc Marshallcsc havc bccn rclatcd toradiation injury to Lhc thyroid gland. The growth statusof childrcn cxposcd to fallout radiatio~~has bccn
studied in 67 uncxposcd a ~ 38
~ dexposed childrcn, 4born to cxposcd
childrcn exposcd in tcfcro,39 childrc~~
parcnts and 53 childrcn born to ur~cxposed parents[S26]. Retardation in both statural growth and skclctal
maturation has been obscrved among cxposed boys, ascomparcd with uncxposcd childrcn. Thc retardation
was notcd among boys who wcrc undcr 5 years of age

883

w11c11cxposcd to [Ire fallout, being niost prolnincetalnong tl~oscagcd 12-18 mortl~sa t t l ~ ctime of cxposurc. No sig~~ificai~t
diffcrcnccs wcrc notcd in thegrowth pattcnls hutwccn cxposcd and uncxposcd girls
and hctwccn childrcn b o n ~to cxposcd or uncxposcdp;ircllls.
60. Thc i~~cidcncc
of subclinical hypothyroidis~~lwas
31% among childrcn less than 10 ycars of age at exposurc aftcr an cstimatcd thyroid dosc of >2 Gy. No
casc of hypothyroidis~noccurrcd in this agc group at
lowcr doscs (Tablc 8). Amoi~gsubjects 10 ycars oroldcr, OIIC case (1 %) of hypothyroidisn~was obscnlcd
at all cstimatcd thyroid dosc of c l Gy, one casc (8%)
at 1-2 Gy and four cascs (9%) a t doscs highcr than
2 Gy. Only two of the subjccts cxposcd a1 lcss than 10
ycars of age had clinical hypothyroidism. The incidcnce of hypothyroidism began to increase approximately onc decade aftcr cxposurc. A thorough rc-evaluation of the absorbcd dosc in thc thyroid was done
by Lessard et al. [L9]. The rccalculated cumulative
external doscs of gamma rays wcrc close to the initial
estimates, but doscs from intcrnally deposited radionuclidcs wcrc niucl~highcr. Most of the thyroid dose
rcsultcd from short-livcd radioltuclides. Thc rc-cvaluation of thc thyroid absorbcd dose makes thc obscrved
results conipatiblc with those of olher studies withsimilar doscs [R20].
61. Rallison ct al. [R21, R22) observcd two cases ofhypothyroidisni in 1,378 childrcn exposed to 13'1 fallout from r~uclcar weapons tcsts, comparcd to fourcases in 3,801 non-imadiatcd control subjccts. The
follow-up tirnc was, on avcragc, 16 years, and the
Incan thyroid dose was estimated to be c0.5 Gy. The
diffcrcnce in the incidcncc of hypothyroidism between
chc two groups was not statistically significant.
Clinical cxaminatiolis wcrc pcrformcd it1 1990, andlcvcls of Srcc T4 and thyroid stimulating h o r m o ~ ~ c
wcrc mcasurcd in childrcn living in Russia, Belarus
and Ukrainc at thc time of thc nuclear plant accident
in Chcrnobyl in 1986 and in children born in 1989
[HI. Thcrc was no cvidcncc Ulat thyroid function had
hecn affccted in a way that could be dctectcd cithcr
clinically or by laboratory tcsting at that timc.
62. Thyroid disorders wcrc studicd 30 ycars aftcr
urldcr 20 ycars of agc a t
cxposurc in 978 i~~dividuals
thc tirlie of thc bo~nhingsin Hiroshima and Nagasaki[M21. M22]. Thc cstimatcd doscs from thc atoniic
bornb fallout radiation wcrc based on T65 dosi~~ictry.
Thcrc wcre 200 n~iilcsand 277 fcmalcs in thc >1.0 Gy
cxposed group and 219 ~iialesand 282 fc~nalcsin theurlcxposcd (0 Gy) group. Of thcsc, 128 wcrc aged 0-9
years and 349 wrcrc 10-19 ycars at the tirrlc of thebombings in the >1.0 Gy group; and 139 suhjccls were
agcd 0-9 ycars and 362 wcrc 10-19 ycars a t thc timeof the bonlbings ill the unexposcd group. Tlrcrc wcrc

no significant dilfcrcnccs in mean serum TSH lcvcls
or nican seruni thyroglobulin levels between thc 0 Gy
(unexposed) group and Ihe >1 Gy (exposed) group. In
a recent analysis IN71 of 2,774 subjects of the Nagasaki Adult Health Study cohort, the prcvalcrice of
hypothyroidism was 5% in exposed subjects arid 2%
in controls. 111oue ct al. 1171 studicd nearly 2,600
individuals from the same cohort and obscrvcd hypothyroidism in 3% of the subjects. The fitted relativerisk increased fiom 1 for those less than 5 ycars at thelime of the bombings to 3 for those 30 ycars at thetinle of the bombings.
63. Summary. Thyroid dysfunction may result from
irradiation of the thyroid gland or the hypothalamicpituitary axis. A substantial proportion of patients
receiving radiotherapy for various paediatric turnours
have impaired thyroid function. The incidence of
hypothyroidism varies with the definition used and ishighest when elevated TSH levels are used to define
the impairment. Young children seem to be more sensitive to radiation-induced hypothyroidism. Various
studies show that hypothyroidism is dose-dependent.
The prevalence of hypothyroidism is increased inleukaemic children who have received cranial radiotherapy of 18-24 Gy over 2-2.5 weeks. The thyroid
doses in these cases have been calculated to be 3%
8 % of the brain dose, i.e. 1-2 Gy. However, the children also received associated chemotherapy, which niay
affect the risk for hypothyroidism. No epidemiologic
study has demonstrated hypothyroidism in children
after a thyroid dose from external irradiation el Gy.
There is limited evidence that dose rate nlay be ofimportance and that the risk of hypothyroidism is
rcduccd when fraction size is reduced. There arc insufficient data on the effects of l3'l to detcrniine a
possible threshold dose for the induction of hypothyroidism.

C. OVARY
64. The ovary is a highly radiosensitive organ, andsingle doses of 0.6-4 Gy have caused temporary sterility in adults, with higher doscs required to produce thesame effect when fractionated. Permanent sterility
results from 25-10 Gy in a single dose and from 6 Gy
with protracted exposure [ F l , 11, U3]. The radiosensilivity of the ovary depends on the degree of maturity,and the thrcshold for permanent sterility decreases
with age, although the age-related differences are hardto estimate IA12, Fl]. The fact that the ovary of ayoung woman is more resistant is explained by the
reduction, ovcr time, in the fixed pool of oocytes,
since these cells are not replaced. The radiation dose
required to destroy all the oocytes is herefore larger
in younger than in older women. Ovarian dysfunction
has been observed in more than 50% of adolescer~ts

and yo~111g
womc~iafter doscs of 25-4.0 Gy. Rccovery
has bccn age-rclatcd. After 4 Gy, p c r ~ ~ i a ~ ~amenent
orrhca alid i~ifcrtilityhavc occurred ill approximately
one d~irdof youngcr wolncn and in all worilen older
than 40 ycars of iigc IA12, H121.
c ovarian dysfunction
65. The niost comeion ~ i u s ofin patients trcatcd for pacdiatric tumours is direct
damage to the gonads by radiation and/or cytotoxic
agents. The ohscrvcd ovarian effects have basicallyheen fibrosis arid follicle dcstructio~i with elevatedlcvcls of lutciriizing l~ormoncand follicle stimulating
hormone. Irradiation oftlie I~ypothalamic-pituitaryarea
can also result in goriadotropin deficiency or hypcrprolactinaemia, which may impair subsequent reproductive function [A13, R23]. Quiescent ovaries havebeen found in childrcn after radiotherapy with 2030 Gy to the abdo~nenovcr 21-30 days, either alone
or combined with chemotherapy [H13]. Chemotherapy
used for a short time has been reported to be without
effect on the small follicles, whereas prolonged
treatment destroys tlicm [M23].
66. Pelvic or abdominal irradiation has been
associated with ovarian failure, resulting in elevatedlevels of follicle-stinlulating hormone, amenorrhea andfailure to develop secondary sexual characteristics [G7,
0 9 , S32, S33, W6]. In a study by Wallace et al. [W6],ovarian failure occurred before 16 ycars of age in 19
paticnts irradiated ill childhood for abdominal tumours
with 30 Gy in 16-26 fractions over 21-38 days. An
upper limit for the LD50 of the human oocyte wasestimated at 4 Gy. Stillnian el al. [S33] observed signsof ovarian failurc in 12% of 182 long-term survivorsof childhood cancer. Of 25 patients (68%) with bothovaries within the treatment fields (nican ovarian dose:
32 Gy), 17 showed ovarian failure, as compared with
5 of 35 patients (14%) whose ovaries were on theborder of the treatment ficld (mean: 2.9 Gy), none of
34 patients with one or both ovaries oulside h e treatment ficld (mean: 0.5 Gy) and none of 88 patients
receiving no radiation to the ovaries. The likelihood of
ovarian failure in patients with both ovaries in theficld was 19.7 (95% CI: 5.3-728), higher than thosefor other irradiated paticnts. Subseque~itfertility has
heen obscrvcd in prcpubcrlal girls aftcr pclvic doses of
10-30 Gy, despite follicular depletion and elevated~ i c (H13, L11, S32).
follicle-stimulating h o r ~ ~ i o levels
67. Horning ct al. [HI21 studied 103 women aged
13-38 years (median agc: 19 years) with Hodgkin's
discasc trcatcd by c l ~ c ~ ~ ~ o l l ~aclroa ~p ~(ay e = 34), totallyniphoid irradiation alone (n = 19) or irradiation plus
cheniothcrapy (n = 50). The pelvic dose was 3040 Gy, delivered with conventior~al fractionation.
Menses werc present in 94% after total-lymphoid irradiation alone, 85% aftcr chemotherapy alone and in
48% after total-lynil)hoid irradiation plus chemo-

ANNEX I: LATE DETERMlNlSllC RADIATION EITECTS IN CIIILDWN

therapy, of which 47%, 56% and 20%, respectively.
were regular. Chemotherapy was associated with theliighcst and combiliation therapy with the lowest probability of regular Iiienses. Tlic probability of regularmenses decreased with a p at treatnicnt (Figure VI).
When age at treatment, interval after conipletion oftreatment, stage of diseasc, number of cyclcs ofchemotherapy and pelvic radiation dose were included
in a multivariate analysis to detemiine factors predicting regular menses, o~ilyage was significant for
any of the three treatment modalities.

68. Irradiation of the central nervous system andchemotherapy can destroy gonadal function by causing
darnage to the hypothalamus or direct damage to the
gonads themselves [B18].Various hormonal effects
have been observed after cranial or craniospinal radiotherapy with 25-50Gy fractionated over 3-4weeks,
e.g. elevated, normal or reduced levels of gonadotropins, secondary amenorrhea arid lack of pubertal
progression [A13,B10, C17, L10,R23, SlS].Leipcr
et al. [L12]observed early puberty in 10% of 233
children given cranial radiotherapy with 18-24Gy in
10-15fractions over 2-3weeks for acute lcukaemia ata mean age of 4 years. Three girls had precocious
puberty, i.e. signs of sexual maturation occurring
before 8 years. Early onset of menarche after cranialradiotherapy has also been observed by others [B19,
M15, 01,R23, S15]. Othcrs have reported normal
levels of gonadotropins and oestrogens after 24 Gy
cranial radiotherapy in 2 Gy fractions over 2.5 weeks[DS,0 7 , Vl].
69. Hamre et al. [HI41assessed gonadal function in
163 children treated for acute lcukaemia at an averageage of 6 years and who were randoniized to receive 18
or 24 Gy to one of three fields: cranial, craniospinal or
craniospinal plus 12 Gy abdominal, including theovaries or testes. Gonadal evaluation 4 years later
showed elevated levels of follicle-stimulating hormone
and/or luteinizing hormone in 36% of the patients.
There was an association between elevated gonadotropins and the radiotherapy field: 9% of patients who
had cranial fields had elevated Ievcls, as compared to
49% for craniospinal fields and 93% for craniospinal
plus abdominal fields (p < 0.001). Girls receiving
24 Gy had a relative risk of 14 for elevated folliclestimulating hormone and 8.7 for elevated luteinizing
hormone compared with girls rcccivi~~g
18 Gy. Craniospinal plus abdominal radiotherapy was significantly
associated with abnormal gonadotropin levels and lackof pubertal development.

70. Patients who receive only cheniotherapy prior tobone marrow transplantation have nonnal pubcrtal development and normal levels of gonadotropins and sex
hormones. The majority of children receiving 10 Gy
single whole-body exposure cxpcrie~~cea delayed onset

885

of puberty, and their gonadotropin levels reflect primary
gonadal failure. Nearly half of children receiving
fractioriated whole-body irradiation have nonnal
puberbl developnie~~tand nonnal gonadotropin levels
IB13,D2,S24,S341.Ovarian failure appears to develop
in almost all fenialcs of postpubertal agc after wholebody irradiation with 10-12Gy. Normal gonadotropin
levels have been observed in the majority of girls who
were prel)ubertal at UIC time of transplantation.
71. Sanders el al. [S23]studied ovarian function in
142 children (52 girls) treated with bone marrowtransplantation at the median age of 10 years. ,411
patients had received chemotherapy, and one third of
the patients also had received radiotherapy to thecentral nervous system. Patients were given chemotherapy and whole-body irradiation, as a single dose of
9.2-10Gy (11 = 79) or as fractionated doses of 22.3 Gy daily for 6-7days to a cumulative dose of 1215.8 Gy (11 = 63). Of 35 girls who were prepubertal attransplant, 10 had delayed development of secondary
sexual characteristics at evaluation 4 years later.
Gonadotropin arid oestradiol levels were determinedfor 1 1 of 16 girls older than 12 years of age, and 7
had elevated levels of follicle-stimulating hormone,
low levels of oestradiol and delayed onset of puberty.
Gonadal failure occurred in nearly all who were postpubertal at transplant, with amenorrhea and elevatedlevels of luteinizing hormone and follicle-stiniulating
hormone. I t was not possible to determine how manyof these endocrine abnormalities occurred as a resultof treatment administered prior to transplantation. No
information was provided on the effect of fractionation
on gonadal functio~~.

72 Sarkar et al. IS351 studied fertility in 33 subjects
after l3'l therapy for thyroid cancer in childhood oradolescence. They received a mean 1 3 1 ~amount of
7,250MBq, with a range of 2,960-25,560MBq, andthe estimated cumulative gonadal dose ranged from0.08 to 0.69 Gy. The incidence of infertility and miscarriage did not differ significantly from that in thegeneral population.

73. Summary. The effects of radiation on the ovary
are age- and dose-dependent. The ovary of young
women is less sensitive to radiation-induced deterministic effects because of their higher number ofoocytes, although it is difficult to define the magnitudeof these differences. A variety of factors complicate
the study of a possible association between radiationdose and the effects on the ovary, including the underlying disease for wllich treatment was given. Unfortunately, most studies have been performed on a limited
number of patients of varying ages at exposure, whoreceived a variety of treatment modalilies and hadvarying lengths of follow-up. The available data thercfore do riot allow an a ~ ~ a l y s iof
s the dose-cffectANNM I: IATE DETiiKhtlNIS71C RADIATION III-FECIS IN CIIILDRIN

887

of cl~ildl~ood
in UIC postpubertal male, plns~na tcstosteronc andcanccr lrcatcd during prcl)ubcrty andlcvcls wcrc normal. O~rlyone boy had an
gonadokopi~~
puberty wit11 a rlicall tcsticular dose of 1.9 Gy (range:elevated follicle-sti~nulati~~ghornionc Icvcl. The
0-25Gy). Spcrm sarnplcs wcrc obtained from 23 subradiation-induced damage to tlic gem~inirlc p i t l ~ c l i u ~ ~ ~jects, and thc 4 who rcfuscd had fathered healthy
thus resulted in raised lcvcls of follicle-stimulating
childrc~~.
Four paticnts were oligospcrmic and 14 werc
The four sterile mcn had reccivcd at:~zoospcr~nic.
hormone aftcr pubcrty but not bcforc. In rcspcct oflcast 1.4 Gy to thc tcstcs without chemothcrapy and as
pelvic radiothcrapy and/or chcmothcrapy for Hodgkin's
low as 0.08 Gy in co~nbinationwith alkylating zigcnts.
disease in childhood, G T ~ CctI Iill. IG71 did not observc
Sterility was niainly associated with alkyli~tingagents.
any diffcrcncc in gor~adalft~nctionb c t w c c ~nine~ boysand n~alcadolcscc~itswho received a gonadal dosc of
1 Gy and scvcn p;~ticntswho rcccived o ~ d ychemo79. Alicr chemothcrapy and whole-body irradiation
with a single exposure of 10 Gy, dclaycd pubertal
therapy. Six and live men, rcspcctivcly, had clcvatcd
lcvcls of follicle-stirnulatin& hormone up to cigl~tyears
dcvelopn~cnt occurred in one of 12 boys (hc also
rcccivcd testicular irradiation); four werc still
aftcr completion of trcalrncnt.
prcpubcrtal at cvaluation and scvcn boys had ~ ~ o r n l a l
78. Abnornial pubcrty and gonadotropin deficiency
pubertal devclopmcr~t [B13].Four of the boys withnormal pubcrtal dcvclopmcr~thad clcvatcd lcvcls of
have been observcd in about 10% of children irrafollicle-stimulating hormone with normal luteinizing
diated to the hypothala~nic-pituitary rcgion with 25hormone and testosterone. Anolher seven boys reccived
50 Gy over 3-4wccks [LlO,R23]. After cranial radioliactionatcd whole-body irradiation with 12-14Gy in 6
therapy for lcukacmia in childhood, varying results
fractions over three days, and five of them were still
have bcen observcd. Quigley ct al. [Ql]found eviprepubcrlal and two had achieved pubcrty, one after
dence of germ-cell damage in 25 boys who received
tcstoslcrone adminiskation. Dccg el al. [D2]observed
chemotherapy and 24 Gy in 15 fractions ovcr threethat 5 of 16 boys subjected to whole-body irradiation
weeks. Germ-cell damagc was confirmed by the abdeveloped secondary sex characteristics appropriate forsence of genn cells in testicular biopsy specimens andtheir age and 11 had delayed onset of puberty. Fortyby the small size of the tcstcs in all boys. Boys
one malc patients who were past puberty at the tinie ofrcachcd puberty at a mean age of 12 years. Plasma sex
transplantation developed primary gonadal failure andsteroids were nornlal. but the level of luteinizing
azoospcrmia. Two had rccovery of sperr~latogcncsis
hormone aftcr stimulation with gonadotropin-releasing
approximately
six ycars after transplantation, and one
hormone was elevated in pubertal children, suggesting
of
then1
had
two
normal children. Gonadal failurecompcnsation for decreased gonadal function. Sklar ct
be nearly universal after wholctherefore
appearedtoal. IS411 evaluated testicular function in 60 long-term
body
irradiation
with
10-12Gy in patients of postsurvivors of childhood acute leukacniia who had been
pubertalage.
Sandcrs
et al. IS231 studied gonadal
randomized to cranial radiotherapy with 18 or 24 Gy
function
in
90
boys
1-17
years old who had bone(n = 26), 18 or 24 Gy plus intrathecal mcthokexate (nIllarrowtransplantation
aftcr
prior chemotherapy and= 23) or 24 Gy aar~iospinalradiotherapy plus 12 Gy
radiotherapy
tothecentralnervoussystem (n = 55).
to the abdomen including gonads (n = 11). T r e a t m c ~ ~ t
Whole-body
irradiation
was
given
as
a single dose of
was dclivercd in 1.2-2Gy daily fractions, and the9.2-10Gyorfractionated
doses
of
2-2.3
Gy daily for
scattered dose in the tcstcs was 0.4-3.6 Gy after
6-7
days
to
a
cunlulative
doseof
12-15.8
Gy. Ataaniospinal radiothcrapy. Primary germ-cell dysevaluation on average four years later, 21 of the 63
function on average five ycars after cessation ofboys who werc prepubertal at transplant had dclaycd
therapy was significantly associated with type ofdcveloprnent of secondary sexual characteristics.
radiotherapy field: 55% aftcr craniospinal plus
Gonadal failure occurred in nearly all who wereabdominal field, 17% ahcr craniospinal and 0% ahcr
postpubertal at transplant.
cranial radiotherapy (p c 0.01). Leydig cell function
was unaffected in UIC majority of patients regardless of
80. Summury. The efrccki of radiation on the testis
type of radiolfierapy. Lciper et al. [LIZ]observed
arc agc- and dosc-dcpcndcnt. Radiation appears toearly puberty in five boys treated with 18-24Gy inhave its greatest effect on the germ cells rather than
10-15 fractions ovcr 2-3 weeks. The mcan age foron Leydig cells. It is difficult to draw any certain
onset of pubcrty in these children was 9 years, whichconclusions regarding the elfcct of ionizing radiation
was greater than two standard dcvia~ionsfrom theon the gonadal function in boys and malc adoiesccnts.
mean. Precocious puberty, i.e. signs of scxual maturaThe data have been obtained from studies based ontion occurring before 9 ycars, has also bcen reported
l~eterogcneousmaterials, with grcat variation in agc at[B19, L12]. Von Muchlcndal~l et al. [Vl] noted
and treatment n~odalities. Furthcrn~ore,
exposure~ ~ o r n ~lcvcls
a l of lutcinizing hormone and folliclegonadal
functionhas been assessed in many different
stimulating hormonc in 17 boys after 8-18Gy ofways. The threshold radiation dosc that will damagc
cranial radiothcrapy. Jaffc et al. [J4] evaluatedIhe germinal epithelium in childhood cannot thtrcfore
reproductive function in 27 male long-term survivors

be clearly defined at present. Tcsticular function rnay
be comprorniscd at doscs as low as 0 5 Gy. Lcydig
cell function appears more rcsisbnt to ionizing
radiation, and impaired function occurs after 10 Gy or
more. Testicular function is also impaired by chemotherapy and may also be abnonnal prior to therapy formalignancy h a t docs not involve the testis. Irradiation
to the prepubertal gonads may not always result in
irreversible damage. Whole-body irradiation has beenshown to produce primary gonadal failure of various
degrees in Lhe majority of boys receiving 10 Gy,
regardless of pubertal status. In most of these patients,
Leydig cell function appeared adequate.

