United Nations Scientific Committee on the Effects of Atomic Radiation

S O U R C E S , E F F E C T S A N D R I S K S O F I O N I Z I N G R A D I AT I O N

UNSCEAR 2013 Report
Volume II
SCIENTIFIC ANNEX B:
Effects of radiation exposure of children

SOURCES, EFFECTS AND RISKSOF IONIZING RADIATION
United Nations Scientific Committee on the
Effects of Atomic Radiation
UNSCEAR 2013
Report to the General Assemblywith Scientific Annexes

VOLUME II
Scientific Annex B

UNITED NATIONSNew York, 2013

NOTE
The report of the Committee without its annexes appears as Official Records of the General
Assembly, Sixty-eighth Session, Supplement No. 46.
The designations employed and the presentation of material in this publication do not imply
the expression of any opinion whatsoever on the part of the Secretariat of the United Nations­
concerning the legal status of any country, territory, city or area, or of its authorities, or­concerning the delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those that were in use at the time thedata were collected or the text prepared. In other cases, however, the names have been updated,
where this was possible and appropriate, to reflect political changes.

UNITED NATIONS PUBLICATION
Sales No. E.14.IX.2
ISBN: 978-92-1-142293-1
e-ISBN: 978-92-1-054215-9© United Nations, December 2013. All rights reserved, worldwide.
This publication has not been formally edited.

CONTENTS
Page

VOLUME I:
Report of the United Nations Scientific Committee on the Effects of Atomic Radiation
to the General Assembly
Scientific Annexes
Annex A. Levels and effects of radiation exposure due to the nuclear accident
after the 2011 great east-Japan earthquake and tsunami

VOLUME II:
Scientific findings on effects of radiation exposure of children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Annex B. Effects of radiation exposure of children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iii

v
1

Scientific findings on effects of radiation exposure of children
Note: The findings and conclusion, together with information on members of delegations
to UNSCEAR and scientific staff and consultants, presented here are based on scientificannex B of the UNSCEAR 2013 report and are extracted from the Official Records of theGeneral Assembly at its Sixty-eighth session, Supplement No. 46.
[…]
45. Epidemiological studies reported in the literature vary with regard to the specificage groups they consider. For the purposes of the Committee’s evaluation of theeffects of radiation exposure on children, the term “children”, in contrast to“adults”, included those exposed as infants, children and adolescents. The
evaluation did not specifically address effects of in utero exposure to radiation
because such information is contained in other comprehensive reports. The
evaluation also did not address the many beneficial uses of radiation exposure forchildren, such as in medical diagnosis and therapy, which are outside the mandate of
the Committee.
46. Sources of exposure to children that are of particular interest include accidental
exposures, and specific regions with enhanced levels of natural backgroundradiation, as well as diagnostic and therapeutic procedures. The data reviewed by
the Committee were derived from studies covering a wide range of doses, variable
dose rates, whole and partial body exposure and children of different ages. The
effects described in the annex are often very specific to a given exposure scenario.
47. At its sixtieth session the Committee considered the effects of radiation exposure ofchildren and reached the following conclusions:(a) For a given radiation dose, children are generally at more risk of tumour
induction than are adults. Cancers potentially induced by exposure to ionizing
radiation at young ages may occur within a few years, but also decades later. In its
report on its fifty-fourth session, the Committee stated that estimates of lifetime
cancer risk for those exposed as children were uncertain and might be a factor of
2 to 3 times as high as estimates for a population exposed at all ages. * That
conclusion was based on a lifetime risk projection model combining the risks of all
tumour types together;(b) The Committee has reviewed evolving scientific material and notes thatradiogenic tumour incidence in children is more variable than in adults and depends
on the tumour type, age and gender. The term “radiation sensitivity” with regard tocancer induction refers to the rate of radiogenic tumour induction. The Committee
reviewed 23 different cancer types. Broadly, for about 25 per cent of these cancer
types, including leukaemia and thyroid, skin, breast and brain cancer, children wereclearly more radiosensitive. For some of these types, depending on thecircumstances, the risks can be considerably higher for children than for adults.
Some of these cancer types are highly relevant for evaluating the radiologicalconsequences of accidents and of some medical procedures;*

Official Records of the General Assembly, Sixty-first Session, Supplement No. 46 andcorrigendum (A/61/46 and Corr.1) paras. 21-22.

v

(c) For about 15 per cent of the cancer types (e.g. colon cancer), children
appear to have about the same radiosensitivity as adults. For about 10 per cent ofcancer types (e.g. lung cancer), children appear less sensitive to external radiation
exposure than adults. For about 20 per cent of cancer types (e.g. oesophagus
cancer), the data are too weak to draw a conclusion regarding any differences inrisk. Finally, for about 30 per cent of cancer types (e.g. Hodgkin’s disease andprostate, rectum and uterus cancer), there is only a weak relationship or none at all
between radiation exposure and risk at any age of exposure;(d) At present, projections of lifetime risk for specific cancer types
following exposure at young ages are statistically insufficient. Estimates currently
do not adequately capture the known variations, and additional studies are needed;(e) For direct effects that occur after high (either acute or fractionated) doses(so-called deterministic health effects), the differences in outcome between
exposure in childhood and in adulthood are complex and can be explained by theinteraction of different tissues and mechanisms. These effects may be seen afterradiation therapy or following high exposures in accidents. The difference between
the radiation sensitivity of children and that of adults for deterministic effects in a
specific organ is often not the same as the difference for cancer induction. There aresome instances in which childhood exposure poses more risk than adulthood
exposure (e.g. risk of cognitive defects, cataracts and thyroid nodules). There areother instances where the risk appears to be about the same (e.g. risk ofneuroendocrine abnormalities), and there are a few instances where children’s
tissues are more resistant (e.g. lungs and ovaries);(f) Because of all the above considerations, the Committee recommends thatgeneralizations on the risks of effects of radiation exposure during childhood should
be avoided. Attention should be directed to specifics of the exposure, age at
exposure, absorbed dose to certain tissues and the particular effects of interest;(g) There have been many studies of possible heritable effects following
radiation exposure; such studies were reviewed by the Committee in 2001. It has
been generally concluded that no heritable effects in humans due to radiation
exposure have been explicitly identified (specifically in studies of offspring ofsurvivors of the atomic bombings). Over the past decade, there have been additional
studies that have focused on survivors of childhood and adolescent cancer following
radiotherapy, where gonadal doses are often very high. There is essentially noevidence of an increase in chromosomal instability, minisatellite mutations,transgenerational genomic instability, change in sex ratio of offspring, congenital
anomalies or increased cancer risk in the offspring of parents exposed to radiation.
One reason for this is the large fluctuation in the spontaneous incidence of theseeffects;(h) Health effects and risks are dependent on a number of physical factors.
Because children have smaller body diameters and there is less shielding by
overlying tissues, the dose to their internal organs will be larger than for an adult fora given external exposure. Because they are also shorter than adults, children may
receive a higher dose from radioactivity distributed in and deposited on the ground.
These factors are important when considering doses to populations in some areas
with high levels of radionuclides in and on the ground. In diagnostic medical
exposure, children may receive significantly higher doses than adults for the samevi