E. hlUSCULOSKELETAL SYSTEM
81. Two processes of bone formation occur within
the human skeleton: membranous bone fornlation andenchondral bone formation [PlO]. Flat bones and thecortices of long bones are formed by membranous
bone formation, in which there is no pre-existing
cartilage template, and osteoid tissue is laid down
adjacent to existing collagen, cartilage or bone. In
enchondral bone formation, which is responsible forlongitudinal bone growth, new bone is formed at theepiphyseal growth plate. Chondroblast proliferation is
responsible for widening of the epiphyseal growthplate and lengthening of the bone, and osteoid isformed by osteoblasts. External irradiation affects, inparticular, dividing chondroblasts and small bloodvessels. Membraneous bone formation is disturbed toa lesser extent than enchondral bone growth. Epiphyseal irradiation causes arrest of chondrosis due to
direct effects on the cholidrocytes and secondary
vascular effects. Radiotherapy also disrupts the normal
processes of resorption of bone at the cpiphysis.
Actinomycin D and adriamycin enhance the effects ofradiotherapy (€61. Bone absorbs less radiation in the
megavoltage range than in the orthovoltage range, andit has been believed that there is less growth disturbance in bone after megavoltage therapy. However,
the major radiation changes occur in the chondroblasts
and the fine blood vessels of the physis. Since bothare materials of unit density, it is reasonable to expect
growth disturbances to be largely indepcl~derit ofradiation voltage quality.
82 The first evidence of growth disturbances
following x-ray treatment in patients under 20 years ofage was reported in 1929 by Hueck et al. [H15]. In
adults, cartilage tolerates 40 Gy over 4 weeks or >70
Gy over 10-12 weeks, and bone tolerates 65 Gy over
6-8 weeks. Higher doses cause necrosis [C24]. These
tissues are more sensitive in children, and some
growth retardation may occur after 1 Gy, dependingon the age a t irradiation and the conditions of exposure 111, TlO]. The maximum growth depression has

been obscrvcd in cl~ildrcl~
treated up to the age of 6
years I I I I ~ i n y o ~ ~ np~lbertyg[G9, P10, R25, R26).
Rocatgenographic changcs of the bone in children lessthan 1 year of age occur aftcr conventionally fractionated radiotherapy of >4 Gy, while a dose of >18 Gy
with si~llili~rfractioni~tio~lis required to produce
significant changes in children 1-2 years of age and>26 Gy is required in older children [N5, TlO]. Otherskclctal changes occur in children at doses >20 Gy,
including scoliosis, kyphosis and slippcd capital
femoriil epipllysis.
83. Growth in children can be adversely affected bydirect radiation damage to long bones and spine, malnutrition, steroid therapy, cytotoxic drugs, thc presenceof residual tumour and endocrine complications [B3,
B23, B24, B25, D17, G8, P11, P12, S20, S42, T10,
W7j. The effects of ri~diotherapyon the skeleton are
related to the anatomical site, the target volume, theradiation dose, the source and pattern of the radiation
used, the age of the patient and chemo~berapy.These
effects may be seen in any bone but are most often
observed in the spine after fractionated radiotherapy
with cumulative doscs of 20 Gy or more [P13]. The
severity increases with increasing radiation dose andwith decreasing age at'tirne of treatment. Mature bone
and cartilage may also be devitalized by ionizing
radiation without showing clinical consequences until
stressed by, for example, iufection or trauma. Prednisorle and doxorubicin depress cartilage responsivenessto soniatolnedin and also growth-hormone-stimulated
sonlatomedin productiol~ [P12]. 11 is difficult toquantify the cffects of ionizing radiation on growingbones for several reasons:
(a)

@)
(c)
(d)

there is a lack of large groups of patients ofvarious ages in whom the same epiphyseal cartilage has been irradiated with a range of doscs;
the turnour itself and other heatmcnt modalities
can contribute to the growth disturbance;patients must be followed until growth is completed;often patients with growth disturbances have
deformities corrected surgically, making it
impossible to qual~tifythe dalnage [G8].

84. Children lcss than 6 years old and at the time of
the adolescent growth spurt, i.e. duriug periods ofrapid bone growth, are especially sensitive to irradiation of the vertebral colu~nn. Impaired growth has
been observed after total doses of 25 Gy, and higher
doses to the entire spi~reresult in suppression of spinal
growtl~and decreased sitting height ID17, P10, P11,
S Z ] . Probcrt et al. [PlO] observed changes in both thesitting and stalidil~gheights o f 4 4 children heated withmegavoltage radiation, particularly among thosereceiving >35 Gy in 2-2.5 Gy fractions, whereas onlysobserved among tllose receiving
slight c h a ~ ~ g ewere
c25 Gy with sirrlilar fractionation (Figure VII). Shalet

el al. IS431 measurcd growth after radiotherapy forbrain tuniour in 37 childrcn who had reccivcd craniospinal irradiation will1 27-35 Gy to tile vertcbrac in
17-20 fractions ovcr 3-4 wccks and in 42 children who
rcccivcd cranial radiotherapy. Tllc cranial dose was not
stc~tcd.All had cornplctcd thcir growth ;it the tilnc ofevaluation, and at U~at timc thcre wcrc significa~~tdiffcrcnces between the two groups on standard dcvialion scores for standing heigl~tand sittil~gheight, but
1101 for leg length. The youngcr the child was at tllc
time of treatment the greater the subsequent skelctal
disproportion; the estimated cvcntual loss in hciglit
was 9 cm when spinal irradiation was givcn at 1 year,
7 cm whcn given at 5 years, and 6 cm whcn givcn a:
10 years.
85. Growth retardation has also been observed ina intendcd treatment ofchildrcn injccted with 2 2 4 ~ fortuberculosis of bone and soft tissue [M24, S44]. Spicss
el al. [S44] obtaincd the adult heights of 133 patients
injected as juveniles. Radium-224-induced growth
retardation was greatcst in young childrcn, who had
the greatest amount of potential growth aftcr exposure.
The growth rctardation increascd with radiation dose,
arid thcre was a 2% decrease in potcntial growth postirradiation pcr gray for averagc skelctal doses up to
20-25 Gy.
86. Functional and cosmetic disabilities involving
bone, teeth, muscle and othcr soft tissucs havc bcen
reported to occur aftcr radiothcrapy in up to 38% of
survivors of paediatric canccrs, in particular aftcr
treatment for solid tumours (D19, L16, M2, M25,
S43]. The clinically significant problems often involvebone abnornlalitics, such as scoliosis, atrophy or
hypoplasia, avascular necrosis and osteoporosis. Scoliosis may occur following radiotherapy to scgmcnts ofthe spinal column in patients with solid turnours [H16,J5, S42, S45, W8]. Scoliosis has been most apparent
in children treated with orthovoltage radiation to fields
cxtending to the midline, resulting in asymmetricradiation of the vertebrae. The dcgree of scoliosis has
increascd with dose and has been mild aftcr 20-32 Gy
and significant after higher doses [ 0 1 0 , P10, R27].
Vcrtcbral abnormalities havc bcen less pronou~~ccd
with high voltage radiotherapy and with radiation
fields encompassing the entire vertebrae, and significant scoliosis below 35 Gy is uncommon [H16, P10,
T l l ] . The cases of scoliosis that occur at prcsent areusually not s o severe that orthopaedic intervention isrequired.
87. Slipped epiphyscs can dcvelop in paticnts who
have received radiotherapy to the proxinial femoral
epiphysis, combined with chcn~othcrapy,in childhood[B26, L17, R1, S46, W9, WlO]. S i l v e n n a ~et~ al. IS461
studied 50 patients undcr 15 years of age who hadradiotherapy that included the non-fused capital

fcmoral epiphyscal plate in the treatment ficld. Mcan
dose to thc cpiphyscal plates was 23 Gy (range: 1.55 3 Gy), and 10% of the 8 3 plates at risk showed cpipl~yscalslippage or othcr severe radiographical abnormalities. Cl~ildrenundcr the age of 4 years at the timc
of irradiation wcre at higher risk (47%) than older
ct~ildrcn(5%). No complications occurrcd below 25
Gy and no dose-response curvc was obtained. A mcan
diffcrcnce of up to 12 crn in clinical length bctwccn
unirradiatcd and irradiated extremities has been
observed after 26 Gy to the cpiphyscal plates [G8].
Figure V1lI shows the relationship bctwecn age at
irradiation, dose and shortening for 20 patients who
had epiphyseal plate irradiation. Damage increased
dramatically at doses up to 40 Gy but levelled off
beyond that. Shortcning was strongly age-dependent,
amounting to 9-12 cm in several patients who wereless than 1 year old. When growth expected to remain
after irradiation was taken into account, age at irradiation did not influence h e final effect, and the radiationdose was the most important factor. Radiation-induced
aseptic necrosis of the fcmoral heads have been
observed in childrcn aftcr doses of 30-40 Gy [L17].
Chemotherapy may be a contributing factor, since
aseptic ostconecrosis has bcen reported in children
after chemotherapy alone [P14]. Slipped proximal
humera] cpiphysis has also been reported aftcr slightly
higher radiation doses than those received by childrcn
with slippcd capital femoral cpiphysis [E6]. That theshoulder is not as stresscd as the hip may be thercason why slipped proximal humeral cpiphysis is lessfrequent than slippcd femoral epiphysis.

88. Bony hypoplasia of the orbit with facial asymmetry was reported in half of 50 children with orbital
rhabdomyosarcoma aftcr 50-60 Gy in 5-6 weeks[H17]. Thc dcgree of hypoplasia appeared to be higher
the younger the child was at the time of trcatmcnt.
Other conilnon findings werc asymmetry of thc face
and/or ncck and the presence of dental problems, bothof which occurrcd in 58% of the patients. Evidence ofmuscle atrophy or fibrosis of thc subcutaneous tissues
was evidcnt in 40% of the patients in the head or faceand 33% in the ncck. Hypoplasia of bones in treatedsites was documented in one dird of the patients andjudged to bc largely due to radiotherapy. Similar lateeffects have been observed by others [E7, GlO].
89. Radiotherapy niay also have advcrse effects ondeveloping dentition, including root abnormalities,
iricomplctc calcification, delayed or arrested toothdcveloprncnt and caries [B27. D19. H18, J6, M261.
These and other maxillofacial abnormalities, such as
kismus, abnormal occlusal relationships and facial
dcformitics are more severe in patients irradiatcd at an
earlier age and at higher doses. Jaffc et al. [J6]observed dental arid maxillofacial abnormalities in
82% of 45 long-tern survivors of childhood cancer

after iiiaxillofacial radiotl~crapy.Younger patients andthose treated with higher doscs, i.c. rhabdornyosarcoma patients (median dosc: 55 Gy) as opposed tol-iodgkin's diseasc and Icukacniia patients (median
dosc: 35 Gy, p < 0.001) h:~d more severe abnonnalilies. In a study by Sonis ct al. [S47], abnor~naldental
dcvelopnicnt occurred five or niore years later in 94%
of 97 children with acute lcukacrnia treated bcforc 10
alone (n =ycars of age with intrathccal ~ncU~otrcxatc19) or in combination with 18-24 Gy c r a ~ ~ i aradiol
Ulcrapy (n = 78). All c h i l d r c ~who~ received lrcatnicnt
before 5 ycars of age and those who received radiohcrapy had Uic most scvcrc abnornialitics. Tooth
brcakagc due to tooth resorption has been comrnon
among patients injected with 2 2 4 ~ aespecially,thoseinjected iiS teenagers [S48]. The incidence of toohbrcakagc increased significantly with dosc. The tooth
fractures rcscrnblcd those observed in radium dial
painters in the Uriited Statcs lR25). Children given asingle whole-body exposure of 10 Gy for marrowtransplantation have developed similar disturbances indental development and facial growth similar to thoseseen after 18-65 Gy fractionatcd radiotherapy to themaxillofacial region for Icukacniia or solid tumours[D20,
S2.51. The most scvcrc effects have bcen seen inchildren irradiated when they were less than 6 ycars ofage.
90. Anthropomctric analyses were performed in 1990
on children living in Russia, Belarus and Ukraine at
the time of the nuclear plant accident in Chcrnobyl in
1986, and in children born in 1989 [HI. The main
conclusion horn these studies was that there were no
significant differences in height or weight between thecontrol and contaminated regions.
91. Summary. Growth in children can be adversely
affected by direct radiation damage and by malnutrition, other treatment modalities, the presence ofresidual tumour, and endocrine late radiation effects.
Most clinical data arc based on small and hctcrogeneous groups of patients treated in different ways atvarying ages. The skeletal eflccts have also beenassessed in a variety of ways, and i t is not possible togive any estimates of latc deterministic effects basedon large-scale epidcniiologic data. Skeletal changes inchildren generally occur at doses exceeding 20 Gy andinclude scoliosis, kyphosis, slipped femoral cpiphyses,
hypoplasia, growth retardation, dcntal problems etc.
Absolute shortening of the long hone depends on theabsorbed radiation dose and the age at the tinie of
irradiation. Exposure at ages less than 6 ycars andduring puberty appears to have h e greatest effect on
growth retardation. However, other studies haveobserved that whcn growth expected to occur after
irradiation was taken into account, Lhe age at irradiation did not ir~fluencethe final effect, and h e radiationdose was then the most important factor. Scoliosis andkypllosis arc conimon alter spinal or flank irradiation
followi~lgdoscs of >20 Gy. Slipped fcn~oralcapital
epipl~ysisdocs not occur bclow 20 Gy, and this latc
effect is more c o n ~ n ~ oillt ~cl~ildrenunder 4 ycars ofage a1 dlc ti~ncof irradi:~tion.A dose exceeding 20 Gy
is rcquircd to arrest cncondral bonc lormation, anddoscs ol' 10-20 Gy cause t l ~ cpartial arrest of bone
growth. Tllcrc is little altcr;~lionin bonc growth below
10 Gy of fractionated exposure directly to the bone.
No radiation-related effect on height has bcen
obscrvcd in cl~ildren living in Russia, Belarus or
Ukraine at the time of tllc Cllcn~obylaccideat.

F.

EYE

~g
chcn~othcrapy and cortico92. l o ~ ~ i z i rradiation,
stcroids have all bcen found lo increase the risk ofcataract formation [C20, H19, 11, 011, P15,S49, U3].
Different cornporlents of the eye have different sensitivity to ionizing radiation, ilnd the lens is especiallysensitive whcn uniformly irradiated. There are difrercnt forms of cataract, and radiation-induced cataract isin its early stages a characteristic lesion, which isdefined as a posterior subcapsular opacity. The threshold dose for cataract in adults is about 2 Gy of x raysfrom a single exposure and 4-6 Gy when fractionatedover 3-13 wecks [ F l , M271. Minimal stationary opacities have been obscrvcd after single doscs of 1-2 Gy,
and with 5 Gy more serious progressive calaracts
occur [U3]. The threshold dosc for cataract formation
is increased by non-uniform irradiation [B28]. Higher
radiation doses yield more progressive cataracts witha greater loss of vision. The average latent period is
2 ycars but lnay be up to 35 years. The combinationof radiotherapy and chemotherapy enhances the risk
for cataract for~iiation[F7]. Other late radiation cffects
in the eye include retinopathy, optic neuropal~yandlacrimal gland atrophy. These types of injuries rarely
occur below 45 Gy.
93. Dccrcased vision due to cataract formation in theircated eye is commolr ia children treated for orbital
rhabdomyosarcoma after doses to thc tuniour of 5060 Gy in 2 Gy fractiol~sover 5-6 weeks [H17]. The
time to first reported evidence of cataract varied from
one to four years after radiotllcrapy. Otber reported
structural late eKects include changes in the cornea orr c t i ~ ~cnophthalmos,a,and stenosis of the lacrimal duct.
[Q2] estimated
94. Qvist and Zacllau-Christia~~sc~~Ihe ~niainiu~nlenticular dosc to produce cataract inchildrer~to be 13.8 Gy from radium moulds; the maximum non-cataract dose for infants was 9.9 Gy and forschool-aged children, 11.4 Gy. Notter ct al. [N8]observed cataracts after considerably lower doses in
234 patienLs who had been irradiated will1 2 2 6 ~ a containing applicators for skin hacmangioma between

1920 and the mid-1950s. An ol)l~thal~~~ologic
examination was conducted in 1961-1965. Of 468 cycs
examined, cataract was observed in 5 1 (1 1 Ti). No
cataract was obscrvcd i n Ihc 246 cycs rcccivi~~gc2.5 Gy in the Icns. The prrvalencc of cataract was
8% (100 eycs) aftcr ;I Icnticular dosc of 2.5-3.5 Gy
and 54% (122 eycs) aftcr higher doscs.
95. Stcfani et al. [S37, C25] rcportcd on the devclol)mcnt of cataract in 899 patients rccciving multiple
injcctions of 2 2 4 ~ afor the intcndcd trcat~ncnt oftuberculosis or ankylosing spoadylitis. Cataracts were
found in 6% of the 218 juver~ilcpatic~~ts
and in 5 % of
the 681 adult patients. In those with known injected
activities, juveniles recciving >1 MBq kg-' of 2 2 4 ~ a
had a cataract incidence of 14% (11 of 80) compared
to 0.8% (1 of 131) rccciving lcss than that amount.
The cataract incidence increased significantly withdosage in both juveniles and adults.
96. The dose received by the lens in cranial radiotherapy for acutc lcukacmia is of importance for the
induction of cataract [KIO]. The dose to the lens isapproximately 15%-30% of the midline dosc, depending on the type of treatment fields. Ncsbit ct al. IN31
found one case of posterior subcapsular cataracts in 50
survivors of childhood acute Icukaernia. In contrast,
lnati ct al. (131 observed a 50% incidcncc of cataract
formation in 69 children with acutc Icukaemia given
24 Gy cranial radiotherapy in 13 fractions over 2.5
weeks, intrathccal nicthotrcxilte and high doscs ofsteroids. All cataracts wcre sn~alland did not impair
vision. In another study of 34 long-term survivors of
acute Icukaemia, all 18 patients in the non-irradiatedgroup had normal results in eye examinations, while
4 of 16 of those receiving 24 Gy to the whole braill in
1 2 fractions over 2.5 weeks had ocular abnonnalitics[ W l l ] . None of the ocular findings could, however, bedefinitely attributed to radiation, and all patients had
normal visual acuity.
97. Posterior subcapsular cataracts occur in the great
majority of patients aftcr 10 Gy of single whole-body
exposure but in only about 20% after 12-15.8 Gy of
fractionated exposure [A14, B13, CEI, D21, L23, S24,
V7]. Among 105 paticnts givcn 10 Gy single-dose
whole-body irradiation, 80% developed cataracts by
six years compared to 19% of 76 patients givcn fractionated whole-body irradiation (12-15 Gy in 2-5 Gy
fractions over 6-7 days) and 18% in patients who did
not receive radiotherapy [D2]. This last figure indic.g. steroids orcates that factors other than irradiatio~~,previous treatments may have contributed to thedevelopment of cataracts. Nearly all cataracts
developed after a singlc exposure need to be removcd,
whereas a smaller fraction of those dcvcloped aftcr
fractionated exposure require removal.

98. 111 ii study conducted among subjccts of the
Adult Hcalth Study of Hiroshi~naand Nagasaki, a significant excess risk for postcrior subcapsular changcs
was obscrvcd for all ages in the group receiving >3 Sv
ia conip;iriso~~with tl~osein the control group amorlg
rcsidcats in Hirosl~inl;~
but 1101in Nagasaki [C21 1. The
study w ; ~ sbased on Ihe T65 dosimetry and the cxaniination was conducted 011 2,385 persons. The relativerisk of cataract for pcrsons in Hiroshima exposed to>3 Sv was 4.8 in persons under age 15 years at thetime of the bombings, 2.3 in pcrsons 15-24 years at
the time of the bombings and 1.4 in pcrsons more than
25 years at the time of the bombings. The relative riskfor postcrior subcapsular changcs in Hiroshima for
pcrsons under age 15 ycars at the time of the bombings was 2.8 in the 1-1.9 SV group, 4.3 in the grouprccciving 2-2.9 Sv and 5.3 in the group recciving >3
Sv. A con~parisonof relative risks in the different age
groups suggested a stronger effect in Hiroshima for
persons under age 15 years at the time of the bombings. These results support h e hypothesis that younger
individuals are more sensitive to radiation-induced
cataract than oldcr individuals. A more recent assessment of the dose-effect relationship for cataract
induction has been made using the DS86 dosimetry
systcni 1015, 016). This new study confirms the previous findings of a higher sensitivity in young persons.
The magnitude of log relative risks for cataracts in
pcrsons aged 40, 50, 60 and 70 years at the time of
examination was 8.2, 6.4, 4.6 and 2.8-fold highcr,
respectively, than in pcrsons aged 80 ycars at the timeof examination. The bcst-fitting rclationship for
posterior postcapsular changes suggested a linearquadratic dose-response.
99. Summary. The available data on radiationinduced cataract formation in adults suggest a sigmoid
dose-response relationship with an apparent threshold.
This threshold varies from 2 to 5 Gy aftcr x rays andgamma rays given as single exposure and is about
10 Gy for doscs fractionatcd over a period of months.
Data on radiation-induced cataracts in children are
scarce and are based on small groups of patients
rccciving different treatment niodalities. Cataracts havebeen reported aftcr 24 Gy cranial radiotherapy forchildhood leukac~niaresulting in 5-7 Gy in the lens.
Cataracts have been obscnred after 2.5 Gy or more inh e lens, and in one study the prevalence of cataract
was 8% (100 eyes) aftcr a lenticular dose of 2.53.5 Gy. Whole-body exposure of I 0 Gy in childhood
has also been associated with cataract formation in theniajority of cases, wlicreas fractionatcd wholc-body
irradiation with 12-15.8 Gy is associatcd with cataract
in about 20% of the patie~lls.Cataracts wcre observedin the survivors of the atomic bombings in Japan
exposed to >3 Gy, and the risk for cataract was higher
in persons lcss than age 15 years at the tin~cof tile
bombings than in persons oldcr than that.

H92

UNSCFAR 1993 REPOI1'T

100. Ionizing radiation affec~ssmall and large vcssels
within the treatment field, and changes may develop
within months and up to two decades after radiotherapy [K2]. The main chitngcs tbat occur consist ofpremature athcrosclerosis with vascular occlusion. The
heart was formerly thought to be relatively resistant toionizing radiation. The increasing use of radiotherapy
to the mediastinum, however, has been associated withwell-documented instances of cardiac abnormalities.
Late effects following radiotherapy have been reported
in both adults and children and usually occur as
cardiomyopathy, coronary artery disease, pericardial
effusions or constrictive pericarditis [A15, B29, 830,
D17, G11, G12, K11, L1, P9, R28, T9].Interstitial
myocardial fibrosis and coronary artery changes havebeen reported after 30 Gy, and pericarditis has beenreported after 15 Gy [B29, G12, K12, M28, M29). In
children as well as in adulb, a dose of 40 Gy to theheart appears to be the critical dose for clinicalcardiomyopa thy.
101. The incidence of post-irradiation pericarditis
increases with dose and fraction size [SO]. In patients
irradiated for Hodgkin's disease, the frequency ofradiation-related pericarditis correlates with thepericardial dose [C22]. C a m e l and Kaplan [C22]found a 7% incidcnce of pericarditis after doses<6 Gy, 12% after 6-15 Gy, 19% after 15-30 Gy and
50% after >30 Gy. Symptomatic pericarditis may first
appear as late as 45 years after therapy [B29, G13,
H20, K12, S.511. Kadota et al. [K12] evaluated cardiopulmonary function in 11 children who received radiotherapy for Hodgkin's disease with a mean dose of
36 Gy (range: 20-55 Gy) with conventional fractionation. Mean age at radiotherapy was 11 years, andevaluation was performed, on average, nine years
later. Ten patients had no clinical evidence of
cardiopulmonary dysfunction, and one had constrictive
pericarditis. Four had thickened cardiac valves on
echocardiography, without significant stenosis orinsufficiency. Only three had normal cardiopulmonary
function, and the others had one or more abnormal
tests.
102. Makinen et al. [M30] evaluated cardiac sequelae
in 41 individuals who had received chest radiotherapy
or doxorubicin for childhood cancer at a median of 17
years earlier. Radiotherapy had been used in 21
patients, and in 13 of them irradiation was directed at
the heart witb doses of 12-60 Gy in 8-30 fractions
over 12-47 days. Of the 41 patients, 20 (49%) showedsome abnormality in cardiac tests (e.g. abnormal ECG
or echocardiogram, reduced exercise capacity), andeach additional year of follow-up was associated witha 1.3-fold increase in pathologic cardiac findings. The
risk of an abnomlal cardiac test result in the 13

patients who had received radiotherapy to the hcart
was 12.8 tiales the risk for other patients (95% CI:
1.8-90.8). No dclailcd analysis of the effect of radiotherapy wils presented.
103. T l ~ eii~~tl~riicyclincs
doxorubici~iand daunoniycin
are cardiotoxic and may cause electrocardiographic
cl~arlgcsand congestive heart failure. There is a doseresponse rclatio~ishipbetween the total dose of anthracyclincs and cardiomyopathy, and children appear to
be more susccptiblc to drug-induced cardiomyopathy[P16, P17, S52, V3, V4]. Several studies have shownthat mcdiastinal irradiation enhances the myocardial
toxicity of antbn~cyclines[B31, G14, M31, P16, P181.
Gilladoga et al. [GI41 observed severe cardiomyopatl~ywith congestive heart failure in 16% of 50 children
receiving adriamycin and in 3 % of 60 children recciving daunomycin. Four of 8 children who also had incidental cardiac irradiation prior to or during adriamycin
administration had severe cardiomyopathy. In contrast,
Von Hoff ct al. [VS] observed a lower risk of cardiomyopathy for children than for adults at any given
cumulative doxorubicin dosage.
104. S ~ t n m a r y .Radiation exposures cause occlusionof both sniall and large blood vessels. Cardiac abnormalities have been observed particularly following
irradiation of the mediastinum. Patients may haveabnormal cardiac function without clinical evidence ofsuch dysfunction. Myocardial fibrosis has occurred
after 30 Gy. The few data available suggest that 40 Gy
with converitiorial fractionation can be considered asa a i ~ i c a ldose for clinical cardiomyopathy in bothchildren and adults. The anthracyclines are cardiotoxic
arid enhance the effects of mediastinal irradiation.