examination if the technical parameters for delivering the dose are not specifically
adapted;(i) Regarding internal exposure, because of the smaller size of infants andchildren, and thus because their organs are closer together, radionuclides
concentrated in one organ irradiate other organs of children’s bodies more thanoccurs in adults. There are also many other age-related factors involving metabolism
and physiology that make a substantial difference in dose at different ages. Several
radionuclides are of particular concern regarding internal exposure of children.
Accidents involving releases of radioactive iodines (for example, in a nuclear power
plant accident) can be significant sources of exposure of the thyroid gland, and thus
have the potential to induce thyroid cancer. For a given intake, the dose to thethyroid for infants is eight or nine as large as that for adults. For intakes of
caesium-137, there is very little difference in dose between children and adults.
Internal exposure of children also occurs in the medical use of radionuclides. The
spectrum of procedures normally performed on children is different from that
performed on adults. Potentially higher doses in children are offset in practice by
the use of a lower amount of administered radioactive material.
48. The Committee recognizes that continued research is needed to identify the fullscope and expression of the differences in effects, mechanisms and risk fromexposure to ionizing radiation for children and for adults. This is necessary because
for a number of studies (such as of the atomic bombing survivors, children exposed
to radioiodine after the Chernobyl accident and those who have had computed
tomography scans), the lifetime results remain incomplete. Future long-term studies
following childhood exposure will face significant difficulties owing to unlinked
health records, administrative and political barriers and ethical and privacy
considerations.
49. Important areas of future research and work also include evaluation of potential
radiation effects for children: (a) in areas of high natural background exposure; (b)after high-dose medical procedures involving interventional fluoroscopy; and (c)after cancer radiotherapy (including evaluation of potential interactions with othertherapies). The Committee has identified the following areas for future research as
well: development of databases on radiation doses for children who can be tracked
in the long term; and evaluation of effects following whole and partial irradiation ofjuvenile organs. Studies at the molecular, cellular, tissue and juvenile animal levelare potentially informative.

vii

Members of national delegations attending thefifty-eighth to sixtieth sessions of the United Nations
Scientific Committee on the Effects of Atomic Radiation
Argentina

A. J. González (Representative), A. Canoba, M. di
Giorgio

Australia

C. M. Larsson (Representative), C. Baggoley, G. Hirth,
S. B. Solomon, R. Tinker

BelarusJ. Kenigsberg (Representative), A. Stazharau, V. Ternov

Belgium

H. Vanmarcke (Representative), S. Baatout, H. Bijwaard,
H. Bosmans, G. Eggermont, H. Engels, F. Jamar,
L. Mullenders, H. Slaper, P. Smeesters, A. Wambersie,
P. Willems

BrazilJ. Hunt (Representative), D. R. Melo (Representative),
M. Nogueira Martins (Representative), M. C. Lourenço,
L. Holanda Sadler Veiga

CanadaC. Purvis (Representative), B. Pieterson (Representative),
N. E. Gentner (Representative), D. Boreham, K. Bundy,
D. B. Chambers, J. Chen, S. Hamlat, R. Lane, C. Lavoie,
E. Waller

China

Pan Z. (Representative), Chen Y., Du Y., Gao H., Liu J.,
Liu S., Pan S., Su X., Sun Q., Wang Y., Yang H., Zhang
W., Zhu M.

Egypt

T. S. El-Din Ahmed (Representative), M.A.M. Gomaa(Representative)

Finland

S. Salomaa (Representative), A. Auvinen, E. Salminen

FranceL. Lebaron-Jacobs (Representative), A. Rannou(Representative), E. Ansoborlo, M. Bourguignon,
J.-R. Jourdain, F. Ménétrier, M. Tirmarche

Germany

W. Weiss (Representative), A. A. Friedl, K. Gehrcke,
P. Jacob, T. Jung, G. Kirchner, J. Kopp, R. Michel,
W. U. Müller

India

K. B. Sainis (Representative), B. Das, P. C. Kesavan,
Y. S. Mayya, K. S. Pradeepkumar

Indonesia

S. Widodo (Representative), Z. Alatas, G. B. Prajogi,
G. Witono, B. Zulkarnaen

Japan

Y. Yonekura (Representative), S. Akiba, T. Aono, N. Ban,
M. Chino, K. Kodama, M. Kowatari, M. Nakano,O. Niwa, K. Ozasa, S. Saigusa, G. Suzuki, T. Takahashi,
Y. Yamada, H. Yamagishi

viii

MexicoJ. Aguirre Gómez (Representative)

Pakistan

M. Ali (Representative), Z. A. Baig

Peru

A. Lachos Dávila (Representative), B. M. García
Gutiérrez

PolandM. Waligórski (Representative), L. Dobrzyński, M.
Janiak, M. Kruszewski

Republic of Korea K.-W. Cho (Representative), S. H. Na (Representative),
K.-H. Do, D.-K. Keum, J.-I. Kim, J. K. Lee, S. Y. Nam
RussianFederation

M. Kiselev (Representative), A. Akleyev, R. Alexakhin,
T. Azizova, V. Ivanov, N. Koshurnikova, A. Koterov,
I. Kryshev, B. Lobach, O. Pavlovskiy, A. Rachkov,
S. Romanov, A. Sazhin, S. Shinkarev

Slovakia

E. Bédi (Representative), M. Chorváth, Ž. Kantová,
K. Petrová, L. Tomášek, I. ZachariášováSpain

M. J. Muñoz González (Representative), M. T. Macías
Domínguez, B. Robles Atienza, E. Vañó Carruana

Sudan

M.A.H. Eltayeb (Representative), I. Salih Mohamed Musa
(Representative), E.A.E. Ali (Representative)

SwedenL. Hubbard (Representative), L. Moberg (Representative),
A. Almén, L. Gedda, J. Johansson Barck-Holst

UkraineD. Bazyka (Representative)

United Kingdomof Great Britain
and Northern
Ireland

J. Harrison (Representative), J. Cooper (Representative),
S. Bouffler, J. Simmonds, R. Wakeford

United States ofAmerica

F. A. Mettler Jr. (Representative), L. R. Anspaugh,
J. D. Boice Jr., N. H. Harley, E. V. Holahan Jr.,R. J. Prestonix

Scientific staff and consultants cooperating with the United
Nations Scientific Committee on the Effects of Atomic
Radiation in the preparation of its scientific report for 2013
G. N. Kelly
V. Golikov
L. S. Constine
H. D. Nagel
D. Nosske
R. Shore

Secretariat of the United Nations Scientific Committee on
the Effects of Atomic Radiation
M. J. Crick
F. Shannoun
H. Yasuda (seconded)x

ANNEX B
EFFECTS OF RADIATION EXPOSURE OF CHILDREN

1ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

3

CONTENTSI.

INTRODUCTION......................................................................................................................................5

II. SCOPE AND METHODOLOGY ............................................................................................................5
III. SOURCES OF EXPOSURE......................................................................................................................7
A. BACKGROUND RADIATION ........................................................................................................8
B. MEDICAL RADIATION USES ........................................................................................................8
C. NUCLEAR WEAPONS.................................................................................................................. 11
D. ACCIDENTS AND INCIDENTS .................................................................................................. 11
IV. ANATOMICAL DEVELOPMENT AND PHYSIOLOGY ................................................................. 12
A. ALIMENTARY TRACT .................................................................................................................. 17
B. RESPIRATORY SYSTEM .............................................................................................................. 18
C. NEUROLOGICAL SYSTEM ......................................................................................................... 19
D. SKELETAL SYSTEM ...................................................................................................................... 20
E. GENITOURINARY SYSTEM ........................................................................................................ 22
F. ENDOCRINE SYSTEM.................................................................................................................. 24
G. FEMALE BREAST .......................................................................................................................... 25
V. DOSIMETRIC ASPECTS....................................................................................................................... 25
A. EXTERNAL EXPOSURE................................................................................................................ 26
B. INTERNAL EXPOSURE ................................................................................................................ 26
VI. HEALTH EFFECTS ................................................................................................................................ 28
A. MALIGNANT NEOPLASMS........................................................................................................ 28
B. DETERMINISTIC EFFECTS.......................................................................................................... 33
C. HERITABLE EFFECTS ................................................................................................................... 38
VII. FUTURE RESEARCH............................................................................................................................. 40
VIII. SUMMARY AND CONCLUSIONS .................................................................................................... 41
ACKNOWLEDGEMENTS............................................................................................................................ 43
APPENDIX A. DOSIMETRY....................................................................................................................... 45
APPENDIX B. MALIGNANT NEOPLASMS ........................................................................................... 71
APPENDIX C. DETERMINISTIC EFFECTS............................................................................................159
REFERENCES...............................................................................................................................................221

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

5

I. INTRODUCTION
1.
The Committee—in its 2000 Report (annex F), 2001 Report and 2006 Report (annex A)—has
previously considered the effects, and associated risks, of ionizing radiation exposure on vulnerable
populations [U10, U11, U12]. Several population groups are specifically identifiable as being more
vulnerable to radiation exposure than the population as a whole. These include embryos/foetuses,
children, and those persons with abnormalities of DNA repair, co-morbid conditions or concomitantinsults or stresses. Children are clearly the largest and most easily recognizable vulnerable populationgroup.
2.
Knowledge of the effects of radiation exposure on children is, and will continue to be, of greatsocial, public health, scientific, and clinical importance. Exposures range from those due to fallout fromatmospheric nuclear weapon testing to exposures from accidents, natural radiation and medical
procedures such as computed tomography (CT) and radiotherapy. Radiation effects have been studied
for over a century, and many of the large epidemiological studies and reports of the sources and effectsof ionizing radiation exposure have included children as part of the groups studied. Therefore, there isalready a large amount of scientific literature on the topic. To date, however, there have been nocomprehensive reports specifically addressing all aspects of radiation exposure of children and theconsequent health effects and associated risks. Information is often buried in epidemiological reports on
general population exposure. Scientific investigations and radiation protection efforts have occasionallyfocused on “critical” or “most exposed” individuals and “vulnerable” or “radiosensitive” populations.
3.
The general perception that children are more vulnerable to radiation exposure than are adults isonly partly true. The susceptibility of children to the effects of ionizing radiation has been a focus ofinterest for over half a century. There is a loosely stated notion that children might be two–three times
more sensitive to radiation than adults. Is this really true? In the broad spectrum of adverse healtheffects, children are at greater risk for some but not all effects. For a few effects, children may be moreresistant than adults. For example, while there are clear instances of an increased risk for children,
compared to adults, of the radiation-induction of some types of cancer, children actually have adecreased risk or no difference in risk for other types. There are similar examples with regard to noncancer (deterministic) effects.