105. The lung is the most radiosensitive organ in Lhethorax. The mechanism for respiratory damage inyoung children may be different from tbat in adults orin adolcsccnts. Specific radiation effects in children can
include the impaired forn~ation of new alveoli or
failures in tlie development of the thoracic skeleton arid
thus a reduced size of the lung (B32, R17]. Interstitial
fibrosis of the lung, resulting in decreased total lungcapacity, vital capacity and diffusion, is a late effectthat has been observed in adults after d a e s of >30 Gy
and above [D22, H21, L l , L18, M18, M32, S54]. The
effect i n children appears to be similar for the same
dose and fractionation schedules [D17, S53, T9,W121.
Children younger U~an3 years a1 Ule time of treatment
may be at higl~errisk for lung dysfunction (M32j. The
effects depend on the target volume and on the concurrent use of chemotherapy [W13]. Interstitial pneumonitis and pulmonary fibrosis have also been reported
after chemotherapy in children and adults (A16).

106. Restrictive lung volun~cwith total lung capacity
bctwccn 62% and 80% of normal capi~cilywas rccordcd aftcr trcatlncnt for Hodgkin's discasc in 5 of
11 paticnts (nlca~rage: 1 1 years) who rcccivcd 111al1tlc
licld radiothcrapy with 20-55 Gy [K12]. Six childrcn
had rcduccd cxcrcisc tolcraucc, n~anifcstcdby rcduccd
rnaximum oxygcn uptakc (<65% of prcdictcd) arid
cxcrcisc duration (<75% of prcdictcd). Millcr ct al.
[M32] observed reduced forccd vital capacity and/or
total lung capacity in half of 29 childrcn with childhood canccr. Thc incidcncc of pulmonary dysfunction
was high in both irradiated childrcn and in individuals
who did not rcceivc radiotherapy to thc thorax.

107. After fractionated pulmonary radiothcrapy for
Wilms' tumour at age 2-4 ycars with a lung dosc of
20 Gy, children may dcvclop dyspnoca and cvidencc
of interstitial and pleural thickening on chcst x-ray
examination up to 14 years after treatment [W14].
Mcan total lung volumcs may bc reduced by approximatcly 40% after such radiothcrapy owing to effects
on lung growth and on chest wall growth. Restrictive
lung changes aftcr fractionated radiothcrapy with 1114 Gy to thc wholc lung have bccn rcported in othcr
studies of children with paediatric tumours [B32, L191.
Benoist et a]. [B32] studied the effects of whole-lung
irradiation on lung function in 48 childrcn treated forWilms' tumour with pulmonary metastases. The mean
age was 3 years, and all paticnts reccivcd fractionatedradiotherapy with 20 Gy bilateral pulmonary irradiation over three weeks plus actinomycin D. Greatly
reduced sagittal and frontal thoracic diamctcrs wereobserved in nearly all of the cases 3-4 years aftcr
radiotherapy. Lung volun~esand dynamic lung compliance and functional residual capacity decreased withtime. Static pressure volurt~ccurves, blood gases andcarbon monoxide transfer were normal, making it unlikely that post-radiation pulmonary fibrosis wasinvolved.
108. Littman ct al. [L19] cvaluatcd pulmonary
function in 33 paticnts trcated for Wilms' tumour andfollowed for up to 20 years aftcr diagnosis. All but
five childrcn received at least one course of actinomycin D. Eightecn childrcn who did not receive lung
irradiation had normal pulmol~ary function. Radiotherapy was givcn to 10 children for pulmonary
metastases and to 5 childrcn as prophylaxis with alung dose of 12-14 Gy and varying fractionations.
Patients trcated for lnetastases Iliid findings suggeslivc
of moderately reduced lung volumes, whereas patie~~ts
recciving prophylactic trcatmcr~lhiid esscl~tiallynonn;~llung volumes. Vital capacity and functional residual
capacity were significandy lower i n the irradiatedgroup of patients than in the non-irradiated patiellts.
Residual volume was lower in the irradiated group as
was forced expiratory volume. The fact that patierlts
who were treated for metastatic disease had greater

ab~~orlnalities
ill pullnonary funclio~~
than those irradiated for prophylaxis suggests that the prcscllce ofmctas~atic~ ~ o d u lande s additional lung t r c a t n ~ c ~could~thave aggravatcd the cffccts.
109. Two studics did not obscrvc any i ~ i ~ p a i n ~ lof
cl~tlung fu~~ction
in paticnts 15 ycars old or lcss after
wholc lullg irradiation with 20 Gy in 1.5-2 Gy Gactions livc tin~cspcr week [B39, Zl]. According toMargolis ct al. [M34], the n~aximurnsafc dosc to thc
wholc lung for paticnts receiving aclinonlycin D is
15 Gy in 1.5 Gy fractions. Howcvcr, doses lower &an
that may affcct pulmonary function. Wohl ct al. [W14]reported that total lung capacity averaged 71% of the
cxpcctcd valuc in six childrcn treated with fractionatedand bilateral pulmonary irradiation for Wilrns' tumourand evaluated more than scven ycars later. Thc exposures at the midplane of the cl~estranged from &1 2 Gy dclivercd ovcr an average of 11 days. The totallung capacity for cight children receiving no radiotherapy was 94% of the expected value. Springmeyer
ct al. [S53] found rcstrictivc ventilatory changes in 79
patients with haen~atologicmalignancies or aplastic
anaemia one year or more after bone marrow transplantation. There was a mean loss in total lungcapacity of 0.8 and in vital capacity of 0.5, but thcsechanges were not significantly associated with wholebody irradiation.
110. Surnmary. The lung is a radiosensitive organ,
and radiotherapy during a period of lung growth andchest wall growth primarily results in a reduction of
the subsequent size of both lungs and chest wall.
Respiratory damage in young children is rnorc scvcre
than in adults at the same doses. The effects dependon the targct volume and concurrcnt usc of chemotherapy. Interstitial fibrosis may occur 6-12 rno~iths
after absorbed doscs to the lung of 30 Gy or more. A
lung dose of 15 Gy in 1.5 Gy fractions is generally
considered as the rnaxi~nurn safe dose in childrcn
rcccivi~~gradiothcrapy to the whole lung and simultaneous treatment with actinornycin D. Howevcr, rcslrictivc lung changes have b c c ~reportcd after doscs of
11 Gy or more in childrcr~ trcatcd for paediatrictumours, arid rcduccd total lung capacity has beenfound after 8 Gy or more to the wholc lung withsimilar fractionation.

I.

BREAST1 1 1. Breast dcvelol)~nc~~t
is rcadily i~ihibitcdhy radiotherapy in infancy, and scvcre hypoplasia of brcast
tissue has bccn rcportcd i n women having a history ofbreast irradiation in childhood [D19, F8, F9, G15,
H22, K13, U l l ] . Breast hypoplasia or aplasia havealso bccn notcd as sequclae after radiothcrapy for
pacdia~rictumours i n childhood [F8]. The knowledge

894

UNSCEAR 1933 Rli1'011'1'of dose-cffrct pattcnls is scarcc 111, 151. Moss [M35]statcd Illat an cxposurc giving a ski11 dosc of 15-20 Gy
ovcr cigl~ldays would ilnpair hrcast dcvcloptnclrl.
Accordiag to Rubill ct ;!I. [R2], a dosc cxcccding
10 Gy to thr prrpubcrtal fcln;rlc brcast of cot~vcntior~ally Sractiol~:~tcd
x-ray tltcriipy 111:ry rcsult i l l t l ~ cabscl~cc of brcast dcvclopnrclrt i l r 1963% of tllc
paticl~~s.
112. Fiirst ct al. IF91 studicd thc l)rcvalcr~ccand
dcgrce of brcast hypoplasia ill 129 womcn irradiatcd
in infalrcy or childhood for hacniangioma in the brcast
rcgion. The patients wcre trcatcd in 1934-1943 at anagc of 4 ycars or lcss. Radiotherapy was n~aitrlygiven
with applicators containing 2 2 6 ~ awith, flat applicalors
or ncedlcs and/or tubcs having hccn uscd. Mcan absorbed dosc to Urc brcast anlagc for t11c wholc cohort
was 2 3 Gy (rangc: 0.01-18.3 Gy). Brcast asynimctry
was estimated by rcsponscs to a mail questionnaire to
all paticnts and by the clinical cxaniinatiorr of 53
paticnts living in Stockholm county. Brcast hypoplasia
on the trcatcd sidc was reported by 57% of thepatients and on the contralatcral side by 8%. Amongwonicn reporting a smallcr brcast on thc untrcatcd
side, the nican dosc to thc trcatcd brcast was 0.5 Gy(range: 0.01-1.0Gy). In 28 of thc 5 3 clinically
cxamined patients, breast hypoplasia excccdir~g10%
was found on the trcatcd sidc, and five paticnls had
hypoplasia of more than 10% on tlrc contralatcral sidc
(Figurc IX). The Iicqucncy and t l ~ escvcrity of impaired brcast dcvclopmcnt itrcrcascd with tllc radiatio~rdose. In this study, the possibility of a tl~rcsholddosc
for radiation-induccd breast hypoplasia could rrcithcr
be established nor rulcd out, and thc rcsults suggcstcd
h a t the available risk cstiniatcs for brcast hypoplasia
underestimate Lhc cffcct 111, R21. At lowcr doscs, thedosc-cffcct relationship nlay bc c o ~ r f o u ~ ~ dbyc dnormal
variations in brcast size. At highcr doscs and withlargcr fields than wcrc uscd in thc Swcdish study,
Lhcrc may also bc a radiation cffcct OII tllc chcst wallwith subscqucrrl growth impairrnenL
113. Summary. Tllc scnsitivi~yof brcast tissue in theirradiatcd child is rccognizcd, with low Urrcshold doscs
for thc occurrcrtcc of clilrical cffccb. Onc study hasrcportcd that hypoplasia occurs in niorc than 50% ofchildrct~trcatcd with radiothcrapy at lcss that1 4 ycars
of agc with doscs to thc brcast of thc ordcr of 2 Gy.
Highcr doscs cause inocascd incidcncc ; I I I ~scvcrity of
impaired brcast dcvclopnic~~t.

114. Late radiation effects ol'thc gas~ro-intestinal tract
dcvclop n~onthsor ycars aftcr cxposurc alrd include
fibrosis, stricture, intestinal pcrforatiolr and fistula
formation [RI]. The liver appears to h a w a low thres-

hold for 1;itc injury, and ill adults vcno-occlusivc
discasc has I)cct~obscrvcd aStcr sitlglc doscs of 10 Gyor 18-30 Gy wit11 co~rvc~rlionirlfraclionatiolr [FlO].
T l ~ cd i ~ ~ u ; ~isg cduc to cl~;~ngcs
that il~tcrfcrcwith~uitosisill t l ~ cirr;~diatcd l i ~ l ) i ~ t ~ andc y tto~ ~vascul;~r
clr;~ngcs I l l ] . R:~dialio~r-iliduccd livcr disci~se isclrs l.:~ctcrizcdstructur;llly Ily progrcssivc fibrosis andobliteration of ccntral vcins, possibly by injuring
prcCcrcnti;llly tllc cndotl~clial cells of ccntral vci~is[FIO, L20j. Vcno-occlusive discasc nlay also bc
caused by ;~l~tincopl;istic
drugs, and hepatic fibrosis
has b c c ~obscrvcd in childrcl~receiving cl~cmotherapy[M36, N6j.
115. Tllc risk for radiatiolr-ioduccd livcr datrragc incrcascs wlrel~I;lrgc volui~icsof the liver arc irradiatcd
or w11c11t l ~ clivcr is irradiatcd aficr rcscction. A largcr
dose caa bc tolcri~tedif ot~lypart of thc livcr is cxposcd [FI, 16, K14]. In children, Tcfft ct al. IT131
aftcr radiothcrapy to the livcr
notcd livcr abeor~n;~lilics
with doscs of 12-30 Gy. This could be rclated to thegrcatcr sensitivity of thc younger child, who gcrrerally
also rcccivcd the lowcr doscs. Tbomas ct al. [ T l l ] observed livcr fibrosis i t ~3 of 26 long-term survivors of
Wil~ns'tunlour wlio had rcccivcd at lcast 30 Gy to thelivcr in 1.5-2 Gy fractions. Hcpatic discasc, ranging
froni abnormal livcr cnzylnes and thrornbocytopcnia todeath, has ;ilso bccn rcported by othcrs [S45, T12].
116. Hepatitis followi~~g
irradiation and chcniolhcrapy
at doscs and volurncs of irradiation ordinarily considercd within tllc tolerance of hepatic function has
bcen rcporlcd [K15]. Fatal livcr damage occurrcd in a
13-year-old boy who had received adriamycin bcforc
and during radiothcrapy of 24 Gy ie 17 fractions ovcr
28 days to thc uppcr abdon~crri~rcluditrgthc entire
livcr. A 13-year-old girl had modcratc clil~icallivcr
changcs Sollowing 25 Gy in 23 fractio~lsovcr 3 2 days
witlr adri;~t~~ycilr;itl~ninistcrcdbeforc and during irradiation. 111 this cast niuch of the rig111 lobc wasshicldcd during r;rdic~tlrcrapy.Aboul 20 patients havc
bccn rcportcd to havc dcvclopcd liver discasc aftcr
fractiollatcd radiotl~crapywith 12-40 Gy to t l ~ clivcr inchildlrood togcll~cr with chc~nothcrapy [J7j. Most
paticnts wcrc asylnptomatic, and U~circo~rditionwas
discovcrcd bcc;tusc of hepatomegaly or abnor~iialitics
shown ia a routil~clivcr scil~~igrain.
When hepatitis isobscrvcd following radiation cxposurc, cspcially if
exposure is rcccived i n conjunctio~r with clrclnoIhcr;lpy, it is ilnportanl to ~loteLhat not o111y 1)ostirr;.diatioe cffcck but illso toxic and il~fcctious
colnplicirliolrs rcquirit~g approprialc tlrcra1)cuticprol)l~ylarticIrlc;lstlrcs will occur.

117. n r c stnil11 il~tcstirrehas a high radiosc~rsitivity
but is Sorrrcwl~atsparcd by its mobility. Thus, rcpcatedcxposurc of' a particular scglncnt is avoidcd. This is1101 t l ~ cc;isr for t l ~ crcctuln, which is fixcd to adjaccl~t

tissucs ilnd conscquc~~tly
c x l ~ c r i c ~ ~ ctbc
c s cffcc~$of
to scvcri~lyc;lrs after cxposllrc [ F l , K16, L21, M38,
[I-111. 111adult.., t l ~ crisk 01'
radiation niorc frcquc~~tly
M39. U l ] . Thc critical dose for thc kidncys ill adults
snlall l)ou.cl con~plicatio~~sdcl>cnds(III radi:~tiondosc,
is usually sct at about 23 Gy ovcr l'ivc wccks. Rubill
volunnc of bowcl irradi;~tcdand fractionatio~~scl~cdulc.
IR3] s~~ggcstcdthc critic:~l dose for 5% chronic
Surgcry incrcascs thc risk of dcvcloping radiation~~rphrosclcrosis
to be 20 Gy with convc~~tional
fraccntcropatby. The ~nanifestations of latc rl1di.t'$1 1011
results frorn lcsionis oftio~latior~.
Radiatio~l~~cl)liritis
cntcropathy arc considcrcd to bc duc m a i ~ ~ ltoy vastllc tubulcs and ~nlicrovasculaturcof thc kidney. Radiacular and conncctivc tissue damagc. Magc ct al. [M37]tion injury to largc and mcdium-sizcd artcrics can alsorcportcd late gastro-i~~testin;~lcffects i l l 17 c h i l d r c ~ ~ rcsult i l l stenosis or occlusior~[h138]. The scvcrity of
rccciving abdominal fractionatcd radiothcrapy with 30radiation injury sccms to be a function o f t h c radiation
dosc and thc sizc of tllc vcsscl. L ~ r g c rdoscs and55 Gy. Stcnosis, subn~ucousi~lfiltrationsand nlcscntcrs~nalicrvcsscls arc rnorc likcly to end in total occluitis wcrc obscnrcd 2-13 nio~ltllsaftcr radiothcrapy. No
sion, wl~crcaslargcr vcsscls or sniallcr doses result in
dctails of thc radiothcrapcutic rcgi~ncnswcrc b'.IVCII.
Thc combincd cffects of r:~diation dainagc to t l ~ cstcnosis or hypopl;~siaof thc vcsscl. Children arc morc
susccptiblc to vascular injury, bccausc of thcir small,niucous mcnibranc and cxaccrbation of alrcady cxistgrowing arteries and rclativc scnsitivity to a givcn
ing gastro-intestinal infcctio~~scan cause pcrforationdose of radiation. Radiation injury to the rcnal artcry
and ulceration.
niay produce a rcnovascular hypcrtcnsior~,which can
bc distinguished from the more common radiation
118. Donaldson ct al. [D23] rcvicwcd latc r;~diation
nephritis.
cffects in the gastro-intcstinal tract of 44 children
receiving whole abdominal radiothcrapy for lym121. Rcnal injury is rtiore sevcrc in childrcn, and thcyphoma, Wilms' tumour or tcratoma. Of 14 long-lcrm
have limited tolerance for combined chcmothcrapy andsurvivors, 5 dcvclopcd scvcrc radiation injury withradiothcrapy. A nor~nsl crc;~tinine clearance andsmall bowcl obstruction wiUli11two ~nonthsaftcr comglomcrular filtration ratc may be anticipated bclow apletion of radiotherapy. Their mean agc at the lime offractionatcd dosc of I 5 Gy whcn actinomycin D istherapy was 6 ycars, and the abdominal dosc was 31
uscd c o ~ ~ c u r r c ~ but~ t l yprogrcssivc,
renal insufficicncy
Gy (rangc: 10-40 Gy) dclivercd in 7-20 fractions ovcr
occurs after doscs of 20 Gy and morc [JS]. However,
11-39 days. Surgery contributed to the prcscncc ofradiation nephritis has been rcportcd 20 ycars after
abdominal adhesions and fibrosis.
14 Gy to the kidney in childhood 10121. Reduced
crcati~iirlcclearance has been found in 18% of 108
119. Summary. The risk of radiation-induced liverchildrcn who undcnvcnt nephrccloniy for nlaligna~~tdamage increases with increasing volume of the livcr
disease and rcccivcd < I 2 Gy to the remailling kidncy
inadiatcd and after liver resection with regencrating
and in 33% among those rccciving 12-24 Gy [M33].
livcr tissue. Some data suggcst that cl~ildrcnarc nlorc
In anothcr study, Lcvitt et al. [L24] obscrvcd thatsensitive to such late effects than arc adults. Livcr
childrcn with Wilms' tumour and less than 2 ycars oldabnormalities have bccn obscrved aftcr 12 Gy with
convcr~tional fractionation and oftcn in c o ~ ~ i b i n a t i o ~ ~who rcccivcd chcmothcrapy with > I 2 Gy to the rcmaining kidney had a worse rcnal prog~~osisthan othcr
ri~diation-induccdhepatitis
with chcmothcrapy. Cli~~icalchildrcn. In children cxposed in itrero in Hiroshinia
has rarcly bccn rcportcd at doscs bclow 30 Gy in 0.9and Nagasaki. urinary cxami~~ation
rcvealcd transient
1.0 Gy fractions fivc times per wcck. Casc-reports
proteinuria, which was not found in adults [Fll].
have presented data on livcr damage in cl~ildrcnaflcr
24-25 Gy in 1.1-1.4 Gy fractio~~swith
concomitant usc
122. Radiotherapy for Wilms' tumour has also bccn
of anthracyclines. Radiation cffccts in the gastro-intcassociated with latc cffccls in the kidllcy [A17, K16,
stinal tract include fibrosis, stricture, pcrforation andM40, V61. McGill ct al. [M40] rcportcd post-irradiaformation of fistulac. Thcrc arc hardly any data availtion rc~~ovascular
hypcrtcruion in a boy who received
able on such cffects in childrcn.
chcmothcrapy and fractio~~atcdradiothcrapy with
30 Gy to the abdo~ncnat Lhc agc of 9 lnol~thsand ia
anothcr boy 14 montl~sof agc who reccivcd 51 Gy to
K. KIDNEY
tllc abdonlc~~.
Scvcrc l~ypcrtc~~siorl
dcvclopcd 6-8 ycars
later. Koskimics [K16] rcportcd lhrcc p a t i c ~ ~agcdb120. The urinary system shows a wide rangc in radiosensitivity, with ihc kidney bcing thc most s c ~ ~ s i t i v c 1-2 ycars with Wil111s' tumour who dcvrlopcd I~ypcrtcnsion more than 10 ycars after rccciving >36 Gyorgan, the bladder htiving an intcni~cdiatesensitivity
postopcrativcly to rhc tumour area. Thc hypcrtcnsion
and the ureter bcing niorc resistant, although the fullwasco~~sidcrcd
to be of rc11;11origin for d ~ r c crcasons:Icngtl~ is scldom irrediatcd [Ul]. Late radiation
thelikelil~oodofrenal damage was supported by grosssequclac of thc kidney are directly rclatcd to the total
macroscopicchangcsin the nearby organs: twodose to the tissuc and are charactcrizcd by tissue
patienb
hadprotcirll~ria
i~ldicatingrc11:11dami~gc;andr~ccrosisand librosis, which rnay occur a few months

other causes known to cause secondary hypertension
had bee11 excluded. In another study of 14 patientswith Wilms' tumour evaluated at a median of 17 years
later, four had elevated diastolic blood pressure andtwo had mild proteinuria [B33]. That study provided
no data on the radiothcrapy. Arncil et al. \A171
reporled ncphritis four months aftcr surgery in twochildren aged 2 and 5 years who received actinomycin
D and vincristine followed by 15-20 Gy to theremaining kidney fractionated over 2-3 weeks.

123. Radiation nephropathy is common after wholebody irradiation for bonc marrow transplantation [T3,
V8]. After 12-14 Gy in 6-8 fractions over 3-4 days,
the child may develop anaemia, haematuria andelevated creatinine. This renal insufficiency is due
both to the radiotherapy and to the chemotherapeutic
regimens employed.
124. Summary. Late effects following irradiation of
the kidncy include nephritis, tissue necrosis andfibrosis, renal dysfunction and hypertension.
Available-data do not indicate that children are more susceptible
to radiation-induced renal injury than adults. Radiation
nephritis has been reported after fractionated doses of
1 4 Gy, and decreased aeatine clearance has occurred
after doses around 1 2 Gy. The seemingly higher
sensitivity among children can probably be explainedby the combination of radiotherapy and chemotherapy,
which can enhance the side-effects in the kidncy [R3].

L. BONE MARROW
125. Few studies have bccn performed to determine
tbe long-term deterministic effects on bone marrow
function after exposure to ionizing radiation in childhood, and most available data refer to exposure inadulthood. Rubin et al. [R29] studied the repopulation
and redistribution of bone marrow in 27 adults irradiated for Hodgkin's disease wilh 40-45 Gy of fractionated radiotherapy to large segments of their bonemarrow (mantle and inverted fields). Bone marrow
scanning techni ues using w m ~ c - s u l p h u rcolloid,
which parallels Fe activity and can be used to reflect
haematopoietic activity, indicated that prolonged
suppression of bone marrow occurs immediately following completion of radiotherapy and persists for 2-3
yean. Partial to complete bone marrow regeneration
after fractionated radiothcrapy with 40 Gy occurs in
85% of the exposed bonc marrow sites at two years.
Mechanisms of this recovery may include increased
hacmatopoietic production in shielded marrow sites,
expansion ofbone marrow space and infield regcneration of bone marrow. The study suggested that thedose-response data for bone marrow suppression
following localized and sebmental exposun: need to berevised upwards for fractionated radiotherapy. At the9

40 Gy level thcre was evidence of prolonged suppression of bone marrow activity starting in the immediate
post-irradiation period and continuing for one year.
Regeneration of bonc marrow activity and expansionof ~ O I I Cmarrow occurred aftcr one year following the
40 Gy treatment and continued to improve with timefrom the first to the third post-irradiation year.
Baisogolov and Shiskin [B36, B37, B381 observedbone marrow hypoplasia in 8% of examined bonemarrow from exposed parts in 200 patients irradiatedfor I-lodgkin's disease, and in 89% the marrow wasaplastic.
126. Magnetic resonance imaging can detect radiationinduced marrow changcs. There are at least two
distinct types of late marrow patterns [S57]: homogeneous fatty replacement and another pattern possibly
representing hacmatopoietic marrow surrounding tbe
central marrow fat. These changes have been observedin the lumbar vertebral bone niarrow of adults after
15-50 Gy delivered over 3-6 weeks. No similar studies
have been performed in pacdiatric patients.
127. No evidence exists of a late radiation effect ofprimary disturbance of haematopoiesis in the absenceof malignant disease in the populations of Hiroshima
and Nagasaki [F12]. There is no evidence for radiation-induced disturbance of granulocyte function, but
the age-related accelerated decline in the immunological functions of T-lymphocytes and age-related alteration in the number of certain subsets of circulating Tand B-lymphocytes appear to be radiation-related
128. The Cheniobyl accident does not appear to havecaused statistically significant effects on the major
haematological parameters of children living in Russia,
Belarus or Ukraine at the time of the accident, or who
were born later [A18, 18, K17, Kl8, L25,L29, V9].
There were no differences between control and contaminated settlcmcnls. From the calculated and measured radiation dose levels, no changes should havebccn expected as a direct result of radiation exposure.

129. In childrcr~ having an intact thymus, immune
function recovers more rapidly and does not necessarily have permanent effects. Blomgren et al. [B34] analysed peripheral lymphocyte populations and serum
immunoglobuli~~
levels in 10 long-term survivors ofWilms' tumour (age: 0.5-6 years). and 6 long-term
survivors of non-Hodgkin lymphoma (age: 3-13
years). All received chemotherapy, and the tumour
dose was 7-32 Gy and 2-21 Gy, respectively. Lymphocyte counts, as well as frequencies of E,EA and EAC
rosette-forming cells, did not differ Goni those ofhealthy controls. Serum levels of immunoglobin E
were somewhat lower in patients treated for lymphoma, but for other immunoglobulins h e r e was nodifl'ercnce between patients and controls. The treatment did not have any long-lasting effects on the lym-

phatic systcni. In comparison, adults rcceiving radiotherapy for breast cancer dcvclopcd T-cell lymphopcnia that persisted for a decade. Studies on niore than
900 childrcn from contami~~atcd
areas in Russia andUkraine havc not demonstrated any radiation-related
effect on T-cells [L26, L27, L28j.

130. Summary. Studies of bone niarrow suppression,
recovery, latc marrow changes and effects on the
immunc system pertain only to adults. Too few data
exist on the effects of ionizing radiation on bonemarrow and on imniune function to determine or evensuggest critical levels for clinical effects to appear.

CONCLUSIONS
131. Deterministic effects of ionizing radiation inhumans depend on the dosc and can be expected tohavc thresholds below which the radiation effccts are
too small to impair function of the irradiated tissue ororgan. In children, tissues are actively growing, and aradiation-induced deterministic damage in a tissue ororgan will often be more severe than in adults. Examples of such deterministic scquclae include effccts
on growth and development, hormonal deficiencies,
organ dysfunctions and cffects on intellectual andcognitive functions.

fractions or after 10 Gy givcn as a single whole-body
exposure. Necrosis occurs after considerably higher
doses, and a whole-brain dose o f 5 4 Gy in 2 Gy fractions over six weeks is generally considered to be a
critical dose for radiation-induced necrosis in children
older than 5 years. For children 3-5 years old the dosc
should be reduced by about 20%, and for children lessthan 3 years old the dose should be reduced by about
30%. Brain doses of 1 8 Gy or more of fractionatedradiotherapy have been associated with neuropsychologic effects and decline in IQ.

132. Well-designed epideniiological studies of latc
deterministic effects are generally lacking, and it istherefore not possible to draw any firm conclusions
about the exact critical dose levels at which various
late deterministic effects appear. Most data concerning
such cffects are obtained from the clinical follow-up
of groups of patients treated for paediatric tumours.
These groups generally comprise small numbers ofpatients of differcnt ages and who were followed for
different lengths of time. The treatment modalities
have usually included surgery, radiotherapy andchemotherapy, and it is not always possible to single
out the effect of radiation alone. A variety of factors
complicate the study of a possible association between
effect and dose, including the underlying disease andassociated clinical findings, other treatment modalities,
the impact of illness on body iniage and lack of school
attendance.

135. Endocrine syslern. The most important endocrine effects of radiation exposure are impaired
secretions of growth hormone, thyroid-stimulating
hormone, gonadotropins, thyroid hormones and oestrogcns/testosterone. Impaired growth has bcen observed
after fractionated radiotherapy to the brain withcumulative doses of more than 24 Gy and aiter >1 Gy
in a single exposure among the survivors of the atomic
bombings in Japan, whereas impaired growth hormone
secretion has been observed in patients after 1 8 Gy of
fractionated radiotherapy. Hypothyroidism has beenreported in leukaemic children receiving thyroid dosesof 1-2 Gy over 2 - 2 5 weeks from cranial radiotherapy
and chemotherapy. In subjects under 20 years at thetime of the bombings in Hiroshima and Nagasaki,
those exposed to greater than 1 Gy had a significantly
higher incidence of thyroid disorders than those in theunexposed control group. No study has so far dcmonstrated hypothyroidism in children after a thyroid dose
<1 Gy. There are insufficient data on the effects of1 3 1 ~to determine a possible threshold dose for the
induction of hypothyroidism.

133. The methods for assessing a given deterministic
effect vary greatly, and this makes conlparisons between different studies difficult. Based on the available
findings, some general conclusions can be drawn.
Children appcar to be more sensitive to radiation thanadults, and, in general, younger children arc more sensitive than older children. Radiation doses indicated inthis Annex are usually given with fractionation over a
period of several weeks. The deterministic cffecls
following radiation exposures ill childhood arc summarized in Table 9.
134. Brain. Leukocncephalopathy, microangiopathy
and cortical acrophy have been reported after cumulative brain doses of 18 Gy or more givcn in 1.8-2 Gy136. Gomds. The cffects of radiation on the testisand ovary are age- and dose-dependent. Tbc radiation
dosc required to ablate ovarian function seems to bearound 20 Gy for girls: because of the greater numberof oocytcs in young girls, higher doses arc tolerated
before castration. Infcrtilily occurs in approximately
one third of girls receiving 4 Gy and in almost all
women over 40 years of age. Ovarian failure has bcen
documented in prepubertal girls following 1 0 Gy ofwhole-body irradiation and occurs in all pubertal girls.
Amenorrhea has been observed in two thirds of girls

A N N F X I:LATE D I X R M I N I S T I C E I T E C I S IN C l l l L D l l l i N

899

T ~ i t ) l e1
Eslin1111n or doses Tor 3 964%

a n d 258-508 i n c i d c n c - c s or c l i n l c ~ ~ l ldyc t r i n ~ c n b ~c lle l e n ~ i i n i s l i cc r r c c l c I n n d u l L c

a1 f i v e years t ~ n c mr dinlion cxlxlsurc a[11. K21
Approximc darc (Gy)O~KM

Bone narrow
Ovary
Testis
Lens
KidneyIibw

Hean
Thyroid
Piluilary
Brain
Spinal cord
Bras1
Skin
Eye
k p h a ys
Bladdu
Bonc
Uraer
Mudc

licornunr
JirU

Whdc
Whdc
Whdc
Whde
Whde
Whdc
lobc
Whdc
Whdc
Whdc
Whd c

5 m'
Whdc

100 cm2
Whd c

75 cm'
Whdc

10 m?
5-10anWhde

Injury UI jilr !cars

Eflcrr in J%J%
ofpuirn~l lypopiaria
Pcrmancnl slcril~ty
Pcrmancnl slcrihly
G~araah'rphraclcrosir
L ~ r rfailurc
Pncummi~is,fitrcsis
Puiwditis, pancarditis
llypothyrtidism
I lypopituitarism
h'enosirSenorisI\lrcphy. neaosis
Ulccr, severe fihoris
Panoph~halmitis
Lflar. scr~aure
Uccr, cantraawc
Nccroris, fraclurc
Striaurc
AtrcphyEffcrt in 2S%-50%
ofpaim

2

5

2-3

60

6-12
20
12
2s
45
60
>lo0
150
200-300
>60
A0
>I00
70
100
75

60
60
75

150
1W

5-15
5
3
35
50
40

45
45
50
50

>50
55
55

SO

>I00

' Ikrcd m ruponrcr d paticats convmlimally trcald uith franimalcd lhcrapculic x- a gmma-irra&al~m.

Table 2Estimnh o f doses f o r 190-5% u n d 25%-50% i n c i d e n c e s o f c l i n i c a l l y d c l r i r n e n t u l d c t c r n l i n i s l i c cff~cLs
i n c h i l d r e n 111 f i v e years c i R e r r l ~ d i u l i o ne x p o s u r e a[[I. R21
Approximnrc dart (Gy)
Ordm

fild

Brcas~
Cartilage

5 cm2

Booc

10 cm2

Mlpclc'Trcormcnl

Injun a file years

No dercloprncnt
Arres~cdg o u t h
h t c s ~ c dgos*zh
Ilypoflasia

Effcrr in 1%5R
ojpn/;cnu

Efirr in 2SQ-5w
of pnrirne

10
10
20

I5
30
-33

9-30

50-50

Bard m rcsponra of palicnts convcn~~onallylrcarcd uirh fradlmated thciapcut~cx- a girmn~airrr&al~on

Tat>lc 3
E~CCLS
on UIC hraln In childrcn treated for acute leukaemia delcclcd hy con~pulcdlonioyri~physcnns

Trcornunr
Raiiothcrapy
dasc ro r k t r a i nNu&ofparunrr

Ch~haa"yAhamoliria

~umha

~ocmr

56

40
40

ppc nf bruh ubnnrmnlirirr dcrccred

fw

lntracncbral calilicatiau. c o n i d auophy
lntraccrebral ulilicatimr, cortical atrophy
lntrncerebral calificatimc, cortical atrophyln~rnccrcbralwlilicatims, cortical auophy
lntrrccrebral colilicutims, cortical atrophyln~rncercbralcalificatims, conical atrophy
lntrncerebral calificatimr
Conical atrophylntraccrcbral caliliutimr, conical atrophy
Conical atrophylntracerebral cslilicatims
Cortical atrophy
White mollcr hypodencity, cortical atrophy
Cortical atrophy
Cortical atrophy
Cortical atrophy

[B6l

(GY)

IT

24
24
24
24
24
24
24
24
24
24
24
20
18
0
0
0

23
19
24
32
72

lT

14

13
1I
13
17
35
6

lT
IT

25

10

30
45
19

12
11
3
5
1
5
3

IT
TT
IT
IT

lT

IT
IT
IT
IT

N+lT
N+IT
N+IT

44

27
55
12
43
9

8
1

56

54
53
49
43

24
16
11

4
9

Z
19
4

IPS]
IRS)
11'7
ICl41
[Ell

Iwsl
PSI
ISSs]

I031
I0131
[Dal
I021
[Ell
[OlJI
Ips]

IT = i n t n t h m l rnethotrexatc and IT + I V = inaathcul and intravcncur rncthoucxatc.

Table 4
EKccts on Ulc hraln of n~dlolhcrapyLo Ule ccntrnl nervous syslcni In ct~lldrcn

Eficr
Lcukocnccphalopa~hy

CNS therapy>20 Gy i n 15-2.0 Gy franionr

Comments

Rrf.

Y m n g children m a c sensitive

W6. P3.
R41

p ~ r vsystemic r n c t h c ~ u a t c
10 Gy whdc-body irraQatiw
Mineralizing mincangiopnthy>IS Gy i n 1.5-2.0 Gy fracl~onr

Y w n g children more sensitive[B4. D5]

Mid atrophy>I8 Gy i n 1.5-2.0 Gy h s n i m

Sevciat atrophy in young children

IC3. D3,and i n t n t h m l rncthotrcxate
G r e b n l nmcsir>54 Gy i n 1.8 Gy hadions

DS,U]
lB35, K2j

ANNM 1: U T E DEIEKMlNlSnC EFTECTS IN CliILDR1.N

901

TIIhl e 5
Avcrt~ge~ d u l hclyhlctof Individu~llscxposcd In the lowcr dose groups In Hiroshln~trt ~ n dN I I R I U I~I ~n~ dunder I S ycrm old ~ t the
t LInlc of boml~lng
113141

Abaage dvl~
heighr (cmj in dare groupAge a timeSao/-intiycorsj

0 GY

sO.09 Gy

0.10-0.99 Gy> 1.00 Gy

Ilimabimr
Male

0-5
6-1 1
12-17

166.4
1623
164.3

166.1 "
164.2
163.6

165.9 "
166.3
164.3

161.5
1622
163.4

Female

0-5
6-1 1
12-17

153.3
1325
1521

153.6 "
153.6
1523

IS29
153.6
152.2

150.4
150.5
151.9

Nqsrnki
Male

0-5
6-1 1
12-17

166.2
164.0
163.2

166.2
164.1
163.9

166.2
1627
161.8

Female

0-5
6-11
12-17

1528
152.4
151.8

1529
151.3
151.6

150.8
151.5
151.2

diffuml (p c 0.01) cornpard wilh the svcragc d group exposed 10 > 1.00 Gy.
* Sigificandy
Significantly different (p c 0.05) compared uith the average of g o u p exposed l o > 1.00 Gy.

Table 6
Average adult hcighls of children exposcd in the higher dose group in Hiroshima undundcr 18 yulrs old ut the tinic of bombing

[Dl41
r
Sa

A ~ w o g rd u l l heighr (rmJ "Age a limeof bombing(VCWS)In dare group 1.0-2.49 Gy

In dare group > 2.5 Gy

Male

0-5
6-1 1
12-17

164.2 (12)162.7 (13)163.2 (43)159.8 (18)161.5 (lo)163.5 (45)

Female

0.5
6-11
12-17

151.8 ( 1 1)
150.4 (17)1521 (58)149.8 (23)150.5 (11)a1.7 (59)Tr~hle7
Average hcialll of Indivitltrrtls l'ollowed in the Adult Ilcallh S111dyrtntl untlcr r t ~ c1 0 yer~rsnt the tlnlc of homhing
1141

h'umba of inlbrduals in parcnthesu.
tlomopncily I ~ dI ~ r i a n c cf a lour dcxc goups; dl = 3.

Table 8Thyroid hyporunction in ir~dividui~ls
cxposcd lo Trtllout rndiutiorl in lhc hlitrshttll lslrrrtds[C161
Incidmcc of thyroid h>po/unctionfur variour r c t h n l d dm-

AXclo rhc rhvroid

a!a p w c

(vcars)

0 GY< 1.W (;?.

1.00-2.00 Gy

CIO

1n2u(0.4%)a101/37] (0.3%)0164 (0%)
11100 (1%)

1/12 (8%)

22.00 (;ysns (31%)
4/45 ( 9%)Tnl)le 9~ ~ l i nofi lowest~ ~ l m~d i ~ ~ t l odosesn~~ssociatcd
wilh 111k
dclcn~~lnictic
cll'crlc I ~ I I Icw~x~surcIIin cl~lldhoodlo
in thc form or ~rnctlon~~tcd
rntllolliempy
Ionizing mdlr~Uon,~1su111ly

1:flccrO r x ~

Durc (Gy)

TatirGerm cell depletion
lrydig cell dysfunaim

0.5
10

Ovary

Amcnonhca
Infcrtilily
Ablntim> 0.5

Thyroid gland

tlypothyraidism

> 1

Brain

G p ~ ~ i funarmsvc
1Lstopn1hdogic changes
Xcurocdarinc elleas

4

M

18
18, (10> I&(> 1 ")Brcan

I lypoplaria

2EyeG~araa2

Lung

Ebrosir

8-11

Liker

Fibrosis

12

KidneyReduced acatinine clcanna

I2

Skdc~mSkdcld changes

10

Cardiovasmlnr system

Cardimyopathy

40

Bone manow

l lypofunctim

Single whdc-body exposure.

hruffiacnt data avarlablc

UNSCMR 1993 EPORT

903

Chcmolhcrapy(inlravcnous
rnclho~rcxalc)

Radioihcrapy(cranial irradiation)
Figure I.
Approximi~k incidence r a t s of clinical leukocnccph~~lopnlhy
in patients trcnted bycranial Irradiation, chcmothenpy or cori~binntion thcrupics.
P4I

I
75

I
100
10 SCORE

I
125

Figure 11.
1Q score dislrihution in children t m k d for ~ c u l elymphocytic Ieubcnila
hy cranial radiolhernpy (RT), inlrathecal mclholrcxute (IT) or inln~venousn~clhotrexuk(IV).

Ill21

TIME AFTER RADIOTHERAPY (years)
Figun? 111.
hfaximurn growth hormone response Lo growth-ho~monc-rclcusing hormone
in children lrcntcd Tor brain turnours hy rndiothcrupy.

[W

Cranial0 Craniospinal
Othcr
None

I
0

I
1

I

I

I

2
YEARS

3

4

Figure IV.
h l u n s h n d a r d devlntion score or hciphl in rhildrcn Lretlkd ror mulipnunt disease by rndiotheri~py
to various siks. HcsulLs tor those receiving crnnlal nnd crnniospinal trealrncnl
were significantly lower ( p < 0.001) a1 1 4 years Ulun tit the t l n ~ eo r lnltial lrenlrncnt.
IG2l

DOSE (Gy)Figum V.
Ihymid-stimuli~ling hornionc levels In 116 pnlicnls irgcd 16 ycurs or lcss
Lrenkd for Hodgkin's dkcusc by rudiolhcrupy.
IC 1512030

AGE AT TSIEATMENT ( y e a s )Figure V1.
I'mbuhlllty of rcgulnr menses In wonien ln?ll(cd for Hodgkin's disease
Ily lolal lyniph Imrdltrtion 07.1) tind/or chcniolhcnipy.
lHlZl

ANNEX I: IAX: DETERMINISTIC EFFECIS IN Cl IllnREN

907

AGE AT lyIRST IRRADlAnON (ycars)

0 Standinkheight
Siltingighl

AGE AT 1:IRSI' IRKADlAnON (ycan)

1:igut-e VII.
Ileviution fmnl mean s b n d i n g and silting hcighk in rhildrcn lrei1Lcd by rudiothcri~pywith c25 Gy o r >35 Gy.
[I'lOl4

1 year old
1-5 years old
11 years old

Figure V111.
I~oscslTccl rclutionship Tor bone shortening in childrcn Lfcutid hy mdiothenpythat included cpiphysial pllrle irrudiation.
lG8l

-100

1

I

I

I

I

I

1

0

2

4

6

8

10

12

DOSE (GY)
Figure IX.
1)iIrercncc In t ~ r c u tvolurnc in 53 women treatid in childhood Tor hirerriangioniu
by radiotherapy ot the hrcusl region.

PIA N N M I: W l E DEERMINISIIIC EFFECTS IN ClIlLDREN

909

References
A1

Allen, J.C. 'lhe effects of cancer therapy on the
nervous system. J. I'cdiatr. 93: 903-909 (1 978).
A2 Aur, RJ.A.. J.V. Simone, 11.0. ilustu et al. Central
nervous systcm therapy and cambination chemotherapy of childhood lymphocytic lcukcrnia. Rlood 37:
272-281 (1971).
A3 Aur, RJ.A., J.V.Simonc, H.O. Hustu el al. A comparative study of ccntral nervous system irradiationand intensive chemotherapy early in remission or
childhood acute lyrnphocytic leukemia. Canccr 29:
381-391 (1972).
A4 Atkinson, K., 11. Clink, S. Lawler et al. Encephalopathy following bone marrow transplantation. Eur. J.
Cancer 13: 623-625 (1977).
A5 Abbatucci, J.S., T. Dclozier, R. Quint et al. Radiation
myelopathy of the ccrvical spinal cord: time, dosc andvolume factors. Int. J. Radiat. Oncol. Biol. Phys. 4:239-248 (1978).
A6 Atlas, S.W., R.L. Grossman, R.J. Packer et al. Magnetic resonance imaging diagnosis of disseminatednecmtizing leukoencephalopathy. J. Comput. Assist.
Tomogr. 11: 39-43 (1987).
A7 Atkinson, R.L., R.C. Atkinson and E.R. Ililgard.
(eds.).
Mental abilities and their measurement.
p. 349-381 in: Introduction to Psychology, Eighth
Edition. Harcaut Brace Jovanovich, Inc., New York.
1983.
A8 Ahmcd. S.R. and S.M. Shalct. Hypothalamic growth
hormone releasing factor deficiency following cranial
irradiation. Clin. Endocrinol. 21: 483-488 (1984).
A9 Abayomi, O.K. and A. Sadeghi-Nejad. The incidenceof late endocrine dysfunction following irradiation forchildhood medulloblastoma. Int. J. Radiat. Oncol.
Biol. Phys. 12: 945-948 (1986).
A10 Ahmed, S.R., S.M. Shalet and C.G. Beardwell. The
effects of cranial irradiation on growth hormone
secretion. Acla Paediatr. Scand. 75: 255-260 (1986).
A l l Albertsson-Wikland, K., B. Lannering, I. Marky er al.
A longitudinal study on growth and spontaneous
growth hormone (GH) secretion in children with
irradiated brain tumors. Acta I'acdiatr. Scand. 76: 966973 (1987).
A12 Ash, P. The influence of radiation on fertility in man.
Br. J. Radiol. 53: 271-278 (1980).
A13 Ahmed, S.R., S.M. Shalct, R.H.A. Campbell et al.
Primary gonadal damage following treatment of brain
tumors in childhood. J. Pediatr. 103: 562-565 (1983).
A14 Applebaum, F.R. and E.D. Thomas. Treatment of
acute leukemia in adults with chemoradiolhcrapy andbone marrow transplantation. Cancer 55: 2202-2209(1985).
A15 Applefeld, M.M. and P.H. Wicrnik. Cardiac disease
after radiation therapy for 1.lodgkinYsdisease: analysisof 48 patients. Am. J. Cardiol. 51: 1679-1681 (1983).
A16 Alvarado, C.S.. T.F. Boat and A.J. Newman. h t e onset pulmonary fibrosis and chesl deformity in twochildren treated with cyclophosphamide. J . Pedialr. 92:
443-446 (1978).