II. SCOPE AND METHODOLOGY
4.
This annex includes information on adverse effects following radiation exposure of children.
Although the medical benefits of using radiation for diagnosis and therapy of illnesses such as cancer
are well recognized, the assessment of the beneficial effects is not included within the scope of thisreport. The annex aims to present a detailed review of the current scientific literature that will highlightthe differences in radiation effects and associated risks between children and adults. The objective is toinclude information on the magnitude of the doses from various radiation sources to which children are
exposed, the relevant aspects in the development of the anatomy and physiology of children, dosimetry
and the health effects of radiation exposures (including cancer, benign tumours, tissue reactions andheritable effects). It will answer the following questions:6 UNSCEAR 2013 REPORT−

What are the most important sources of ionizing radiation exposure of children and the levelsof exposure, both now and potentially in the future?

−

What are the dosimetric differences between children and adults?

−

How does ionizing radiation affect children differently from adults?

−

How sensitive are children to radiation exposure in comparison with adults?

−

What are the factors that make children more sensitive to radiation exposure?

−

Are children more sensitive to all radiation sources and effects or just to some?

−

What gaps exist in our knowledge on radiation effects following childhood exposure that may
guide future research?

5.
This annex is intended to provide a reference for specialists in radiation protection, radiation
biology, epidemiology and other health sciences, and regulatory authorities. It provides a review of thehealth effects in children arising from exposure to sources of ionizing radiation.
6.
The definitions of “child” and its derivative “childhood” are not consistent in scientific and legal
literature. The most common understanding is that childhood ceases with the completion ofdevelopment, usually between the age of 18 and 19, even though neurocognitive development
continues through the twenties. However, some of the epidemiological literature considered in thisreport includes groups of up to only age 16; other papers have involved studies of different age groups.
In this report, the term “child” is used in contrast with that for “adult”. Therefore, the scientific
literature the Committee reviewed is for those <20 years of age and includes infants, children andadolescents.
7.
Data on the risks of radiation exposure in childhood and possible differences with those in
adulthood come from studies of exposure to radiation due to accidents, medical diagnostic radiology,
radiotherapy, the atomic bombings in Japan, fallout from nuclear weapon testing, and potential
radioactive discharges from nuclear installations. All the various studies have some limitations. One of
the major difficulties in the assessment of the effects of exposure in childhood is that it takes many
decades to be sure that all the effects have become manifest. Almost all the epidemiological studies
remain incomplete in terms of lifetime follow-up. Thus, for risk assessment, there is a need for lifetime
projection models.
8.
Accidental exposures involving high doses to children are quite rare but when they do occur, thesubjects often have early and late severe injuries. Medical diagnostic exposure typically involves low
doses (<100 mSv) and a very large population would be required in order to be able to observe a
statistically significant number of effects. Studies have now begun to assess possible neoplastic effects
in children who have had CT scans. Studies of survivors of childhood cancer who have hadradiotherapy are useful in that they involve high doses and follow-up has been carried out for a few
decades. These studies are complicated by the disease process and the administration of other types oftherapy (e.g. chemotherapy). The survivors of the atomic bombings received relatively low doses andfollow-up has been carried out for over 60 years. Even with this long follow-up, there are many still
alive who were exposed as children. Studies of those exposed to fallout from nuclear weapon testingand of those living near nuclear installations have usually involved even lower doses and are thus
subject to great statistical uncertainty and more potential bias. Useful information on thyroid cancer has
been gained from the studies of children exposed as a consequence of the Chernobyl accident, but evenwith 25 years of follow-up, the long-term nature of the risk of thyroid cancer as a result of theANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

7

Chernobyl accident is not known. Juvenile animals and in utero exposure of the embryo and foetus are
not part of this review. These are covered, respectively, in relatively comprehensive reports by theCommittee in its UNSCEAR 2008 Report [U14], by the International Commission on RadiologicalProtection (ICRP) [I23] and recently by the National Council on Radiation Protection (NCRP) [N20].
9.
This annex and accompanying appendices examine the potential differences in sources of
exposure and differences in developmental anatomy and physiology that affect the doses received byvarious organs in children compared to adults. The review of the scientific literature elucidates
differences by age at exposure for stochastic and deterministic responses in various organs and tissues.
10. The subject of this annex potentially affects a number of the Committee’s activities. For example,
it will:−

Provide a basis for the evaluation of the potential effects of the marked increase in medical
radiation exposure of the largest vulnerable population as outlined in the UNSCEAR 2008
Report;−Provide information for the possible update of age-group classification—e.g. on infants,
children and young adults—to be used in future surveys of the Committee;−

Provide a basis for the follow-up of children and adolescents exposed as a result of the
Fukushima Daiichi nuclear power plant accident;−

Enhance development of a knowledge base on the levels of radiation exposure and effects
specific to children;−

Imply that future reports will need to highlight those sources that are important for this large
vulnerable population.

III. SOURCES OF EXPOSURE
11. Ionizing radiation exposure of children comes from a wide variety of sources. Some sources arewidespread while others are local. Some sources expose children and adults almost equally while others
expose children to a greater or lesser extent than adults. Worldwide, children typically receive lessexposure than adults since they are not occupationally exposed and undergo fewer medical procedures.
Annex B of the UNSCEAR 2008 Report [U14] has detailed information on exposure of the public fromvarious sources of radiation.
12. Sources of childhood exposure that are of concern include radiation accidents, regions of highnatural background radiation and also diagnostic and therapeutic procedures. The data is derived from awide range of doses, variable dose rates, whole and partial body exposure and children of different
ages. The effects described in this annex are sometimes specific to a given exposure scenario.