A17 Arncil, G.C., F. Ilarris, I.G. Emmanuel el al. Nephritis
in two children after irradiation and chemotherapy forncphroblastoma. Lance1 1: 960-963 (1974).
A18 Andrceva, A.P., E.G. Kazancts, N.A. Karamjan et al.
Erythropoiesis of children exposed to low radiationd o s a in thc contaminaled areas. Sov. Mcd. Rev.
Sicmatol. (1993). (in Russian)
B1 Bloomer, W.D. and S. Hellrnan. Normal tissue responses to radiation therapy. N. Engl. J. Med. 293:
80-83 (1975).
B2 Blcycr, W.A. and D.G. Poplack. Prophylaxis and (reatmcnt of leukemia in the central nervous system andother sanctuaries. Semin. Oncol. 12: 131-148 (1985).
B3 Bloom, H.J.G., E.N.K. Wallace and J.M. Henk. The
treatmbnt and prognosis of medulloblastorna inchildren. Am. 3. Roentgenol. 105: 43-62 (1969).
B4 Blcyer, W.A. and T.W. GriRin. White matter necrosis,
mineralizing microangiopathy, and intellectual abilities
in survivors of childhood leukemia: associations withccntral nervous system irradiation and rnethotrexate
therapy. p. 155-174 in: Radiation Damage to the
Nervous System. (H.A. Gilbert and A.R. Kagan, 4 s . )Ravcn Press, New York, 1980.
B5 Brecher, M.L., P. Berger, A.I. Freeman et al.
Computerized tomography scan findings in children
with acute lymphocylic leukemia treated with threedifferent methods of central nervous systemprophylaxis. Cancer 56: 2439-2433 (1985).
B6 Brouwers, P., R. Riccardi. P. Fcdio et al. Long-term
neuropsychological sequelae of childhood leukemia:
correlation with CT brain scan abnormalities. J.
Pediatr. 106: 723-728 (1985).
B7 Rordcaux, J., R. Dowell, D. Copeland et al.
Intellectual functioning of children who survive brain
tumors. Abstract. p. 2 in: Childhood Cancer Survivors:
Living Beyond Cure. Tenth Annual Mental HealthConference, Houston, Texas, 1985.
R8 Bamford, F.N., P.H. Morris Jones. D. Pearson et al.
Residual disabilities in children treated for intraaanial
space-occupying lesions. Cancer 37: 1149-1151(1976).
B9 Bleyer, W.A. Neurologic sequelac of methotrexate andionizing radiation: a new classification. Cancer Treat.
Rep. 65 (Suppl. 1): 89-98 (1981).
Dl0 Bajorunas, D.R.. F. Ghavimi, B. Jereb et al. Endocrine
scquclae of antincoplastic therapy in childhood headand neck malignancies. J. Clin. Endoainol. Melab.
50: 329-335 (1980).
B11 Berry, DM., M.J. Elders, W. Crist et al. Growth inchildren with acute lymphocytic leukemia: a PediatricOncology Group study. Med. Pediatr. Oncol. 11: 3945 (1983).
012 Bodc, U., A. Oliff, B.B. Bercu et al. Absence of CT
brain scan and endocrine abnormalities with lessintensive CNS prophylaxis. Am. J. Pediatr. Ilcmatol./Oncol. 2: 21-24 (1980).
1313 Barrett, A., J. Nicholls and R. Gibson. Late effecls of
total body irradiation. Radiother. Oncol. 9: 131-135(1987).

910

U N S C M R 3993 WI'OIVI'1314 Hclsky, J.L. and W J . 13101. Adults staturc in rclation
to childhood c x p s u r c to thc atomic bombs of Iliroshirna and Nagasaki. Am. J. Public llcallh 65: 489494 (1975).
1315 Ijantlc, J.I'.. C.K.K. Lcc and S.H. Lcvitt. 'lhyroxinc
administration during ri~diationthcrapy to ttlc ncck
docs not prevent sul)scqucr~tthyroid dysfunction. Int.
J. Itadiat. Onml. Ijiol. I't~ys. 11: 1999-2002 (1985).
U16 Bcckcr, D.V., W.M. McConahcy, B.M. Dobyns ct al.
The results of radioiodinc trcatmcnt of hypcrthymidism. A preliminary rcport of the thyro~oxicosisthcrapy
follow-up study. p. 603-609 in: f:urthcr Advanccs inThyroid Rcscarch. Vol. 1. (K. Fcllingcr and I<. Ilijfcr.
cds.) Vcrlag dcr Wicncr Mcdizinischcn Akadcmic,
Wicn, 1971.
1317 Bcckcr, D.V.Medical radialion: comparison of iodinc131 thcrapy and alternative treatmenls of hypcrthymidism. p. 57-67 in: Radiation and thc n y r o i d .
(S. Nagataki, cd.) Exccrpta Mcdica, Amsterdam, 1989.
1318 Brauner, R., R. Rappaport, P. Cccrnichow ct al.
EIIecti of hypothalamic and gonadal irradiation on
pubertal devclopmcnt in childrcn with cranial, ccrvicaland abdominal tumors and acutc leukcmia. p. 163-173
in: Pathophysiology of I'ubcrly. (E. Cacciari and A.
Prader, eds.) Acadcmic I'ress. London. 1980.
B19 Brauner, R.. P. a c r n i c h o w and R. Rappaport. Prccod o u s pubcrty after hypolhalamic and pituilary inadiation in young childrcn. N. Engl. J. Mcd. 310: 920(1984).
B20 Brauner. R., P. acrnichow, P. Cramcr ct al. Leydigcell function in childrcn after dircct Iesticular
irradiation for aculc lymphoblastic leukcmia. N. Engl.
J. Med. 309: 25-28 (1983).
I321 Blatt. J., D.G. Poplack and RJ. Shcrim. T u S a l a r
fundion in boys a f m chcmothmpy for acuk lymphoMasliclcukcmia. N. h g l . J. Mcd. 301.1121-1124 (1981).
8 2 2 Blatt. J., R J . Shcrins, D. Nicbruggc ct al. Leydig a l lfunction in boys following lreatmcnt for leslicularrelapse of acutc lymphoblastic leukcmia. J. Clin.
Oncol. 3: 1227-1231 (1985).
U23 Butlcr, M.S., W.W. Robertson, W. Kale ct al. Skclctal
sequclac of radiation thcrapy for malignant childhood
tumors. Clin. Orthop. 251: 235-240 (1990).
B24 Bmadbcnt, V.A., N.D. Barnes and T.K. Whcclcr.
Mcdulloblas~omain childhood: long-term rcsults oftreatment. Canccr 48: 26-30 (1981).
B25 Bleher, E.A. and ll. Tschiippeler. Spitvcrindcrungn
an der Wirbcls2ulc nach S~rahlcnthcrapieund komhinicrtcr Bchandlung bci Morbus Ilodgkin im Kindcsund Adolcszcntcnal~cr.Strahlentherapic 155: 817-828(1979).
B26 Rarrcfl, I.R. Slippcd capital femoral epiphysis following radiotherapy. J. Pcdialr. Orthop. 5: 268-273 (1985).
8 2 7 Burke, FJ.T, and J.W. I:rame. The cffcd of inadialion on developing ~ccth.Oral Surg.. Oral Mcd.. Oral
Pathol. 47: 11-13 (1979).
I328 Urittcn, M.J.A., K.E. Il;~lnan and W J . Mcrcdith.
Radiation cataract: ncw cvidcnce on radiation damage
10 the Icns. Br. J. Radiol. 39: 612-617 (1966).
B29 Rmsius. F.C.. U.1:. Wallcr and W.C. Roberts. Radiation heart disease. Analysis of 16 young (agcd 15 to
33 yean) necmpsy pa ti en^ who rcceivcd over 3,500
rads to the heart. Am. J. Mcd. 70: 519-530 (1981).

I3urrls, 1t.J.. R.-Z Bar-Schlomo, M.N. Druck ct al.
I>ctcction of radiation cardionlyopalhy by galcd radionuclidc angiograpl~y.Am. J . Mcd. 74: 297-302 (1983).
Ilillingl~~~rnn,
M.E., J.W. Mason. M.R. Bris~owet al.
Ar~thrr~cyclinc
carciomyopi~lhymonitorcd by morphologic chiingcs. Canccr Trciit, Rcp. 62: 865-872 (1978).
I3c11ois1,M.R., J. Lcmcrlc. It. Jean ct al. Eflccts on
p u l ~ ~ ~ o n ; lfunctionryof whole I I J I I ~ irradiation forWiln~s'tumor in childrcn. Ihorax 37: 175-180(1982).
13;1rrcr;1,M., L.P. Roy and M. Stcvcns. Long-tcrm follow-up aflcr unilaicral ncphrcctomy and radio-thcrapy
lor Wilms' tumour. I'cdizitr. Ncphrol. 3: 430-432(1989).
Dlomgrcn. 11.. S. Ilaydcr. I. Lax ct el. Studies on thelyrnpl~;~tic
system in long-lcrm survivors trealcd for
Wilrns' tumour or non-llodgkin's lymphoma duringchildhood. Clin. Oncol. 6: 3-13 (1980).
Rlooni, I1J.G. lntracranial tumors: response andrcsistancc to therapeutic cndcavors, 1970-1980. Int. J.
Itadiat. Oncol. Biol. Phys. 8: 1083-1113 (1982).
Bi~isogolov,G.D. and 1.1'. Shiskin. Spitfolgen nach
Bcstrahlung (a) Fellzusarnmcnsctzung in beslrahltcn
Knochcnrnarkabschnit~cr~.Radiobiol. Radiother. 2 2(4): 377-381 (1981).
Baisogolov. G.D. and I.P. Shiskin. Zusland desSlrohmas in bcstrahllcn und inlaktcn Abschnitten dcs
mcnschlichcn Knochenmarks. Radiobiol. Radiother. 23(1): 31-35 (1982).
Baisogolov, G.D. and I.P. Shiskin. Blutbildung in
hstrahltcn und unbcstrahllcn Knochcnmarksbereichcn.
Kadiohiol. Radiother. 23 (Nl): (1983).
Ijrcur, K., P. Cohcn, 0. Schwcisguth ct al. Irradiationof thc l u n g as an adjuvant thcrapy in the treatment of
ostcosarcoma of the limbs. Eur. J. Canccr 14: 461-471(1978).
Blot, WJ., I.M. Moriyama and R.W. Millcr. Repmductivc potcnlial of malcs exposed in utcro or
prcpuherti~lly to atomic radialion. ABCC TR139-72(1972).
Cornmittcc lor Radiation Oncology Studies. Normal
tissuc ~ o l c r ~ n cande damage. Cancer 3 7 (Suppl.):2056-2055 (1976).
Casarctt, G. Basic mcch;lnisms for permanent anddelayed radiation pathology. Canccr 37 (Suppl. 2):
1002-1010 (1976).
Croslcy, CJ., L B . Rorke, A. Evans et al. Central
rlcrvous systcm l a i o n s in childhood lcukcmia.
Ncurology 28: 678-685 (1978).
Cor~h~inc,
L.. A. Kanski, S. Llkholm ct al. Advcrsc
cflccts of brain irradiation corrclatcd with MR and CT
imaging. Abstract. Int. J. Itndial. Oncol. Biol. l'hys.
13 (Suppl. 1): 8 8 (1987).
Cap, J., Z. Misikova, A. Follinova el al. Conscqucncesof intensive thcrapy of acutc lymphoblastic lcukcmia
in childrcn in initial complclc remission lasting morc
tti;~nfivc ycan. a c c h . Mcd. 8: 35-44 (1985).
Copclilnd, D.It., J.M. 1:lctchcr. U. I'lcffcrbaum-lcvinc
CI ill. Ncurolsychological scquclae of childhoodcarlccr in long-term survivors. I'cdiiitrics 75: 745-753(1985).
Copcland, D.I<., K.E. Dowcll. J.M. Fletcher et (11.
Ncuropsychological clfccls of childhood canccr
lrcittrncnt. J . Child Neurol. 3: 53-62 (1988).

ANNEX I: IAm DEERMINIS
Calissendorff, n., P. I3olmc and M, cl-Azazi. 'lhc
dcvclopmcnt of calarad in childrcn ns a late sidccflcct of bonc marrow trj~mplanlation.Ilonc Marrow
Transplant. 7: 427-429 (1991).
C9 Chin. 11.W. and Y. Maruyama. Agc at trcatmcnt andlong-term performance results in n~cdulloblastoma.
Cancer 53: 1952-1958 (1984).
C10 Chcrnichow, P.. 0. Cachin. R. Rappaport ct ill.
S q u d l e s cndocriniennes dcs irradiations dc la tctc ct
du cou pour turncurs cxtracranicnncs. Arch. 13.
Pediatr. 34 (Suppl. 7): 154-164 (1977).
C11 Clayton. P.E.. S.M. Shalct. P.H. Morris-Joncs ct al.
Growth in childrcn treatcd for acutc lymphoblastic
leukemia. Lancet 1: 460-462 (1988).
C12 Clayton, P.E. and S.M. Shi~lct.Dosc dcpcndcncy oftime of onset of radiation-induced growth hormonc
dcficiency. J. Pcdiatr. 118: 226-228 (1991).
C13 Gamer. P.. G. Schaison and J.M. Andricu. Maladic dc
Ilodgkin dc I'enfant rdsultants B long tcrmc dutraitcmcnt. Bull. Cancer (FR) 68: 456-464 (1981).
C14 Carli, M., G. Perilongo, A.M. Lavarda er al. Risk
factors for ccrcbral calcilications in patients trwtcd
with conventional CNS prophylaxis. in: Third International Symposium on Therapy of Acutc Leukcmias,
Rome, 1982.
C15 Constine, L.S., S.S. Donaldson, I.R. McDougall ct al.
Thyroid dysfunction aftcr radiothcrapy in childrcn
with Hodgkin's disease. Cancer 53: 878-883 (1984).
C16 Conard, R.A. Late radiation cffccts in MarshallIslanders exposed to fallout 28 years ago. p. 57-71 in:
Epidcmiology andRadiation Carcinogcncsis:
Biological Significance. (J.D. Boice Jr. and J.F.
Fraurncni Jr., cds.) Raven Press, New York, 1984.

C8

C17 Clayton. P.E., S.M. Shalct, D.A. Prim ct al. Ovarianfunction following chcrnotherapy for childhood brain
tumours. Mcd. Pediatr. Oncol. 17: 92-96 (1989).
C18 Clayton. P.E., S.M. Shalct, D.A. Prim ct al. Testiculardamage aftcr chemothcrapy for childhood brain
tumors. J. Pcdiatr. 112: 922-926 (1988).
C19 Castillo, L.A., A.W. Craft, J. Kcrnahan ct al. Gonadal
function aftcr 12 Gy tcsticular irradiation in childhood
acutc lymphoblastic leukcmia. Mod. Pcdiatr. Oncol.
18: 185-189 (1990).
C20 Cornmiltee on Biological Effects of Ionizing Radiiltions (BEIR 111). The Effects on Populations of Exposure to Low Levels of Ionizing Radiation: 1980. United States National Acadcmy of Scicnccs, National
Research Council. National Acadcmy I'rcss, Washington, 1980.
C21 Choshi, K.. I. Takaku, 11. Mishima ct al. Ophtalmologic changes rclatcd to radiation exposure and agc in
thc adult hcalth study sample, Hiroshima and Nagasaki. Radiat. Rcs. 96: 560-579 (1983).
C22 Carmcl. R J . end H.S. Kuplan. Mantlc irradiation i nllodgkin's disease. An analysis of tcchniquc, lurnor
eradication and complications. Cancer 37: 2813-2825(1976).
C23 Cicopani. A.. E. Cacciari. V. Veca et al. Differential
cflccls o l 18- and 24-Gy cranial irradiation on growthrate and growth hormonc release in childrcn withprolonged survival aftcr acute lymphocytic leukemia.
Am. J. Dis. Child. 142: 1199-1202 (1988).

C24 Caccrcs. 13. and M. 7;lharia. Massive prcopcrative
radialion thcmpy in thc Lrwtmcnt of ostcogcnic
sarcoma. Cancer 30 (3): 634-638 (1972).
C25 Chmclcvsky. D., C.W. Mays, 11. Spicss ct al. An cpidcmiological asscssmcnl of lens opacifications that
impnircd vision in palicnls injected with radium-224.
Uadiat. Itcs. 115: 238-257 (1988).
C26 Corntine. L.S., l'.D. Woolf, D. Cann ct al. llypothalarnic-pituitary dysfunction aftcr radiation for brain
tumors. N. Engl. J. Mcd. 328: 87-94 (1993).
Duflncr. I'.K, M.E. Cohcn, P.R.M. 'l'homas cr al. The
Dllong-term cffccts of cranial irradiation on the mntral
ncrvous system. Canccr 56 (Suppl.): 1841-1846 (1985).
D2 Dceg, I IJ.. R. Storb and E.D. Thomas. Bone marrowtransplantation: a rcvicw of dclayed complications. Br.
J. Ilacmatol. 57: 185-208 (1984).
D3 Dcck, M.D.F. Imaging techniques in thc diaposis ofradiation damage to the central nervous systcm. p.
107-127 in: Radiation Damage to thc Ncrvous System.
(H.A. Gilbert and A.R. Kagan, eds.) Raven Prcss,
New York. 1980.
D4 Di Chiro. G.. E. Oldfield, D.C. Wright et al. Cerebral
nccrosis aftcr radiotherapy and/or intraarterial chcmothcrapy for brain tumors: PET and neuro-pathologic
studies. Am. J. Rocntgcnol. 150: 189-197 (1988).
D5 Davis, P.C., J.C. Hoffman, G.S. Pearl ct al. (Xevaluation of cffccls of cranial radiation therapy inchildrcn. Am. J. Rocntgenol. 147: 587-592 (1986).
D6 Duffncr. P.K., M.E. Cohen, S.W. Anderson ct al.
Long-tcrrn effeck of treatment on endocrine function
in childrcn with brain tumors. Ann. Ncurol. 14: 528532 (1983).
D7 Dcutsch. M. Radiotherapy for primary brain tumors invery young childrcn. Cancer 50: 2785-2789 (1982).
D8 Duffner, P.K.. M.E. Cohcn and P. Thomas. Latecllects of treatment in the intclligcnce of childrcn withposterior fossa tumors. Cancer 51: 233-237 (1983).
D9 Danoff, B.F., F.S. Cowchock, C. Marquettc ct al.
k c s s m c n t of the long-term effects of primary radiation thcrapy for brain tumors in children. Canccr 49:
1580-1586 (1982).
D l 0 Danoll, B.F.. F.S. Cowchock and S. Kramcr. Childhood craniopharyngioma: survival. local control.cndoa i n e and neurologic function following radiothcrapy.
11-11. J. Radiat. Oncol. Biol. Phys. 9: 171-175 (1983).
,
M.E. Cohcn, P.R.M. Thomas ct al. The
Dl 1 ~ u f f n e r P.K.,
long-term cffccts of cranial irradiation on thc mnral
nervous systcm. Cancer 56: 1841-1846 (1985).
I112 Duflncr, P.K., M.E. Cohen. M.L. Voorhcss ct al.
Long-term cffccts of cranial irradiation on cndoaine
function in children with brain tumors. Canccr 56:
2189-2193 (1985).
D l 3 Duffncr, I'.K. and M.E. Cohen. Rcccnt devclopmcnk inpediatric ncuro-onmlogy. Cancer 58: 561-568 (1986).
Dl4 Dickinson, W.P.. D.11. Berry, L. Dickinson et al.
Diffcren~ial cffccts or cranial radiation on growth
hormonc response to arginine and insulin infusion. J.
Pcdiatr. 92: 754-757 (1978).
Dl5 Drinnan. C.It.. J.D. Miller. H J . Guyda ct al. Growthand dcvclopmcn~01 long-lcrm survivors of childhood
acutc lymphoblastic Icukemia treatcd with and without
prophylactic radiation of thc central nervous system.
Clin. Invest. Mcd. 8: 307-314 (1985).

Dl6 Dcvney, R.U., C.A. Sklar, M.E. Nesbit ct al. Serial
thyroid lunciion measurements in children withllodgkin's disease. J. Pcdiatr. 105: 223-227 (1984).
Dl7 Donaldson, S.S. and I1.S. Kaplan. Complications oflrcaln~eritof Ilodgkin's disease in children. Canccr'rrcat. Rcp. 66: 977-989 (1982).
D l 8 Danowski, T.S. Tl~yroid. p. 255-256 in: Clinical
Endocrinology. Volun~e11. ' h e Williams & Wilkins
Company, Baltimore. 1962.
Dl9 Dawson, W.U. Growth impairment lollowing radiotherapy in childhood. Clin. Radiol. 19: 241-256(1 968).
D20 DahllBf, G., M. Ban, P. Bolrnc ct al. Disturbances indental development after total body irradiation in bonemarrow transplant recipients. Oral Surg. Oral Mcd.
Oral Pathol. 65: 41-44 (1988).
D21 Deeg, 11J., N. Floumoy, K.M. Sullivan et al.
Cataracts aftcr total body irradiation and marrowtransplantation: a sparing ellcct of dosc fractionation.
Int. J. Radiat. Oncol. Biol. I'hys. 10: 957-964 (1984).
D22 do Pico, G.A., A.L. Wiley, P. Rao el al. Pulmonary
rcadion to uppcr mantle radiation therapy for Flodgkin's discase. Chest 75: 688-692 (1979).
D23 Donaldson, S.S., S. Jundt, C. Ricour et al. Radiationenteritis in children. Canccr 35: 1167-1178 (1975).
D24 Day, R.E.. J. Kingston, J.A. Bullimore el al. CAT
brain scans alter ocntral nervous systcrn prophylaxis
for acute lymphoblastic leukacmia. Br. Mcd. J. 2:
1752-1753 (1978).
D25 Dacou-Voutetakis, C.. A. Xypolyta, S. Haidas el al.
Irradiation of the head. Immediate effect on growth
hormone secretion in children. J. Clin. Endocrinol.
Metab. 44: 791-794 (1977).
D26 DeAngelis, L.M. and W.R. Shapiro. Drudradiationinteractions and central nervous system injury.
p. 361-381 in: Radiation Injury 10 the Nervous
System. (P.Ii. Gutin. S.A. Lcibcl and G.E. Shelinc,d s . ) Raven Press Ltd., New York, 1991.
Esscltine, D.W., C.R. Freeman. LM. Chevalier et al.
El
Computed tomography brain scans in long-term
survivors of childhood acute lymphoblastic leukemia.
Med. Pcdiatr. Oncol. 9: 429-438 (1981).
E2 Ellenberg, L., J.G. McComb, S.E. Sicgel ct al. Factors
affecting intellectual outcome in pediatric brain tumor
patients. Neurosurgery 21: 638-644 (1987).
E3 Eiser. C. lntcllcctual abiliticu among survivors ofchildhood leukacmia as a function of CNS irradiation.
Arch. Dis. Childhood 53: 391-395 (1978).
El Eiser, C. and R. Lansdown. Retrospective study o lintellectual developrncnt in childrcn trcated lor acutelymphoblastic leukemia. Arch. Dis. Childhood 52:
525-529 (1977).
E5 Eiser, C. ECTccts o l chronic illness on intellectual
development. Arch. Dis. Childhood 55: 766-770(1980).
E6 Edcikcn, B.S.. li.1. Libshitz and M.A. Cohen. Siippcd
proximal hurnoral epiphysis: a complication ofradiotherapy to the shoulder in children. Skelel.
Kadiol. 9: 123-125 (1982).
E7 Egawa S., 1. Tsukiyarna, Y. Akine et al. Suppressionof bony growth of the orbit alter radiotherapy forretinoblastoma. Radial. Mcd. 5: 207-21 1 (1967).

Field, S.13. and A.C. Upton. Non-stochastic effects:
conipatibilily with present ICRI' recommendations.
Int. J. Radi;lt. O~COI.
Uiol. I'hys. 48: 81-94 (1985).
Fuxncr, J.E., D.G. I'oplack, P.A. Pizzo ct a\.
I,cukocncephnlopnthy following chernotlierapy for
rh;lIxlon~yos;crcoma:rcvcrsi bi lily ol cerebral changes
dcnic~rislralcdby campuled lornogmphy. J. Pediatr. 91:
77-79 (1977).
I:rccn~an, C.I<., J. Krischcr, R.A. Sanford et al.
Ilyperfractionated radiothcrapy in brain stern tumors:resulLs of a pediatric oncology group study. Int. J.
Itadiat. Oncol. Biol. Phys. 15: 311-318 (1988).
Fuks, Z., E. Glatstein, G.W. Marsa el al. Long-term
elfecls of external radiation on the pituitary andthyroid glands. Canccr 37: 1152-1161 (1976).
I:lcrning, I.D.. '1'.L. Black, E.I. Thompson et al.
Thyroid dysfunction and ncoplasia in childrcn
receiving ncck irradiation for cancer. Cancer 55:
1190-1194 (1985).
Frcitas, J.E., D.P. Swanson. M.D. Gross et al. lodine131: optimal therapy for hyperthyroidism in children
and adolescents? J. Nucl. Mcd. 20: 847-850 (1979).
Fromm. M., P. Littman, R.B. Raney el al. Late ellects
alter treatment of twenty childrcn with soft tissue
sarcomas of the head and ncck. Experience at a single
institution with a review of the literature. Canccr 57:
2070-2076 (1986).
Franpis, P. Etude dosimctrique retrospective chez desenfants ayant fait une scconde tumeur a p h radiotherapie. T h b e N.D.'ordre: 132. L'UniversitC Paul
Sabalier de Toulouse, 1987.
Fiirst, C.J., M. Lundell, S.-0. Ahlbick et al. Brcast
hypoplasia following irradiation o l the female breast
in infancy and early childhood. Acta Oncol. 28: 519523 (1989).
Fajardo, L.F. and T.V. Colby. Pathogenesis of venoocclusive liver disease alter radiation. Arch. Pathol.
Lab. Med. 104: 584-588 (1980).
Freedman, L.R. and R.K. Keehen. Urinary findings ofchildrcn who were in utcro during the atomic bombings o l lliroshima and Nagasaki. Yale J. Biol. Mcd.
39: 196-206 (1966).
Finch, S.C. and C.A. Finch. Summary of the studies
at ABCC-RERF concerning the late hematologic
cffccki of atomic bomb exposure in lliroshima andNagasaki. RERF TR/23-88 (1988).
Giimis, A.S. and M.E. Ncsbit. Neuropsychologic(cognitive) disabilities in long-term survivors ofchildhood canccr. Pediatrics 18: 11-19 (1991).
Griffin. N.K. and J. Wadsworth. Eflect of treatment ofmalignant disease on growth in children. Arch. Dis.
Childhood 55: 600-603 (1980).
Growth liormone Treatrncnt of short Stature. State-ofthe-Art in 1989. Acla Paediatr. Scand. (Suppi.) 362:
1-75 (1989).
Glatstein, E., S. Mcllardy-Young. N. Brast ct al.
Alternation in scrurn thyrotropin ('1511) and thyroidlunction following riidiotherapy in patients withlnalignnnt lyn~phonla.J. Clin. Endocrinol. 32: 833-841(1971).
Green. DM., M.L Brechcr, D. Yakar el al. Thyroid funclion in pdialric patients after neck irrddialion for 1.lodgkin's
disease. Med. Pcdiatr. Oncnl. 8: 127-136 (1980).

Goolden. A.W. and J.U. Davey. T h e ablation of normal thyroid tissue with iodine-131. Ur. J. Kadiol. 36:
340-345 (1963).
G7 Green, D.M.. h1.1,. Brechcr. A.N. Lindsay ct al.
Gonadal function in pediatric palic1lL~ lollowing
trcatmcnt for liodgkin's disease. Mcd. I'cdiatr. Onml.
9: 235-244 (1981).
G8 Gonzalez, D.G. and K. Rrcur. Clinial data from
irradiated growing long boncs in childrcn. Int. J.
Radial. Oncol. Biol. Phys. 9: 841-846 (1983).
G9 Gauverky. F. Ubcr die Strahlenschiidigung dcs w a d senden Knochcns. Strahlcntherapie 113: 325-350(I 960).
GI0 Guyuron, B., A.P. Dagys and I.R. Munm. Long-termcliects of orbital irradiation. IIcad Neck Surg. 10: 8587 (1987).
G I 1 Gottdicner. J.S., M.J. Katin. J.S. Borer et al. Late
cardiac clTezts of thcrapcutic mcdiastinal irradiation.
Assessment by cchocardiography and radionuclide
angiography. N. End. J. Med. 308: 569-572 (1983).
G12 Greenwood, R.D., A. Roscnthal, R. Cassady et al.
Constrictive pcricarditis in childhood due to mediastinal irradiation. Circulation 50: 1033-1039 (1974).
G I 3 Green, D.M., R.L. Gingcll, J. Pearce ct al. The effectof mediastinal irradiation on cardiac function ofpatients treated during childhood and adolescence for
Hodgkin's disease. J. Clin. Oncol. 5: 239-245 (1987).
G14 Gilladoga, A.C., C. Manuel, C.T.C. Tan et al. The
cardiotoxicity of adriamycin and daunomycin inchildren. Cancer 37: 1070-1078 (1976).
G15 Gregl, A. and J.W. Weiss. Mammohypoplasie nachR6ntgenbestrahlung von Hiimangiomcn im Sauglingsalter. Fortschr. Gcb. Rontgenstr. Nuklcarmed. 96: 272277 (1962).
I11 11aucr-Jcnsen. M. Latc radiation injury of the small
intestine. Clinical. pathophysiologic and radiobiologic
aspects. A review. Acta Onml. 29: 401-415 (1989).
112 Hirsch, J.F., D. Renier, A. Pierre-Kahn ct al. Les
mCdulloblastomes dc I'cnfant. Survic ct n%ultats
fonctionnels. Neurochirurgie 24: 391-397 (1978).
113 11arten. G., U. Stcphani, G. llcnzc et al. Slight
impairment of psychomotor skills in children aftcr
treatment of acute lymphoblastic leukemia. Eur. J.
Pediatr. 142: 189-197 (1984).
114 Hanefeld, F. and H. Riehm. Therapy of acutelymphoblastic lcukcmia in childhood: eflects on the
nervous system. Ncuropcdiatrio 11: 3-16 (1980).
115 Hcrbcr, S.M., R. Kay, R. May ct al. Growth of longterm survivors of childhood malignancy. Ach
Paediatr. Scand. 74: 438-441 (1985).
116 Ilirsch, J.F.. D. Renier, P. aernichow el al.
Medolloblastoma in childhood. Survival andfunctional rcsulls. Acta Neurochir. 48: 1-15 (1979).
Heidemann, P.H., P. Stubbe and W. Bcdr. Transient
7
secondary hypothyroidism and thyroxine binding
globulin deficiency in leukemic children during
polychemotherapy: an cffcct of I,-aspari~ginase. Eur.
J. Pediatr. 136: 291-295 (1981).
118 Ilcmpelmann. L.tl. Neoplasms in youthful populations
following X-ray trcatmcnt in infancy. Environ. Res. 1:
338-358 (1967).
H9 tlolm, L.-E.. G. Lundcll, A. Israelsson et al. Incidenceof hypothyroidism occurring long alter iodine-131

G6thcrapy for hyperthyroidism. J. Nucl. Med. 23: 103107 (1982).
1110 Ilolm, L.-E. and I. Alindcr. Relapses after thionamidc
therapy for Graves' disease. Acb Med. Scand. 211:489-492 (1982).
1111 Ilayck, A., F.M. Chapman and J.D. Gawford. Longtcrn~rcsults of treatment of thyrotoxicosis in childrcn
and i~dolcsccntswith radioactive iodine. N. Engl. J.
Mcd. 283: 949-953 (1970).
1112 Ilorning, SJ., R.T. tloppe, 11.S. Kaplan et al. Female
reproductive potential aftcr treatment for llodgkin's
discasc. N. Engl. J. Mcd. 304: 1377-1382 (1981).
i l l 3 Ilimmclstcin-Braw, R.. 11. Peters and M. Fabcr.
lnflucncc of irradiation and chemotherapy on theovaries of children with abdominal tumours. Br. J.
Cancer 36: 269-275 (1977).
I114 Ilamrc, M.R., L.L. Robison. M.E. Nesbit et al.
Gonadal function in survivors of childhood acutelymphoblastic leukemia (ALL). Abstract. Proc. Am.
Soc. Clin. Oncol. 4: 166 (1985).
1115 Ilueck, H. and W. Spiebs. Zur Frage der Wachstumsstiirungen bei Rontgen bcstrahlten Knochen und
Gclcnktuberculosen. Strahlcnthcrapie 32: 322-342(1929).
1-116 klcaston, D.K.,H.I. Libshitz and R.C. Cahn. Skeletal
effects of H2. megavoltage irradiation in survivors ofWilms' tumor. Am. J. Rocntgenol. 133: 398-395(1979).
HI7 Heyn, R.. k Ragab, R.B. Raney et al. Late effects ofthcrapy in orbital rhabdomyosarmma in childrcn. A
report imm the Intergroup Rhabdomyosarcoma Study.
Cancer 57: 1738-1743 (1986).
HI8 llazra, T.A. and B. Shipman. Dental problems inpediatric patients with head and neck tumors
undergoing multiple modality therapy. Med. Pcdiatr.
Onool. 10: 91-95 (1982).
I119 Ilolbcck. S. and N. Ehlers. Long-term visual results ineyes cured for retinoblastoma by radiation. Acta
Ophthalmol. 67: 560-566 (1989).
1120 Ilaas, J.M. Symptomatic constrictive pcricarditis
dcvcloping 45 years after radiation thcrapy to !hemcdiastinum. A review of radiation pericarditis. Am.
tleart J. 77: 89-95 (1969).
H21 Ilost. 11. and J.R. Vale. Lung function after mantle
field irradiation in Hodgkin's disease. Cancer 32: 328332 (1973).
1122 Ilarms, C. Entwicklungshcmmung der weiblichcn
Brustdriise durch Rontgcnbcstrahlung. Strahlenthcrapic
19: 586-588 (1925).
International Commission on Radiological Protection.
I1
Non-stochastic Effects of Ionizing Radiation. ICRP
Publication 41. Annals of the ICRP 14(3). Pcrgamon
Prcss, Oxford, 1984.
International Commission on Radiological Protection.
121990 Recommendations of the International
Commission on Radiological Protection. ICRP
I'ublication 60. Annals of the ICItP 21(1-3). Pcrgnmon
Press, Oxford, 1991.
Inati. A.. S.E. Sallan, J.I<. Cassady el al. Efficacy andI3
morbidity of central nervous system "prophylaxis" inchildhood acute lymphoblastic leukemia: eight years'
wpericnce with cranial irradiation and intrathecal
mcthotrexate. Blood 61: 297-303 (1983).

Ishimaru, T.. T. Amano and S. Kawamoto. Relationship of stature to gamma and neutron exposure among
atomic bamb survivors aged Iw than 10 at the timeof the bomb, llirmhima and Nagasaki. RERF TR11881 (1981).
lnternational Commission on Radiological Protection.
Recommendations of the International Commission on
Radiological Protection. ICRP Publication 26. Annalsof the ICRP l(3). Pcrgamon R w , Oxford. 1977.
Ingold. J.A., G.B. Hced, H.S. Kaplan et al. Radiation
hepatitis. Am. J. Roentgcnol. 93: 200-208 (1965).
Inoue, S., Y. Shibata, 14. ilirayu et al. Thyroid
diseases among A-bomb survivor in Nagasaki. RERF
W 1 2 - 9 2 (1992).
International Chernobyl Project. Assessment ofradiological conxquenccs and evaluation of protective
measuns. Technical Report. International Advisory
Committee, IAEA (1991).
Johnson. F.L.. E.D. Thomas, B.S. Qark et al. A comparison of marrow transplantation with chemotherapy
for children with acute lymphoblastic leukemia insecond or subsequent remission. N. Engl. J. Med. 305:
846-851 (1981).
Jannoun, L. and k1J.G. Bloom. Long-term psychological effects in children treated for intracranial tumors.
Int. J. Radiat. Oncol. Biol. Phys. 18: 747-753 (1990).
Jannoun, L. Are cognitive and educational
development affected by age at which prophylactic
therapy is given in acute lymphoblastic leukaemia?
Arch. Dis. Childhood 58: 953-958 (1983).
Jaffe, N., M.P. Sullivan, H. Ried et al. Male reproductive function in long-term survivors of childhood
cancer. Med. Pediatr. Oncol. 16: 241-247 (1988).
Jaffe, N.. M. McNeese, J.K. Mayfield et al. QIildhood
urologic c a n a r therapy related sequelae and theirimpad on management. Cancer 45: 1815-1822 (1980).
Jaffe. N., B.B. Toth, R.E. Hoar et al. Dental andmaxiliofacial abnormalities in long-term survivors ofchildhood cancer: effects of treatment withchemotherapy and radiation to the head and neck.
Pedia~ics73: 816-823 (1984).
Johnson. F.L. and F.M. Balis. Hepatopathy following
imdiation and chemotherapy for Wilms' tumor. Am.
J. Pediatr. Hematol./Onml. 4: 271-221 (1983).
Kramer, S., M.E. Southard and C.M. Mansfield.
Radiation effect and tolerance of the oenwal nervous
system. p. 332-345 in: Frontiers of Radiation Therapy
and Onmlogy. Volume 6. (J.M. Vaeth, ed.) Karger,
Basel and University Park Press, Baltimore. 1972.
Kingsley, D.P. and B.E. Kendall. CT of the adverse
effects of therapeutic radiation of the central nervous
system. Am. J. Neuroradiol. 2: 453-460 (1981).
Kramer, J. and M. Moore. Iate effects of cancer
therapy on the ccntral nervous system. Semin. Oncol.
Nun. 5: 22-28 (1989).
Kay, H.E.M., P.J. Knapton. J.P. O'Sullivan ct al.
Encephalopathy in acute leukaemia associated withmethotrexate therapy. Arcl~.Dis. Childhood 47: 344354 (1972).
Kramer, J.H., D. Norman. M. Brant-Zawadzki et al.
Absence of white matter changes on magnetic resonanceimaging in children treated with CNS prophylaxis
therapy for leukemia. Can- 61: 928-930 (1988).

Kun, L.E., R.K. Mulhcrn and J J . Crisco. Quality oflife in children treated for brain tumors. lntelleciual,emotional, and academic lunction. J. Neurmurg. 58:
1-6 (1983).
Kirk, J.A., P. Raghupnthy, M.M. Stevens et al.
Cmwth lailure and growth-hormone deficiency after
traitmcnt lor acute lyrnphoblastic Icukaemia. Lancet
1: 190-193 (1987).
Kaplan. M.M.. M.B. Garnick. R. Gelber et al. Risk
factors for thyroid abnormalities alter n d irradiation
for childhood cancer. Am. J. Med. 74: 272-280 (1983).
Katsanis, E., R.S. Shapiro, L.L. Robison et al. Thyroid
dysfundion following bone marrow t r a n ~ ~ l a n ~ t i o n :long-term follow-up of 80 pediatric patients. Bone
Marrow Tntnspl. 5: 335-340 (1990).
Klinc, R.W., M.T. Gillin and L.E. Kun. Cranial
irradiation in acute leukemia: dose estimate in thelens. Int. J. Radiat. Onml. Biol. Phys. 5: 117-121(1979).
Kopelson, G. and K J . Herwig. The etiologies ofcoronary artery disease in cancer patients. Int. J.
Radiat. Oncol. Biol. Phys. 4: 895-906 (1978).
Kadota, R.P., E.O. Burgert, D.J. Driscoll et al.
Cardiopulmonary function in long term survivors ofchildhdod Hodgkjn's lymphoma: a pilot study.
Abstract. Proc. Am. Soc. Clin. Oncol. 5: 198 (1986).
Kolhr, J.. V. Bek and R. Vrabec. Hypoplasiaof the~.
growing breast after contact x-ray therapy for
cutaneous angiomas. Arch. Dermatol. 96: 427-430(1967).
Kraut. J.E.. M.A. Baghaw and E. Glatstein. Hepaticeffects of irradiation. p. 182-195 in: Frontiers ofRadiation Therapy and Oncology. Volume 6. (J.M.
Vacth, ed.) Karger, Basel and University Park Press,
Baltimore, 1972.
Kun. L.E. and B.M. Camita. Hepatopathy following
irradiation and adriamycin. Csncu 42: 81-84 (1978).
Koskimics, 0. Arterial hypertension developing 10
years after radiotherapy for Wilms' tumour. Br. Med.
J. 285: 996-998 (1982).
Kazanets, E.G., A.P. Andreeva. N.A. Karamjan et al.
Pathogenesis of anemia in childrrn of the Bjansk
region. in: Molecular and Gcmtic ~ t c h a n i s m sof
Influence of Low Radiation Doses.Moscow, 1993. (inRussian)
Karamjan. N.A., S.S. Loria, S.G. Pobpova et al.
Hypochronic erythrocytes and secondary erythrocytosis in children from contaminated areas exposed
to low radiation doses. in: Molecular and Genetic
Mechanisms of Influence of Low Radiation Doses.
Moscow, 1993. (in Russian)Li, F.P. and R. Stone. Survivors of cancer inchildhood. Ann. Intern. Me.. 84: 551-553 (1976).
ti. F.P.. K.R. Winston and K Gimbrem. Follow-up ofchildren with brain tumors. Canax 54: 135-138 (1984).
Livrea, P., I.L. Simone. G.B. Zimatore et al. Acutechanges in blood-CSF barrier pcrmsclectivity to serum
proteins after intrathecal methotrexate and CNS
irradiation. J . Neurol. 231: 336-339 (1985).
Lannering. B.. I. Mirky, A. Lundberg et al. Long-termsequelae after pediatric brain tumors: their effect on
disability and quality of life. Med. Pediatr. Oncol. 18:
304-310 (1990).

M10 Mulhcrn. R.K. and LE. Kun. Ncuropsychologic function in childrcn with brain tumors. Ill. Intervalchanges in the six months following treatment. Mcd.
Pediatr. Onool. 13: 318-324 (1985).
MI1 Meadows, A.T.. J. Gordon, DJ. Massari ct al. Ilcdines in IQ scores and cognitive dysfunctions inchildrcn with acutc lyrnl~hocytic lcukacmia trcatcd
with cranial irradiation. Lancet 2: 1015-1018 (1981).
MI2 Moss, tI.A., E.D. Nannis and D.G. Poplack. I h ceffech of prophylactic treatment of thc central
nervous systcm on thc intcllcctual functioning ofchildren with acute lyrnphocytic leukemia. Am. J.
Med. 71: 47-52 (1981).
M13 Muchi, I{., T. Satoh, K. Yamamoto et al. Studics on
thc asscsmcnt of neurotoxidty in childrcn with acutelymphoblastic Icukcmia. Canccr 59: 891-895 (1987).
M14 Mauras, N.. 14. Sabio and AD. Rogol. Neuroendomine function in survivors of childhood acutc lymphocytic leukemia and non-Ilodgkins lymphoma: a study of
pulsatile growth hormonc and gonadotropin secre-tions.
Am. J. Pediatr. Hematol./Oncol. 10: 9-17 (1988).
M15 Motll, C. Disturbed pubertal growth in girls after
acute leukaemia: a relative growth hormone insulfidency with late presentation. Acta Paediatr. Scand.
(S~ppl.)343: 162-166 (1988).
M16 Mo&ll, C., S. Ganvicz, U. Wcstgrcn ct al. Disturbed
pubertal growth in girls treated for acutc lymphobiastic leukemia. Am. J. Pcdiatr. Hematol./Oncol. 4:
1-5 (1987).
M17 Motll, C.. S. Ganvia, U. Westgcn et al. Supprused
spontaneous secretion of growth hormone in girls alter
treatment for acutc lymphoblastic lcukacmia. Arch.
Dis. Childhood 64: 252-258 (1989).
M18 Mefferd, J.M., S.S. Donaldson and M.P. Link.
Pediatric Hodgkin's disease: pulmonary, cardiac. andthyroid fundion following ambined modality therapy.
Int. J. Radiat. Oncol. Biol. Phys. 16: 679-685 (1989).
M19 Maxon, H.R., S.R. Thomas, E.L. Sacngcr ct al.
Ionizing irradiation and the induction of clinicallysignificant discasc in the human thyroid gland. Am. J.
Med. 63: 967-978 (1977).
M20 Maxon, 1I.R. Radiation-induced thyroid disease. Mcd.
Clin. NorUl Am. 69: 1049-1061 (1985).
M21 Morimoto, I., Y. Yoshimoto, K. Sato et al. Scrum
TSH, lhyroglobulin, and thyroid disorders in atomic
bomb survivors exposed in youth: a study 30 ycan
afcr cxposurc. RERF TR/20-85 (1985).
M22 Morimoto. I.. Y. Yoshimoto, K. Sato el al. Scrum
T S I I , thyroglobulin, and thyroidal disorders in atomic
bomb survivors cxposcd in youth: 30-year follow-up
study. J. Nucl. Med. 28: 1115-1122 (1987).
M U Miller. JJ.. G.F. Williams and J.C. Leissring. Multiple
late complications of therapy with cycholophosphamide, including ovarian destruction. Am. J.
Med. 50: 530-535 (1971).
M24 Mays, C.W., 11. S p i s s and A. Gerspach. Skclctal
effects following 224-Ra injections into humans.
Ilcalth Phys. 35: 83-90 (1978).
M25 Meadows. A.T.. N.L. Krejmas and J.B. Belasco. The
medical cost of cure: scquclae in survivors ofchildhood cancer. p. 263-276 in: Slatus of theCurability of Childhood Cancers. (J. van Eys and
M.P. Sullivan. eds.) Raven Prcss, New York. 1980.