8 UNSCEAR 2013 REPORT

A. Background radiation
13. Natural background is the largest worldwide source of ionizing radiation exposure of children.
There is significant geographical variation in the doses received. Doses from cosmic radiation increase
with altitude and geomagnetic latitude, but there is little or no difference between the doses received bychildren and adults who are in the same location. Terrestrial radiation exposure varies as a result of anumber of factors, including the concentration of radionuclides in soil and diet. Radon is the largest
contributor to natural background radiation exposure, but there is little variation in dose with age. The
average annual effective dose to an individual resulting from natural background radiation isapproximately 2.4 mSv [U2, U14]. There are rare circumstances in which adolescents have been
exposed to elevated levels of radon as a result of occupational exposure in tin mines [L34, X1].

B. Medical radiation uses
14. Medical exposure represents the second largest source of ionizing radiation exposure of the world
population, and was recently summarized in the UNSCEAR 2008 Report (annex A) [U14]. Limited
data on the frequency of medical diagnostic radiation procedures on children are available. Those data
are shown in table 1. While there is some variation among countries, approximately 3–10% of all suchprocedures are performed on children. There is a higher percentage of some particular examinations
performed on children (e.g. X-rays of the head, abdomen and extremities). Fluoroscopically-guided
interventional procedures can deliver high doses to various organs of children (particularly to the brain,lens of the eye and the heart) [T16].
15. Additional data from some European countries on the age and sex distributions of various
radiographic examinations are presented in table 2.
16. Very few data are available on the number of children exposed as patients during nuclear
medicine procedures. Nevertheless, there is little doubt that the percentage of various types of
examination for children differs widely from those for adults. Most nuclear medicine procedures inadults are related to cardiac problems or cancer (both of which are rare in children). Renal examinations
constitute the majority of nuclear medicine procedures performed on children in some countries.
Typically, in clinical practice, children receive lower administered activities of radiopharmaceuticals
compared to adults [J7].
17. Children can also be exposed as a consequence of mothers having had nuclear medicine
examinations if the radiopharmaceutical is excreted in the breast milk and breast feeding continues.
Children can also be exposed if they are in the vicinity of a patient treated with radioiodine.
18. Data on the number of children receiving radiotherapy are also very sparse. The percentages are
low since childhood cancer is rare. In the United States of America, 1 in 600 children develop amalignancy and this represents only 1% of patients with cancer. It is estimated that the number ofchildren treated with radiotherapy in the United States is about 2,500 annually out of a total of about
870,000 radiotherapy patients. For most medical procedures, the situation regarding children is likely to
be very different from country to country owing to differences in resources and in the health-caredelivery system.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

Table 1. Percentage of various types of medical examination performed on infants and children(0-15 years old) in well-developed countries
Adapted from UNSCEAR 2008 Report (annex A, table B47) [U14]

Examination

Percentage performedon children (%)

Examination

RADIOGRAPHY

Percentage performedon children (%)

CT SCANNING

Chest (posterior-anterior)

9

CT head8

Chest (lateral)

10

CT abdomen

4

Limbs and joints

15

CT thorax

5

Lumbar spine(anterior–posterior)

7

CT spine

3

Thoracic spine(anterior–posterior)

12

Cervical spine(anterior–posterior)

9

Non-cardiac angiography

2

Head

19

Cardiac angiography

4

Abdomen13

Cerebral angiography2Upper gastrointestinal

3

Lower gastrointestinal

3

Cholecystography

2

Pelvis/hip

9

Urography

7

ANGIOGRAPHY

NUCLEAR MEDICINE

Not available

RADIOTHERAPY

Not available

Table 2. Percentage distributions of averaged European age and sex for some radiographic and CT
examinations
Adapted from EC Radiation Protection N° 154 (table A3.1) [E5]Distribution (%)
Age