M26 McGinnis, J.I'., K.1'. Ilopkins, E.I. 7hompson ct al.
Mandibular third molar development after mantle
radiation in long-Icrm survivors of childhood
I lodgkin's discasc. Orill Surg. Oral Mcd. Oral Pathol.
63: 630-633 (1987).
M27 Mcrriam. G.It., A. Szcchtcr and E.1:. Focht. Thc
cllccls of ionizing rsdintions on thc cyc. p. 346-385
in: 1:ronticrs of Radiation Therapy and Oncology.
Volume 6. (J.M. Vacth, 4.) Kargcr, Basel andUniversity Park I'rcss, Baltimore, 1972.
M28 Marks, R.D.. S.K. Agarwal and W.C. Constable.
it;~diationinduced pcricarditis in Hodgkin's disease.
Acta Itadiol. Thcr. I'hys. Biol. 12: 305-312 (1973).
M29 Martin, R.G.. J.C. Rukdeschel, P. Chang ct al.
Itadiation-related pcricarditis. Am. J. Cardiol. 35: 216220 (1975).
M30 Mlkincn. L., A. Mlkipcrnaa. J. Rautoncn ct al. Longtcrm cardiac sequclac after treatment of malignant
tunlors with radiothcrapy or cytostatics in childhood.
Cancer 65: 1913-1917 (1990).
M31 Minow, R.A.. R.S. Benjamin and J.A. Gottlicb.
Adriamycin (NSC-123127) cardiomyopathy - anoverview with determination of risk fadors. Cancer
Chcmothcr. Rep. 6: 195-200 (1975).
M32 Miller, R.W., J.E. Fusncr, R.J. Fink et al. Pulmonary[unction abnormalities in long-term survivors of childhood cancer. Mcd. Pedialr. Oncol. 14: 202-207(1986).
M33 Mitus, A., M. Tcfft. F.X.Fellers. Long-tcrm follow-up
of rcnal functions in 108 children who underwent
ncphrcdomy lor malignant disease. Pediatrics 44:
912-921 (1969).
M34 Margolis, L. and T.L. Phillips. Whole-lung irradiation
for melastatic tumor. Radiology 93: 1173-1179(1969).
M35 Moss, W.T. Thcrapcutic Radiology. Mosby. St. Louis,
1959.
M36 Mclntosh, S., D.L. Davidson, R.T. O'Brien et al.
Mcthotrexatc hcpatotoxicity in children with Icukemia.
J. I'cdiatr. 90: 1019-1021 (1977).
M37 Mage. K.,J.F. Duhamel, J. Sauvegrain et al. Lesions
radiqucs du tube digestif de l'enfant aprcs irradiation
dc I'abdornen. k p c d s radiologiques. J. Radiol.
Elcctrol. Med. Nucl. 61: 763-768 (1980).
M38 Milher, J.F. Toxic and irradiation nephropathics. p.
1431-1472 in: Strauss and Welt's Diseases of theKidney. 3rd edition. (L.E. Earley and C.W.Gottschalk. cds.) Little Brown, Boston. 1979.
M39 Maicr. J.G. Elfccts of radiations on kidney, bladderand prostate. p. 196-227 in: Frontiers of Radiation'Ihcrapy and Oncology. Volume 6. (J.M. Vaeth, cd.)
Kargcr. Bascl and University Park Prcss, Baltimore.
1972.
M40 McGill. C.W., T.M. Iloldcr, T.11. Smith ct al. Postradiation renovascular hypertension. J. Pcdiatr. Surg.
14: 831-833 (1979).
M41 Molls, M. and M. Stusctlke. Radiotherapy in childhood: normal tilisue injuries and cardnogenesis.
p. 461-481 in: Mcdical Radiology. Radiopathology ofOrgans and Tissues. (E. Schercr, Ch. Streffer and
K.-It. Trott, eds.) Springer Verlag, Berlin, 1991.
N1 Ncsbit, M.E.. I1.N. Sather, L.L. Kobison ct al.
I'rcsymptomalic ccntral nervous sysrcm lhcrapy inpreviously untrcatcd childhood acutc lymphol)liistic
Icuhcmia: comparison of 1800 rad and 240() riid. A
rcport lor Childrcns Cancer Study Group. h n c c t 1:
461466 (1981).
Nclson. D.F.. K.V. Ilcddy, R.E. O'Miira et al.lhyroid
abnormalities following neck irradiiition lor 1 lodgkin's
discasc. Cancer 42: 2553-2562 (1978).
Ncsbit, M.E., L.1,. Robison. 1I.N. Sathcr ct al.
Evaluation of long-tcrm survivors of childhood acutc
lymphoblastic lcukcmia (ALL). Abstract. I'roc. Am.
Assoc. Canar Rcs. 23: 107 (1982).
National Council on Radiation Pmtcction and Mwurcrncnts. Proteclion of the thyroid gland in thc evcnt of
releases of radioiodine. NCRP Rcprt No. 55 (1977).
Ncuhauscr, E.B.D.. M.H. Wittenborg. C.Z. Bcrman ct
al. Irradiation cilccts of rocntgcn thcrapy on thc
growing spine. Iladiology 59: 637-650 (1952).
Ncsbit. M.E., W. Krivit. R. llcyn ct al. Acute andchroniceffects of mcthotrexate on hcpatic, pulmonary,and skeletal systems. Cancer 37: 1048-1054 (1976).
Nagalaki, S. Delaycd effects of atomic bomb radiationon the thyroid. p. 1-10 in: Radiation and the Thyroid.
(S. Nagataki. cd.) Exccrpta Mcdica, Amsterdam, 1989.
Notter. G.. R. Walstam and L. Wikholm. Radiationinduced cataracts alter radium therapy in childrcn. A
prcliminaj rcport. Acta Radiol. 254 (Suppl.): 87-92(1966).
Ochs. J., R. Mulhcrn, D. Fairclough ct al. Prospcctivc
evaluation of central nervous systcm (CNS) changcs
in children with acute lymphoblastic leukemia (N-1,)
treated with prophylactic cranial irradiation (KT) or iv
mcthothrcxatc (MTX). Abstract. Proc. Annu. Mcct.
Am. Soc. Clin. Oncol. 8: A824 (1989).
Ochs, JJ., L.S. Pawey, J.N. Whitaker ct al. Scrial
aanial mmputcd tomography scans in childrcn withleukemia givcn two diffcrcnt forms of central ncrvous
systcm therapy. J. Clin. Oncol. 1: 793-798 (1983).
Obelz, S.W., RJ. Ivnik, W.A. Smithson ct al.
Ncuropsychologic follow-up study of children withacutc lymphocytic lcukemia. A preliminary rcprt.
Am. J. Pediatr. Ilcmatol./Oncol. 1: 207-213 (1979).
Ochs. J., R. Mulhcrn. D. Fairclough ct al. Comparisonof neuropsychologic functioning and clinic;il
indicators of neurotoxicity in long-tcrm survivors ofchildhood lcukcmia given cranial radiation or
parcntcral methotrcxate: a prospcctivc study. J. Clin.
Onml. 9: 145-151 (1991).
Omran. A.R., R.E. Shorc. R.A. Markoff ct al. Followup study of paticnts h a l e d by X-ray epilalion fortinca capitis: psychiatric and psychometric evaluation.
Am. J. Public Ilcalth 68: 561-567 (1978).
Obcrficld, S.E., J.C. Allen, J. Polliick et al. Long-tcrm
cndoainc scquclac alter trcatmcnt of mcdulloblastoma: pro&ctive study of growth and thyroid
function. J. Pcdiatr. 108: 219-223 (1986).
OlifI, A., U. Bode, B.B. Bercu ct al. Ilypothalamicpituitary dysfunction lollowing CNS prophyli~xisin
acute lymphocytic Icukcmia: mrrclation with C1'bcan
abnormalities. Mcd. Pediatr. Oncol. 7: 141-151(1 979).
Onoyama. Y., M. Abe, M. Takahashi ct al. Radiation
therapy of brain tumors in children. Radiology 115:
687-693 (1975).

Olive, I).. 13.1'. lrllcup and M. Picrson. Ovarianfunction in 12 long tcrm surviving paticnts (IrlS) withWilms' tumor. Abstract. I'roc. Annu. Mcct. Am. Soc.
Clin. Oncol. 6: A875 (1987).
0 1 0 Olivcr, J.II., G. Gluck, Il.13. Glcdhill ct al. Musculoskclctal dcforlnitics following Ircatmcnt of Wilms'
turnour. Can. Mcd. Assoc. J. 119: 459-464 (1978).
01 1 Oglcst~y,1l.13.. R.L. Black, L. von Sallmann ct al.
Cataracts in patients with rheumatic discascs treatedwith corticostcroids. Furthcr observations. Arch.
Ophthalmol. 66: 41-46 (1961).
0 1 2 O'Mallcy. B., G J . D'Angio and G.F. Vawtcr. Latecllects of rocntgcn therapy givcn in infancy. Am. J.
Kocntgcnol. 89: 1067 (1963).
0 1 3 Ochs, JJ.. R. Bcrg, L. Ch'icn el al. Structural andfunctional central ncrvous systcm (CNS) changes inlong-term ircutc lymphocytic leukcmia (ALL)survivors. Proc. Am. Soc. Clin. Oncol. 1: 27 (1982).
0 1 4 Ochs, J.J.. P. Bcrger. M.L. Brccher et al. Computed
tomography brain scans in childrcn with acutc
lymphocytic lcukemia receiving methotrcxatc alone ascentral ncrvous systcrn prophylaxis. Cancer 45: 22742278 (1980).
0 1 5 Otake. M. and W J . Schull. Radiation-relatcd posterior
lenticular opacities in iliroshima and Nagasaki atomic
bomb survivors based on the DS86 dosimetry systcm.
Radial. Rcs. 121: 3-13 (1990).
0 1 6 Otake, M., S.C. Finch, K. Choshi et al. Radiationrclatcd optalrnologic changes and aging among
a-bomb survivors: a reanalysis. RERF TR/18-91(1991).
0 1 7 Ochs, J. and ILK. Mulhcrn. Prospective cvaluation ofneuropsychological function following aanial
irradiation or intermediate dose mcthotrexatc. p. 23-30
in: Late Ellccrs of Treatment for Childhood Cancer.
(D.M. Grccn and GJ. D'Angio, eds.) Wilcy-Liss Inc.,New York, 1992.
1'1
I'izzo, P.A., D.G. I'oplack and W.A. Blcyer.
Neurotoxidtics of current lcukemia thcrapy. Am. J.
Pediatr. I lcmatol./Onml. 1: 127-140 (1979).
1'2
Poplack, D.G. and P. Brouwcrs. Advcrsc scqualae of
ccntral ncrvous systcrn thcrapy. Clin. Oncol. 4: 263285 (1985).
Price, K.A. and P.A. Jamieson. The wntral nenrous
1'3
systcm in childhood Icukcmia. 11. Subacutelcukocnceph;~lopathy.Cancer 35: 306-318 (1975).
Price, R.A. ilnd D.A. Birdwcll. The ccntriil ncrvous
1'4
systcm in childhood Icukcmia. 111. Mineralizing
microangiopathy and dystrophic calcificalion. Cancer
42: 717-728 (1978).
1'5
l'avlovsky, S., J. Castano, R. Lciguarda ct al.
Ncuropsychological study in p?tients with N-L. Am.
J. Pcdiatr. IIcmatol./Onml. 5: 79-86 (1983).
I'ackcr, R.J.. R.A. Zimmerman and L.T. Bilaniuk.
P6
Magnctic resonance imaging in thc cvaluation of
trcatmcnt-rcli~tcd central ncrvous systcm damage.
Cancer 58: 635-640 (1986).
1'7Peylan-Ramu, N., D.G. I'oplack. P.A. I'izzo et al.
Abnormal CI' scans of the brain in asymptomaticchildren with acute lymphocytic lcukcmia alter
prophylactic trcatmcnt of the central ncrvous systemwith mdii~tionand intrathccal chemolhcri~py.N. Engl.
I. Mcd. 298: 815-818 (1978).

09

918

UNSCFAK 1993 REPOKI'

I'crry-Kcene, D.A.. J.1:. Conncliy, R.A. Young el al.
llypthalamic hypopituitarism following external
radiotherapy for turnours distant from the adcnohypophysis. Clin. Endocrinol. 5: 373-380 (1976).
Poussin-Kosillo, Ii., 1,.L Niscc and B J . Lee.
Complicalians of total nodal irradiation of llodgkin's
disease stages Ill and IV. Cancer 42: 437-441 (1978).
Probert, J.C. and B.R. Parker. The cKects of radiation
therapy on bone growth. Radiology 114: 155-162(1975).
Pmbert, J.C., B.R. Parkcr and 1I.S. Kaplan. Growth
retardation in children aftcr megavoltage irradiation or
the spine. Canccr 32: 634-639 (1973).
Price, D.A., MJ. Morris, K.V. Rowscll ct al. The
effects of anti-leukaemic d r u g on somatomedin production and cartilage rcsponsivencss to somatomcdin
in vitro. Abstract. Pediatr. Res. 15: 1553 (1981).
Parker, R.G. and H.C. Berry. Late effects of thcrapeutic irradiation on the skeleton and bone marrow.
Cancer 37: 1162-1171 (1976).
Prindull, G., W. Weigel, E. Jentsch el al. k e p t i cocstonecrosis in children treated for acute lymphoblastic leukemia and aplastic anemia. Eur. J. Pediatr.
139: 48-51 (1982).
Parsons. J.T., C.R. Fitzgerald, C.1. Hood et al. The
eCfects of irradiation on the eye and optic nerve. Int.
I. Radiat. Oncol. Biol. Phys. 9: 609422 (1983).
Prout, M.N., MJ.S. Richards, KJ. Chunget al. Adriamycin cardiotoxicity in children. Case reports, literature review. and risk factors. Cancer 39: 62-65 (1977).
Pratt, C.B., J.L. Ransom and W.E. Evans. Age-related
adriamydn cardiotoxicity in children. Cancer Treat.
Rep. 62: 1381-1385 (1978).
Pinkel, D.. B. Carnitla, L. Kun et al. Doxorubicin
cardiomyopathy in childrcn with left-sided Wilms'
tumor. Med. Pediatr. Oncol. 10: 483-488 (1982).
Quigley, C., C. Cowell, M. Jimencz et al. Normal or
early dcvclopment of puberty despite gonadal damage
in children treated for acute lymphoblastic Icukemia.
N. Engl. J. Mcd. 321: 143-151 (1989).
Qvist. C.F. and B. Zachau-firistiansen. Radiation
cataract following fractionated radium therapy inchildhood. Acta Radiol. 51: 207-216 (1959).
Rubin, P. and G.W. Casarett. Clinical Radiation
Pathology. Volume 1. Saunders, Philadelphia. 1968.
Rubin, P. and G.W. Casarctt. A direction for clinicalradiation pathology. The tolerance dose. p. 1-16 in:Fronliers oCRadiaGon Thcrapy and Oncology. Volume
6. (J.M. Vaeth, ed.) Kargcr, Basel and University Park
Prcss, Baltimore, 1972.
Rubin. P. The Franz Buschke lecture: Late ellccls of
chemotherapy and radiation thcrapy: a new hypolhesis. Int. J. Radiat. Onml. Biol. Phys. 10: 5-34 (1984).
Rubinstein, L.J., M.M. Herman, T.F. Long et al. Disseminated necrotizing leukoenccphalopathy: a complication of treated central nervous system leukemia andlymphoma. Canccr 35: 291-305 (1975).
Kimrdi. R., P. Brouwers, G. Di Chiro et al. Abnormal computed lomography brain scans in children
with acute lymphoblastic leukemia: serial long-term
follow-up. J. Clin. Oncol. 3: 12-18 (1985).

K6

Kaimondi, A.J. and T. 7'nmila. 'Thc disadvantages ofprophylactic whole CNS post-operative radiation
thcrapy I'or rnedullot~li~ston~a.
p. 209-218 in: Multidisciplinary Aspects of Brain Tumor Therapy. (P.
l'i~oletti, M.1). Walker. G. nutti ct al., d s . ) Elsevicr/'Nortt~ llolland I3iomedical Prcss. New York.
1979.
R7 Kubinstcin, C.L.. J.W. Varni and E.R. Katz. Cognitive
functioriing in long-term survivors or childhood
Icukcnlin; a prospective analysis. J. Dev. Bchav.
Pcdii~tr.l I : 301 -305 (1990).
8
Rowland. J.II., 0J. Glidewell. R.F. Siblcy et al.
Effccls of dificrent forms of central nervous systemprophylaxis on neuropsychologic function inchildhood leukemia. J. Clin. Oncol. 2: 1327-1335(1984).
119 Icobison, L.L., A.T. Meadows, M.E. Nesbit et al.
Factors associated with IQ scores in long-term
survivors of childhood acute lymphoblastic leukemia.
Am. J. Pediatr. Wematol./Oncol. 6: 115-120 (1984).
R10 Ron, E., B. Modan, S. Floro et al. Mental fundion
following scalp irradiation during childhood. Am. J.
Epidemiol. 116: 149-160 (1982).
R11 Richards. C.E., W.M. Wara. M.M. Grumbach et al.
Delayed onset of hypopituitarism: sequelae oftherapeutic irradiation of central nervous system, eye,and n~iddlecar tumors. J. Pediatr. 89: 553-559 (1976).
R12 Romshc, C.A., W.R. Zipf and A. Miser. Evaluation of
growth hormone release and human growth hormone
treatment in children with cranial irradiation associated short stature. J. Pediatr. 104: 177-181(1984).
R13 Robison, L.L., M.E. Nesbit, I.1.N. Sather et al. HeightoC children successfully treated lor acutelymphoblastic leukemia: a report from the late effects
study committee of Childrcns Cancer Study Group.
Med. Pediatr. Oncol. 13: 14-21 (1985).
R14 Robbins, J.. J.E. Rall and R.A. Conard. Late cflects ofradioactive iodine in fallout. Ann. intern. Med. 66:
1214-1242 (1967).
K15 Rogers, I'.C.J.. CJ.I.1. Fryer and S. Hussein. Radiationdose to the thyroid in the treatment of acutelymphoblastic leukemia (ALL). Mcd. Pediatr. Oncol.
10: 385-388 (1982).
R16 Robison. L.L., M.E. Ncsbit, M.N. Sather el al. Thyroid
abnormalities in long-term survivors of childhood
acute lymphoblastic Icukcmia. Pediatr. Res. 19: 226A
(1985).
R17 Rubin, P., P. van Houtte and L. Constine. Radiation
sensitivity and organ tolerances in pediatric oncology:
a ncw hypolhcsis. Front. Radiat. Ther. Oncol. 16: 6282 (1982).
R18 Robison. L.L. Delayed consequences of therapy inchildhood acute lymphoblaslicleukaemia. Clin. Oncol.
4: 321-332 (1965).
R19 Kefetoff, S., J. Ilarrison, B.T. Kiiranfilski et al.
Continuing occurrence o i thyroid carcinoma after
irradiation to the neck in infancy and childhood. N.
Lngl. J. Med. 292: 171-175 (1975).
K20 Kobbins, J. and W.11. Adams. Radiation effects in the
Marshall Islands. p. 11-24 in: Radiation and theThyroid. (S. Nagataki, cd.) Excerpla Mcdica.
Amsterdam, 1989.

920

UNSCEAR 1993 IU5I'OR'I'

Shalct, S.M.. J.D. Roscnstock, C.G. Bcardwcll el al.
Thyroid dyslunction following external irradiation to
the neck for Ilodgkin's disease in childhood. Clin.
Kndiol. 28: 511-515 (1977).
Schimpff, S.C., C.11. Diggs, J.G. Wiswcll et al.
Radiation-rclatcd thyroid dyslunction: implic3tions forthe trcalmcnt of llodgkin's discasc. Ann. Intcrn. Mcd.
92: 91-98 (1980).
Smith, K.E., R.A. Adlcr, 1'. Clark ct al. 'Ihyroid lunclion aftcr n~anlleirradiation in llodgkin's discasc. J.
Am. Mcd.
245: 46-49 (1981).
Sklar. C.A., T.11. Kim and M.K.C. Itamsay. ?hyroid
dysfunction among long-lcrm survivors of bone marmw transplanlation. Am. J. Mcd. 73: 688-694 (1982).
Sklar, C.A. Physiology o l growth hormonc production
and rclcase, p. 49-54 in: Latc Effccts olTrcatmcnt forChildhood Canccr. (D.M. Grccn and GJ. D ' h g i o ,cds.) Wilcy-Liss Inc., Ncw York, 1992.
Shalct, S.M., C.G. Bcardwcll, P.11. Morris-Joncs ct al.
Ovarian lailurc lollowing abdominal irradiation inchildhood. Br. J. Cancer 33: 655-658 (1976).
Stillman, RJ.. J.S. Schinleld, I.Schifl ct al. Ovarianlailure in long-term survivors of childhood
malignancy. Am. J. Obstet. Gyncml. 139: 62-66(1981).
Sanders, J.E.. C.D. Buckncr, K.M. Sullivan ct al.
Growth and devclopmcnt after bone marrowtransplantation. p. 375-382 in: Advances andContmvcrsies in Thalassemia Therapy: Bone Marrow
Transplantation and Othcr Approaches. (C.D.
Buckner, R.P. Galcc and G. Lucarclli, cds.) Alan It.
Liss Inc.. New York, 1989.
Sarhr, S.D., W.11. Bcienvaltcs, S.P. Gill ct al.
Subsqucnt lcrtility and birth historics of childrcn andadolescents treated with 13'1 lor thyroid canccr. J.
Nuc~.Mcd. 17: 460-464 (1976).
Shcrins, RJ. and JJ. Mulvihill. Gonadal dyslunction.
p. 2170-2180 in: Canccr. Principlcs & I'racticc o l
Oncology. (V.T. Dcvila, S. Ilcllman and S.A.
Koscnbcrg, cds.)
J.B.
Lippincot1 Company,
Philadelphia, 1989.
Stcfani, F.Il., II. Spicss and C.W. Mays. Cataracts inpatients injected with 224-Ra. p. 51-59 in: The
Radiobiology of Radium and Ihorotrast. (W. Giissncr,
G.B. Gerber, U. llagcn ct al., eds.) Urban 8;
Schwar~cnbcrg,Mbnchen, 1986.
Shalct, S.M., A. Tsatsoulis, E. Whitchcad ct al.
Vulnerability of thc hun~anLcydig ccll to radiation
damage is dcpcndcnt upon age. J. Endoainol. 170:
161-165 (1989).
Shalet, S.M., C.G. Bcardwcll, 11.S. Jacobs el al.
Testicular function following irradiation of thc human
prepubertal tcstis. Clin. Endocrinol. 9: 483-490(1978).
Shalet, S.M., A. Ilorncr, S.R. Ahmcd ct al. Leydig
cell darnagc alter testicular irradiation for
lymphoblastic leukacmia. Mcd. Pediatr. Oncol. 13: 6568 (1985).
Sklar, C.A., L.L. Robison, M.E. Nesbit el al. Emccts
of radiation on tcsticular function in long-term
survivors of childhood acutc lymphoblastic leukemia.
A report lmm the Childrens Cancer Study Group. J.
Clin. Oncol. 8: 1981-1987 (1990).

Smith, It., J.K. Ilavidson and G.E. Fatman. Skeletal
cfSccL\ o l orthovollagc and mcgavolt;~gc thcrapy
following lrcalrncnl of ncl~hroblastornir.Clin. liadiol.
33: 601-61 3 (1982).
Shalct, S.M., 13. Gibson, R. Swindcll ct al. Errect ofspins1 irradiation on growth. Arch. Dis. Childhood 62:
461-464 ( 1987).
Spicss, 11.. C.W. Mays and E. Spiess-l'aulus. Growth
rctardi~tionin childrcn injcclcd with 224-Ra. p. 45-50.
in: l'hc It;rdiol~iologyof liadium and 'Ihorotrast. (W.
Gtissncr, G.13. Gcrlxr. U. Ilapcn ct al., 4s.) Urban &Schwancnbcrg, Munchen. 1986.
Schultz, II.,R. Jacobscn. K. Bjnrn Jcnscn et al.
Ncptrrobl:rstoma. Results and complications o f treatmcnt. Acta Itadiol. Oncol. 18: 449-459 (1979).
Silvcrmari, C.L.. P.R.M. Thomas, W.11. McNistcr ct
al. Slipped lemorill capital cpiphyses in irradiatedchildrcn: dose, volume and agc relationships. Int. J.
R;rdiat. Oncol. Biol. Phys. 7: 1357-1363 (1981).
Sonis, A.L., N. Tarbcll, R.W.Valachovic ct al.
DcntoCacial dcvclopmcnt in long-term survivors ofacutc lymphoblastic Icukemia. A comparison of threetrealment modalities. Canccr 66: 2645-2652 (1990).
Sonnabcnd, E.. 11. Spicss and C.W. Mays. Tooth
brcakagc in paticnts injcctcd with 224-Ra. p. 60-64 in:
Thc Radiobiology of Radium and Thorotrast. (W.
Gossncr, G.R. Gcrber. U. Clagen ct al., 4s.) Urban &Schwartcnbcrg, Miinchcn, 1986.
Spacth, G.L. and L. von Sallmann. Corticosteroids andcataracts. Int. Ophthalmol. Clin. 6: 915-928 (1966).
Stcwart, J.R. and L.F. Fajardo. Dose response in
human and expcrimental radiation-induced heartdisease. Application of the nominal standard dose(NSD) concept. Radiology 99: 403-408 (1971).
Scott, D.L. and R.D. Thomas. L ~ t eonset mnstrictive
pcricarditis after thoracic radiotherapy. Br. Mcd. J. 1:
341-342 (1978).
Smith, I'J., 11. Ekcrt, K.D. Waters ct al. Highincidcnce of cardionlyopathy in children treatcd withadrianlycin and D T l C in combination chcmothcrapy.
Cancer Trcat. Rep. 61: 1736-1738 (1977).
Springmcycr. S.C., N. 1:lournoy. K.M.Sullivan ct al.
Pulmonary function changes in long-lcrm survivors ofallagcncic marrow transplantation. p. 343-353 in:
Rcccnt Advanccs in Bone Marrow Transplantation.
(1t.1'. Galc. cd.) N a n Il.Liss Inc., New York, 1983.
Shapiro, S.J., S.D. Shapiro. W.B. Mill ct al. Prospcctive study of long-lcrm pulmonary mnnilcstationsof mantle irradiation. Int. J. ltadiat. Oncol. Biol. Phys.
19: 707-714 (1990).
Sco~ti.G., M. Br,rcchi, G. Masera el al. l'rophylactic
treatment of the ccnlral nervous system i n acutelymphoblastic leukcmia.
findings in 45 childrcn o lthcrapy. J. Neurol. Sci. 2(4): 361-365 (1981).
Shcline, G.E., W.M. Wura and V. Smith. ?hcrapeutic
irradiation and brdin injury. Int. J. Iladiat. Onml. Biol.
Phys. 6: 1215-1218 (1980).
Stcvcns. S.K., S.G. Moore and I.D. Kaplan. Early andlate bonc-marrow changes afier irradia~ion:MR cvaluation. N l t , Am. J. Rocntgcnol. 154: 745-750 (1990).
Trott, K.-R. Chronic darnagc aftcr radiation thcriipy:
challengc to radiation biology. Irrt. J. Iladiat. Onwl.
Biol. I'hys. 10: 907-913 (1984).

ANNW I: LATE DIiIFKMINISTlC EFFECIS IN CIIILDREN

K21 Rallison, M.L., U.M. Ilohyns, F.R. Kcating ct ill.
Thyroid disease in childrcn. A survey of subjccts
potentially c x p s c d to lallout radiation. Am. J. Mcd.
56: 457-463 (1974).
K22 Rallison, M.L., 13.M. Dobyns. F.R. Kcaling ct al.
Thyroid nodularity in childrcn. J. Am. Mcd. k o c .
233: 1069-1072 (1975).
K23 Rappaport, K., R. Brauncr. P. Ckemichow ct al. 1:ffcct
o l hypothalamic and pituitary irrddialior~on pubcrtal
dcvclopmcnt in childrcn with cranial tumon. J. Clin.
Endocrinol. Mctab. 54: 11 64-1 168 (1982).
lC24 Rowley. MJ., D.R. Leach, G.A. Warner el al. 1;flcctof graded doses of ionizing radiation on the humantestis. Radiat. IZcs. 59: 665-678 (1974).
It25 Rubin, P., R.B. Duthic and I,.W. Young. Significanceof smliosis in post-irradiated Wilms' tumor andneuroblastoma. Radiology 79: 539-559 (1962).
R26 Rausch, L.. W. Koch and G. Hagemann. Klinische
und dosimetrische Untersuchungen zur Fragc der kritischen Dosis und typischcr Strahlenschidcn am Skelctt
bestrahlter Angiom-Patienten. Strahlcnthcrapie(SondcrbHnde) 55: 198-514 (1964).
R27 Riseborough, E.J., S.L. Grabias, R.I. Burton ct al.
Skeletal alternations following irradiation for Wilms'
tumor with particular reference to scoliosis andkyphosis. J. Bone Jt. Surg. 58A: 526-536 (1976).
R28 Ruckdeschel, J.C., P. Chang, R.G. Martin ct al.
Radiation-related pericardial effusions in patients with
Ilodgkin's disease. Medicine 54: 245-259 (1975).
R29 Rubin, P., S. Landrnan, E. Mayer et al. Bone marrow rcgeneration and extension aftcr extended field irradiationin Hodgkin's disease. Cancer 32: 699-711 (1973).
R30 Ron, E., B. Modan, J.D. Boicc et al. l'umors of thebrain and nervous system after radiotherapy inchildhood. N. Engl. J. Mcd. 319: 1033-1039 (1988).
Sposto. R. and G.D. Ilarnmond. Survival in childhood
S1cancer. flin. Oncol. 4: 195-201 (1985).
S 2 Shcline, G.E.. W.M. Wara and V. Smith. ?herapeuric
irradiation and brain injury. Int. J. Radiat. Oncol. Biol.
Phys. 6: 1215-1228 (1980).
S3 Silverman. C.L., 11. Palkcs. B. Talcnt ct al. Latc
effecls of radiothcrapy on patients with cerebellar
medulloblastoma. Cancer 54: 825-829 (1984).
Suc, E., C. Kalila. R. Brauner et al. Brain tumours
S4
under the age of three. The price of survival. A
rctrospedive study of 20 long-term survivors. Acla
Neurochir. 106: 93-98 (1990).
Sawyer, M.G., I. Toogood, M. Rim ct al. School
S5
performance and psychological adjustment of childrcn
treated for Icukcmia. A long-term follow-up. Am. I.
I'cdiatr. I lematol./Oncol. 11: 146-152 ( 1989).
Soni. S.S., G.W. Marten, S.E. Pitncr ct al. Elfec~rof
S6
central-nervous-system irradiation on ncuropsychologic functioning of children with acute lymphocytic
leukemia. N. Engl. J. Med. 293: 113-118 (1975).
Shore, R.E., R.E. Albert and B.S. Pasternack. Follow-up
S7
study of patiens treated by x-ray cpilation for tinea
capitis. Resurvey of post-treatment illness and mortality
experience. Arch. Environ. Health 31: 21-28 (1976).
S8 Spunberg, JJ.. C.11. Chang, M. Coldman el al.
Quality of long-term survival following irradiation for
intraaanial tumors in children under the age of two.
Int. J. Radiat. Oncol. Biol. Phys. 7: 727-736 (1981).

91 9

Snmai~n,N.A.. I'.N. Schultz, K.-I'.P. Yang el al. Endoa i n c complications alter radiothcrapy lor tumors of
the hcad and ncck. J. Lab. Clin. Mcd. 109: 364-372(1087).
Shi~let,S.M. Growth and hormonal status of childrcn
trcatcd for brain tumours. Child's Brain 9: 284-293(1982).
Stinlct. S.M., C.G. Beardwcll. B.M. Aamns ct al.
Growth impairment in childrcn trcatcd for brain
tumours. Arch. Dis. Childhood 53: 491-494 (1978).
Shitlct, S.M.. C.G. Beardwcll. J.A. Twomcy ct al.
Endocrine function following the treatment ol acutc
leukemia in childhood. J. Pcdiatr. 90: 920-923 (1977).
Sh;tlct. S.M., C.G. Beardwcll, P.11. Morris-Joncs ct al.
Growtti hormone dclicicncy in children with brain
tumors. Cancer 37: 1144-1148 (1976).
Shalct, S.M.. C.G. Beardwcll. D. Pearson et al. T?IC
effcct of varying doses of cerebral irradiation on
g o w t h hormone production in childhood. Clin.
Endocrinol. 5: 287-290 (1976).
Shalct, S.M.. C.G. Beardwell. I.A. MacFarlane et al.
Endocrine morbidity in adults trcatcd with ccrcbral
irradiation for brain tumors during childhood. Acta
Endocrinol. 84: 673-680 (1977).
Shalct. S.M.. C.C. Bcardwcll, P.11. Morris-Jona ct al.
I'ituilary lunclion alter trcalmcnt of intraaanialtumours in childrcn. Lancet 2: 104-107 (1975).
Samaan, N.A., R. Vieto, P.N. Schultz ct al.
Ilypothalamic pituitary and thyroid dysiunction afterradiotherapy to the head and neck. lnt. J. Radiat.
Oncol. Uiol. Phys. 8: 1857-1867 (1982).
Sama;~n. N.A., M.M. Bakdash, J.B. Caderao et al.
llyppiluibrism alter external irradiation. Evidence
lor both hypothalamic and pituitary origin. Ann.
Intern. Med. 83: 771-777 (1975).
Shalct, S.M., D.A. Price. C.G. Beardwell CI al.
Normal g o w t h despite abnormalities of growth
hormonc secretion in childrcn treated lor acutc
leukcrnia. J. Pediatr. 94: 719-722 (1979).
Shalct, S.M. The effccts of cancer ucatmcnt on
growth and sexual devclopmenl. Clin. Oncol. 4: 223238 (1985).
Shalet, S.M., C.G. Beardwell, P.11. Morris-Jones et al.
Growth hormone deficiency alter treatment of acuteleukaemia in children. Arch. Dis. Childhood 51: 489493 (1976).
Starccski. P.J., I'.A. Lee, J. Blatt ct al. Comparable
effects of 1800- and 2400-rad (18- and 24-Gy) craniitl
irradiation on height and weight in children trcatcd for
acute lymphocytic leukemia. Am. J. Dis. Child. 141:550-552 (1987).
Sandcrs. J.E.. S. Pritchard. P. Mahoney et al. Growthand development lollowing marrow transplanlation lor
leukemia. Blood 68: 1129-1135 (1986).
Sandcrs, J.E. Late effects in children receiving total
body irradiation lor bone marrow transplanbtion.
Radiolhcr. Oncol. 18 (Suppl. 1): 82-87 (1990).
Sandcrs, J.E. Implications o l cancer thcnpy to the headand ncck on p w U 1 and development and other delayed
elfeas. Natl. Cancer Inst. Monogr. 9: 163-167 (1990).
Sutow, W.W., R.A. Conard and K.M. C r i f i ~ hGrowth.
status o l children exposed to lallout radiation on the
Manhall Islands. Pediatrics 36: 721-31 (1965).

2

Thamcs, 11.11., lI.K. Withcn, LJ. I'clcn ct al.
Changes in mrly and Intc radiation responses withaltered dosc fractionation: implications for doscsurvival relationships. Int. J. Kadint. Oncnl. 13iol.
Phys. 8: 219-226 (1982).
'13 Tarbcll, TJ.. E.C. Guini~n, L. Chin ct ill. Itcnal
insufiicicncy i~ftcrlotill body irradiation for pcdiiltricbonc marrow transplanliltion. Radiothcr. Oncnl. 18(Suppl. 1): 139-142 (1990).
'r4 Tamaroff, M., K. Salwcn, D.R. Millcr ct al.
Comparison of ncuropsychoiogic pcrformancc inchildren trcatcd for acutc lymphoblastic lcukcmia(ALL) with 1800 rads cranial radiation plus
intrathccal mcthotrcxatc or intrathccal mcthotrcxatc
alone. Abstract. I'roc. Am. Soc. Oncol. 3: 198 (1984).
TS TamarofC, M., D.R. Miller, M.L. Murphy ct al.
Immediate and long-tcrm post-thcrapy ncuropsychologic performana: in childrcn with acutc lymphoblastic leukcmia trcatcd without ccntral ncrvous
systcm radiation. J. Pcdiatr. 101: 524-529 (1982).
T6 Tamaroff, M., R. Salwen, D.K. Miller ct al.
Ncuropsychologicscquelac in irradiated (1800 rads (r)& 2400r) and non-irradiated childrcn with acutelymphoblastic lcukcmia (ALL). Abstract. I'roc. Am.
Soc. Clin. Oncol. 4: 165 (1985).
T7 Trautman, P.D., C. Erickson. D. Shaifcr ct al.
Prediction of intcllcctual dcfitits in childrcn withacute lymphoblastic Icukcrnia. J. Dcv. 13chav. Pcdiatr.
9: 122-128 (1988).
T8 Tamura, K.. K. Shirnaoka and hl. Fricdman. Thyroid
abnormaiitics associated with trcatmcnt of malignant
lymphoma. Canccr 47: 2701-271 1 (1981).
T9 Tarbcll, N.J.. L. Thompson and P. Mauch. 'Thoracic
irradiation in llodgkin's discasc: discasc control andlong-tcrm complications. Int. 1. Radiat. Oncol. Biol.
Phys. 18: 275-281 (1990).
T10 Tefft. M., P.B. Lattin. B. Jcreb ct al. Acutc and lateeffccls on normal tissucs following combined chcmoand radiotherapy for childhood rhabdomyosarcoma
and Ewing's sarcoma. Cancer 37: 1201-1213 (1976).
'T11 Thomas, P.R.M., K.D. Grilfith, B.B. Fincbcrg ct al.
Lalc effcds of trcatrncnl for Wilms' tumor. Inl. J.
Radiat. Oncol. Uiol. Phys. 9: 651-657 (1983).
T12 Thomas. P.R.M.. M. Tcfft, G J . D'Angio ct al.
Radiation associated toxicities in the Second National
Wilrns' Tumor Study (NWTS-2). Abstract. Int. J.
Radiat. Oncol. Biol. Phys. 10 (Suppl. 2): 8 8 (1984).
T I 3 Tcfft, M.. A. Mitus. L. Das ct al. Irriidi;~tion of thc
liver in childrcn: rcvicw of cxpcricncc in the scutc
and chronic phascs, and in the intact normill and partially resected. Am. J. Roentgenol. 108: 365-385(1970).
T I 4 Twaddlc, V., l'.G. Rritton, A.C. Craft ct al. Intellectual function aftcr trcatmcnt for leukaemia or solid
tumours. Arch. Dis. Childhood 58: 940-952 (1983).
T I 5 Tcrcshcnko, N.Ya., L.I. Burtscva and V.M. Ahdulaeva. Delayed clinical cffccts of contact gimmairradiation thcripy for angioma cutis in young
children. Med. ltadiol. 11: 49-53 (1988). (in Russian)T I 6 Tarbell. NJ.. E.C. Guinan. C. Niemcycr ct al. Late
onsct of renal dysfunction in survivors of bonemarrow transplantation. Int. J. Radiat. Oncol. Uiol.
Phys. IS: 99-10j (1988).

Tichclli, A.. A. Gratwohl. M. Uhr el al. Gcsundhcitszustnnd und SpZtkomplikRtioncn nach allogcner Knochcnmarktransplanlation. Einc u b e n i d t . Schwciz.
hlcd. Wochcnschr. 121: 1473-1481 (1991).
IJnitcd Nations. Sources. Effccls and Risks of lonizing
Itildii~tion.Unitcd Nations Scicnlilic Committee on thc
ITfccLs of Atornic Iti~dii~tion.1988 R c p r t to thc
Gcncrill k c m b l y , with anncxcs. Unitcd Nations .%lapul~lic;itionE.88.IX.7. Unitcd Nations, Ncw York. 1988.
IJnitcd Nations. Genetic and Somatic Effccts oflonizing Itadiation. Unitcd Nations ScientificCnmmittcc on thc Effcas of Atomic Radiation, 1986
Kcport to thc Gcncral hsscmbly. with anncxcs. Unitcd
Ntitions salcs publication E.86.IX.9. United Nations,
New York. 1986.
IJnitcd Nations. Ionizing Itadiation: Sources andI3iological Effects. Unilcd Nations ScicntificCommittee on the Effccts of Atomic Radiation, 1982
Kcport to the General Assembly, with anncxcs. Unitcd
Nations sales publication E.82.IX.8. Unitcd Nations,
Ncw York. 1982.
Unitcd Nations. Sources and Effects of lonizing
ILdiation. United Ni~tionsScicnlitic Committee on thc
Eflccb of Alomic Radiation, 1977 report to the Gcncral
A~scrnbly,with anncxcs. IJnitcd Nations salcs publication E.77.IX.l. Unitcd Nations, Ncw York, 1977.
Undcnvood, G.B. and L.E. Gaul. Disfiguring scquelae
from radium thcrapy. Kcsults of lrcatmcnt of abirthmark adjacent to thc brcast in a female infant.
Arch. Dcrrnatol. Syphilology 57: 918-919 (1948).
Von Muchlcndahl, K.E., I I . Gadncr, H. Richm ct al.
Endocrine function aner anlincoplaslic thcrdpy in 22
childrcn with acute lymphoblastic leukacrnia. llclv.
I'acdiatr. Acta 31: 463-471 (1976).
Vcnosa. M.S.. RJ.A. Aur. J.V. Simonc ct al. Fiveycaw aftcr ccntral ncrvous system irradiation o fchildrcn with Icukcmia. Int. J. Radiat. Onwl. Biol.
I'hys. 1: 209-215 (1976).
Von Iloff, D.D., M. Rozcncwcig and h4. Piccart. l h ccirdiotoxicity of a n t i ~ ~ n c ac gr n b . Scrnin. Oncol. 9:23-33 (1982).
Von I lofl, D.D., M. Rozcn~wcig,M. Layard ct al. Daunomydn-induced cardiotoxicity in children and adults. A
rcvicw of 110 cases. Am. J. Mcd. 62: 200--X8 (1977).
Von Iloff, D.D.. M.W. Layard, P. Basa et al. Risk
fac~ors for doxorubicin-induccd congcstivc h a r t
failure. Ann. Inlcrn. Mcd. 91: 710-717 (1979).
Van Slyck, E.J. and G.A. Bcrrnudcz. Radiation
ncpliritis. Yale J. Biol. Mcd. 41: 243-256 (1968).
Van Wccl-Sipman, M.11.. 1'.'1'. van't Vecr-Korthof, 11.
van dcn Bcrg ct al. Late c f f c ~ t sof tolal body irradiation and cytostatic prcparilivc repimcn for bonemarrow transplantation in childrcn with hcmatologicalmalignancies. Kadiothcr. Oncol. 18 (Suppl. 1): 1.55157 (1990).
Vijn Why, S.K.. A.L. I:ricdman, L.J. Wci ct al. Kcn;jl
insufficiency aftcr bonc miltrow tramplilntation inchildrcn. Ronc Marrow Transplant. 7: 383-388 (1991).
Vli~dirninkaja,E.B., I.V. Zamaracva, E.U. O s i p v a C I
al. Granulocytopoiesis in children from the radiomnt;rminated areas. in: Molecular and Gcnctic
hlcchanisms of lnflucncc of l a w Radiation Do-.
Moscow. 1993. (in 1tussi;ln)Wilhcrs, I I.K. I'rcdicting I;ltc normal tissuc rcsponscs.
Int. J. Radial. Onml. Uiol. Phys. 12: 693-698 (1986).
Withcrs, 11.R.. I.J. Pclcrs, 1I.D. 'lharnes ct al. IIypcrfr;~ction;rtion. lnt. J. I{ediat. Oncol. Uiol. I'hys. 8:
1807-1809 (1981).
Whitt. J.K., RJ. Wclls. M.M. Lauria ct 211. Ganialradiation in childhood i~cutclymphocytic Icukcrnia.
Ncuropsychological scquclac. Am. J. Dis. Child. 138:730-736 (1984).
Wcstcrgren, U. Is growth horrnonc sccrc~ionrclatcd togowth? A c h I'acdiatr. S a n d . 362(S): 32-35 (1989).
Wclls, R.J., M.13. Fostcr, A J . D'Lcolc ct al. *lhccof childrcn
impact of aanisl irradiation on ~ h growthwith acute lymphocytic Icukcmia. Am. J. Dis. Child.
137: 37-39 (1983).
Wallace, W.ll.B., S.M. Shalet, J.11. llcndry ct al.
Ovarian failurc followir~gabdominal irradiation inchildhood: the radioscnsitivity of the human oocylc.
Br. J. Radiol. 62: 995-998 (1989).
Wilimas, J.. E. lhornpson and K.L. Smith. Long-tcrm
rcsulb of treatment of childrcn and adolcsccnb with
Hodgkin's disci~se.Canccr 46: 2123-2125 (1989).
Willich. E., 11. Kuttig, G . Picil ct al. Wirbcldulcnvcrandcrungcn nach Bcstrahlung wcgcn Wilms' tumor
im Klcinkindcrsal~er. Strahlcnthcr. Onkol. 166: 815821 (1990).

Walkcr, S.J., I../\. Whitcsidc, W.11. McAlistcr et al.
Slippcd capital fcmoral cpiphysis following radiation
Clin. Orlhop. 159: 186-193 (1981).
and chcniothcr~~py.
WIO Wolf. ILL., W.I!. Bcrdnn, J.R. Cassady CI al. Slippcd
fcrnor;tl wpi1;il cpiphysis as a scqucla to childhood
for mirlignant lumors. Radiology 125: 781irrddii~~ion784 ( 1977).
W1 1 Wcavcr. 1C.G.. A.R. Chauvcncl, 'l'.J. Smith et al.
0ph1;llrniccv;ilui~tionof long-term survivors of childhood, ;~cutcl yml)hoblastic Icukcmia. Cancer 58: 963968 (1986).
W12 Wart, W.M., T.L. Phillips. LW. Margolis cl al. Kadiirtion pncumonilis: a ncw approach to the derivationof timc-dose factors. Cancer 32: 547-552 (1973).
W13 Watchic. J.. C.N. Coleman, T.A. Raffin et al. Minimal
long-~crm cardiopulrnonilry dyslunction following
treatrncnt for I lodgkin's disease. Int. J. Radiat. Oncol.
Uiol. I'hys. 13: 517-524 (1987).
W14 Wohl, M.E., N.T. Grisarn, D.G. Traggis ct al. Effectsof therapeutic irradiation dclivcrcd in early childhood
upon subscqucnt lung function. Pediatrics 55: 507-514(1975).
%1
Zaharia, M., IJ. Caccrcs. S. Valdivia et al. Poslopcrativc wholc lung irradiation with or without
adrianiycin in ostcogcnic sarcoma. Int. J. Radiat.
O n a l . Biol. 1'11~s.12: 907-910 (1986).
WU