Males

Females

Males

Females

Males

Females

Males

Females

Males

Females

RADIOGRAPHIC EXAMINATIONS
Chest

Lumbar spine

Abdomen

IVUa

Pelvis and hips

0–4

2.30

1.82

0.23

0.21

2.82

2.27

1.39

2.10

0.53

0.35

5–9

0.55

0.44

0.32

0.38

1.18

1.02

1.11

0.68

0.38

0.31

10–14

0.42

0.37

0.92

1.25

0.97

0.97

1.07

0.78

0.38

0.26

15–19

0.78

0.62

1.74

1.81

0.94

1.46

1.10

0.96

0.67

1.13

20–24

1.05

0.87

2.03

1.80

1.27

2.01

1.12

0.79

1.44

2.05

25–29

1.38

1.15

2.58

2.47

1.85

2.21

1.23

1.17

2.34

2.44

30–34

1.80

1.55

3.57

3.29

2.49

2.68

1.50

1.45

3.38

3.47

35–39

2.14

1.79

4.03

3.94

2.81

2.76

1.81

1.72

4.00

3.86

40–44

2.47

2.19

3.83

4.21

2.95

2.84

1.89

2.08

4.51

3.69

45–49

3.05

2.64

3.65

4.67

3.15

2.92

2.11

2.67

4.79

3.92

9

10 UNSCEAR 2013 REPORTDistribution (%)
Age

Males

Females

Males

Females

Males

Females

Males

Females

Males

Females

RADIOGRAPHIC EXAMINATIONS
Chest

Lumbar spine

Abdomen

IVUa

Pelvis and hips

50–54

3.85

3.26

3.97

5.02

3.72

3.22

2.83

3.53

5.76

3.81

55–59

4.67

3.57

3.42

4.75

3.67

3.11

3.14

4.07

5.64

3.66

60–64

5.25

3.91

2.85

4.21

3.92

3.17

3.35

4.59

5.47

3.55

65–69

5.81

4.42

2.48

4.36

4.25

3.45

3.41

5.71

5.50

2.99

70–74

6.25

5.15

2.41

4.74

4.40

3.99

3.67

6.87

5.50

2.93

75–79

5.39

5.23

2.04

4.50

3.91

4.10

3.16

7.43

4.00

2.17

80–84

3.24

4.25

1.26

3.36

2.66

3.99

2.34

6.77

2.05

1.44

85–89

1.65

2.66

0.59

2.06

1.54

3.00

1.37

5.01

0.75

0.54

>90

0.60

1.43

0.22

0.81

0.70

1.62

0.76

3.25

0.17

0.15

Total

52.65

47.32

42.14

57.84

49.20

50.79

38.36

61.63

57.26

42.72

COMPUTED TOMOGRAPHY EXAMINATIONSCT headaCT neck

CT chest

CT spine

CT abdomen

0–4

0.75

0.53

0.25

0.29

0.32

0.16

0.10

0.06

0.09

0.07

5–9

0.76

0.46

0.49

0.20

0.28

0.21

0.22

0.16

0.12

0.08

10–14

0.84

0.70

0.34

0.26

0.22

0.21

0.30

0.30

0.21

0.18

15–19

1.29

1.24

1.08

0.71

0.75

0.47

1.15

0.90

0.63

0.50

20–24

1.62

1.55

1.43

1.09

1.13

0.75

1.76

1.49

0.82

0.83

25–29

1.75

1.94

2.04

1.34

1.45

0.91

2.57

2.10

1.48

1.24

30–34

2.48

2.61

2.68

2.50

2.09

1.31

4.12

2.90

1.94

1.61

35–39

3.01

2.77

4.06

3.41

2.44

1.99

5.26

4.36

2.37

2.06

40–44

2.84

3.08

3.89

4.09

2.84

2.11

5.55

5.13

2.84

2.56

45–49

3.06

3.25

4.64

4.50

3.45

3.07

5.25

5.48

3.27

3.29

50–54

3.79

3.68

6.08

4.70

5.07

3.97

5.43

5.17

4.45

4.32

55–59

4.15

3.45

6.17

4.67

6.02

4.73

4.74

4.59

5.65

4.76

60–64

4.08

3.64

5.77

3.77

7.25

4.88

3.65

3.96

6.03

4.87

65–69

4.27

3.99

4.66

3.38

7.53

4.78

3.08

3.93

7.20

5.07

70–74

4.80

4.53

4.10

3.29

7.42

5.25

2.72

3.72

6.95

5.55

75–79

4.45

4.96

3.03

2.85

5.52

4.01

2.02

3.27

5.49

4.57

80–84

2.99

4.41

1.99

2.54

2.47

2.32

1.10

1.91

2.47

3.16

85–89

1.62

3.02

1.10

1.63

0.95

1.08

0.45

0.80

0.97

1.42

>90

0.56

1.07

0.31

0.67

0.28

0.31

0.06

0.21

0.26

0.61

Total

49.11

50.88

54.11

45.89

57.48

42.52

49.53

50.44

53.24

46.75

Intravenous urogram.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

11

C. Nuclear weapons
19. The largest database concerning age-at-exposure effects is on the survivors of the atomic
bombings in Japan. The Life Span Study (LSS) includes 86,611 persons. Of these, 17,833 were 0–9
years old at exposure and 17,563 were 10–19 years old at exposure [O25]. The radiation dose waspredominantly from external acute penetrating radiation. In addition, populations that include children
have been exposed to fallout from the testing of nuclear weapons. Prior to 1958, 66 nuclear tests werecarried out in the Marshall Islands. The Bravo test contaminated the inhabited Rongelap, Alinginae andUtirik atolls. There were 239 inhabitants—of whom 93 (39%) were children under 10 years of age—
who received severe exposure from the fallout [C43]. Although the number of children exposed locallyas a result of fallout from the testing of nuclear weapons has not been quantified at several sites, acohort of about 4,500 under age 20 downwind of the Semipalatinsk nuclear testing has been followedup [B7], and a leukaemia case-control study of Utah children and adults downwind of the Nevada
atomic bomb testing has been conducted [S114]. With regard to the accident at the Mayak nuclear
complex, there is a Russian “Children’s Registry”, covering the period 1934–2008, which includes
more than 90,000 people who were either born in Ozyorsk (the city nearest the Mayak site) or moved
there before their 15th birthday.

D. Accidents and incidents
1.

Radiotherapeutic and radiographic sources

20. There have been a number of tragic incidents involving exposure of children to industrial
radiography sources [I1, I3, M33]. Due to the limited populations exposed, the details of these
accidents are not very helpful in ascertaining differences in radiosensitivity between children andadults. Similarly, therapeutic misadministration is rare and thus the resulting information is largely
anecdotal.

2.

Nuclear power

21. The 1986 Chernobyl accident has been extensively reviewed in the UNSCEAR 2008 Report(annex D) [U15]. The total population of the three most affected countries (the Russian Federation,
Ukraine and Belarus) was, at the time, 97.9 million of whom 10.1 million (10.3%) were pre-school
children, 11.0 million (11.2%) were school children and 5.2 million (5.3%) were defined asadolescents. Of the 114,511 people who were evacuated in 1986, children and adolescents were insimilar proportion—11,931 (10.4%) were aged 0–6 years, 13,120 (11.5%) were aged 7–14 years and5,815 (5.1%) were aged 15–17 years. More than six million residents of the contaminated areas(defined as areas with an activity concentration of 137Cs >37 kBq/m2) in the Russian Federation,
Ukraine and Belarus were not evacuated. The number of children in this group is not known.
22. The number of children exposed as a result of the Fukushima Daiichi nuclear power plant
accident is not well defined at the moment. Recent census data from Japan indicate that about 13% of
the population is 0–14 years of age.

12 UNSCEAR 2013 REPORT

IV. ANATOMICAL DEVELOPMENT AND PHYSIOLOGY
23. The purpose of this section is to clearly describe the main human anatomical and physiologicalage-related changes that are relevant for radiation risks from exposure during childhood. General issues
are considered first, followed by detailed information on tissue and organ systems.
24. Several factors that vary with age, but predominantly with weight and size, are critical in theassessment of doses and effects. The attenuation of both internal and external radiation by tissue will
increase with weight. In particular, the absorbed dose from a given amount of intake of a radionuclide
will be greater in a small individual with smaller organ masses than in a large individual.
25. Determining radiation exposure and resulting risks is more complicated for children than for
adults owing to the development and associated physiological changes in children. The age-related (anddynamic) factors that contribute to these differences include:−

Size, shape and mass of the individual and organs;−

Growth patterns (developmental dynamics) of the individual including organs and tissues;−

Intake and absorption of material;−

Metabolic requirements;−

Hormonal and endocrine changes and development;−

Dietary intake;−Physical activity.

26. The ICRP has considered many of these age-related factors in developing models for dosimetry
purposes. The reference data are contained in ICRP Publication 89 [I22]. Specific ICRP models havebeen developed for the skeleton [I15], the alimentary tract [I24] and the respiratory tract [I14]. The
ICRP has derived age-dependent dose coefficients based upon these models for various radionuclides[I16, I17].
27. Reflecting the available data, most of the ICRP models are relevant to a European Caucasian
population. However, the parameters involved in particular situations may differ from those assumed in
the models. These differences may be on an individual basis (e.g. the size of the child may differ fromthe average). There may also be significant regional variations (e.g. diet may vary greatly from coastal
to rural inland areas of a country). There may also be global variations (e.g. size, customs, habits anddiet are often significantly different depending on ethnicity).
28. The growth period of the human body is unusually long among mammalian species, extending for morethan a quarter of the normal lifespan. The human growth curve shown in figure I has a distinctive shapethat reflects changes in the post-natal growth velocity that are not found in other mammalian species. This
long growth period is associated with a delay in most aspects of bodily development, especially skeletaland endocrine maturation. Total body mass continues to increase after maturity, but the rate of increase
slows considerably after about age 18 years in males and about age 16 years in females.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

13

Figure I. Increase in body mass during growth as a percentage of mass at age 25 years
Adapted from ICRP Publication 89 [I22] and based on central estimates for Western males

29. There are differences in the growth rate of different parts of the body (see table 3). Studies of theupper and lower limbs indicate that development occurs most rapidly in the distal parts of both regions, andthat girls are ahead of boys even in early childhood. In general, growth and development tend to occur fasterin the upper part of the body than in the lower part. The trunk represents about one third of the length andnearly half of the volume of the entire body at all stages of development, but the thoracic portion of thetrunk develops more rapidly than the pelvic region. Due to this slower development of the pelvic region, theurinary bladder is an abdominal organ in infancy and does not attain its adult position and shape until theage of about six.
Table 3. Subdivision of total surface area of body
Adapted from ICRP Publication 89 [I22]

Total surface area of body (%)
Age
Head

Trunk

Upper extremities

Lower extremities

Newborn

20.8

31.9

16.8

30.5

1 year

17.2

34.4

17.8

30.6

5 years

13.1

33.0

19.6

34.3

10 years

10.9

33.6

19.4

36.2

15 years

8.8

31.9

21.4

37.9

Adult

7.5

34.6

19.4

38.5

30. There is a marked difference in the growth of the various organ systems from birth to maturity. At
birth, the skeleton represents approximately 11% of the body mass. Its post-natal growth parallels that of

14 UNSCEAR 2013 REPORT

the body as a whole, both of which increase in mass by about 20-fold by maturity. The skeletal muscle
system forms about 25% of the body at birth and about 40% in the adult male. The central nervous system(CNS) forms about 15% of body mass at birth and 2–2.5% in the adult male. The brain is the largest
contributor to the mass of the CNS. The visceral group as a whole forms about 9% of the body mass in the
newborn and about 5–7% in the adult male.
31. Organ size and growth vary significantly across tissue types and with age. The percentage of size
attained of total post-natal growth for lymphoid tissue, for example, is greatest in late childhood, evengreater than in adulthood (figure II). Musculoskeletal tissues grow primarily during childhood and earlyadolescence, and gonads do not mature until late adolescence. Organs may be divided into four main
patterns of post-natal growth: general (most tissues), neural, lymphoid, and reproductive. Some tissues
change markedly in their distribution within the body as a person ages, e.g. changes in bone marrow
distribution within the bone.
Figure II. Growth curves of different parts and tissues of the body, showing four main patterns ofgrowthAdapted from ICRP Publications 23 and 89 [I22, I6]

32. Body size and proportion do not grow in a linear or consistent manner. The head and brain areproportionally much larger in younger children. These changes mean that absorbed dose in specificorgans from either external or internal irradiation is quite different at different ages and developmental
stages. The variation in mass of organs and tissues with age is shown in table 4.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

15

Table 4. Reference values for masses (g) of organs and tissues as function of age
Adapted from ICRP Publication 89 [I22]AgeOrgan/tissue

15 years
Newborn

1 year

5 years

Adult

10 years
Males

Females

Males

Females

Salivary glands

6

24

34

44

68

65

85

70

Oesophagus (wall)

2

5

10

18

30

30

40

35

Stomach (wall)

7

20

50

85

120

120

150

140

Small intestine (wall)

30

85

220

370

520

520

650

600

Right colon (wall)

7

20

49

85

122

122

150

145

Left colon (wall)

7

20

49

85

122

122

150

145

Rectosigmoid (wall)

3

10

22

40

56

56

70

70

Liver

130

330

570

830

1 300

1 300

1 800

1 400

Gallbladder (wall)

0.5

1.4

2.6

4.4

7.7

7.3

10

8

Pancreas

6

20

35

60

110

100

140

120

Brain

380

950

1 310
(1180)a

1 400(1220)a

1 420

1 300

1 450

1 300

15

250

25

500

Large intestine

Breasts
Circulatory system
Heart – with blood

46

98

220

370

660

540

840

620

Heart – tissue only

20

50

85

140

230

220

330

250

Blood

290

530

1 500

2 500

4 800

3 500

5 600

4 100

Eyes (2)

6

7

11

12

13

13

15

15

Skin

175

350

570

820

2 000

1 700

3 300

2 300

Muscle, skeletal

800

1 900

5 600

11 00024 00017 00029 00017 500Lung – with blood

60

150

300

500

900

750

1 200

950

Lung – tissue only

30

80

125

210

330

290

500

420

Total skeleton

370

1 170

2 430

4 500

7 950

7 180

10 5007 800

Bone, cortical

135

470

1 010

1 840

3 240

2 960

4 400

3 200

Bone, trabecular

35

120

250

460

810

740

1 100

800

Bone, total

170

590

1 260

2 300

4 050

3 700

5 500

4 000

Marrow, active

50

150

340

630

1 080

1 000

1 170

900

Marrow, inactive

0

20

160

630

1 480

1 380

2 480

1 800

Cartilage

130

360

600

820

1 140

920

1 100

900

Spleen

9.5

29

50

80

130

130

150

130

35

30

25

20

Thymus

13

30

30

a

40 (35)

16 UNSCEAR 2013 REPORT

AgeOrgan/tissue

15 years
Newborna

1 year

5 years

Adult

10 years
Males

Females

Males

Females

Thyroid

1.3

1.8

3.4

7.9

12

12

20

17

Kidneys (2)

25

70

110

180

250

240

310

275

Urethras (2)

0.77

2.2

4.2

7.0

12

12

16

15

Urinary bladder

4

9

16

25

40

35

50

40

Testes (2)

0.85

1.5

1.7

2

16

35

Prostate

0.8

1.0

1.2

1.6

4.3

17

Ovaries (2)

0.3

0.8

2.0

3.5

6

11

Uterus

0.4

1.5

3

4

30

80

Total body (kg)

3.5

10

19

32

56

53

73

60

Values in brackets are for females.

33. Variation in height, mass and surface area at various ages is shown in table 5. As mentioned
earlier, most reference values refer to Caucasian populations.
Table 5. Reference values for height, mass, and surface area of total body
Adapted from ICRP Publication 89 [I22]

Height (cm)Surface area (m2)Mass (kg)

Age
Males

Females

Males

Females

Males

Females

Newborn

51

51

3.5

3.5

0.24

0.24

1 year

76

76

10

10

0.48

0.48

5 years

109

109

19

19

0.78

0.78

10 years

138

138

32

32

1.12

1.12

15 years

167

161

56

53

1.62

1.55

Adult

176

163

73

60

1.90

1.66

34. The age-related factors that contribute to differences in radiation effects and risks from childhood
exposure include size of the individual and organs, growth patterns (rate of development at differentages) of the individual and tissues, intake and absorption of material, metabolic requirements, hormonaland endocrine changes and development, diet and physical activity. Examples of some importantdifferences are presented in table 6.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

17

Table 6. Major anatomical and physiological differences between children and adults
Tissue or factor

Comments

Body size

Growth period is unusually long compared to other mammals and occurs for about 25% oflifespan. Rapid growth (about 20-fold) over first 16–18 years; then slows but mass increases

Body proportion

The head and brain are disproportionately large at birth. The trunk represents about one thirdof the body volume at all stages

Alimentary tract

Transition from liquid to textured diet at age 6 months. Milk is an important component ofdiet. Increase in transit time of material in the colon with increasing age. Absorption of someradionuclides is greater in infants than in children and adults. Children can ingest variable
amounts of dirt

Respiratory
systemSignificant increase in the number of alveoli up to 2 years of age. After this, there is an increase
in alveolar size. 20-fold increase in air-tissue interface between birth and adulthood. Youngchildren are mostly nose breathers. Deposition may be higher in children but volume ofinspired air is smaller

Brain

Comprises 10% of infant weight and 2% in an adult. Axon diameter and myelin growsignificantly during first 2 years but their growth is not complete until adulthood. Pruning ofsynapses occurs during childhood. Grey matter peaks at 1 year of age and remains high until 7
and then declines 40% by age 16

Skeletal andcartilage

Bone growth occurs most at the ephipyses at the ends of long bones. The epiphyses fuse
during puberty. There is more vascularity and remodelling of bone in infancy and childhood. A
much greater percentage of the skeleton is cartilage rather than bone at young age

Bone marrow

With increasing age there is a significant regression of red bone marrow from the peripheral
skeleton to the more central portions

Kidneys andbladderMaximum number of glomeruli are present at birth. Hypertrophy can occur as a result ofgrowth of renal tubules. Bladder moves from abdominal position to the pelvis duringchildhood. Children void every 2–3 hours and before bladder capacity is reached

TestesPrior to age 12, the testis is small, increasing in volume by over fivefold during puberty

Ovaries anduterusNumber of primordial follicles peaks shortly after birth. Rate of recruitment to mature follicles
increases from birth to age 14 and then declines with age. Rapid growth in size of ovaries withpuberty. Uterine volume is <3 ml before age 8 and increases to 15–20 ml by age 13

Thyroid

Rapid rise in thyroid stimulating hormone after birth, declining to normal levels in about
5 days. Uptake of iodine is broadly similar to that of an adult. TSH, triiodothyronine andthyroxine serum values are highest in first year of life and decrease slowly by about 20–40% bylate adolescence

Growthhormones

GH level rises throughout puberty, increasing body height

Reproductive
hormones

Puberty initiated by the hypothalamus of the brain releasing gonadotropin releasing
hormone, luteinizing hormone and follicle stimulating hormone

A. Alimentary tract
35. The alimentary (gastrointestinal or digestive) tract comprises the oral cavity, mouth, pharynx,
oesophagus, stomach, small intestine, colon, rectum and anus. Associated organs and tissues are theliver, pancreas and salivary glands. Some parts of the alimentary tract are relatively susceptible to18 UNSCEAR 2013 REPORT

radiation-induced carcinogenesis (e.g. stomach and colon) while other parts are relatively resistant (e.g.
rectum and pancreas). In addition, some parts (e.g. the small intestine) are quite vulnerable to cellkilling at doses of the order of a few grays (Gy), owing to the rapid turnover of cells in these parts. As
shown in table 4, the masses of the different parts of the alimentary tract increase with age.
36. Starting at age of about six months, infants transition from a liquid diet to increasingly textured
foods. Dietary composition varies significantly around the world. Even so, infants and children
generally have a higher proportion of milk in their diets than adults. Ingestion of milk is a common
route of exposure to the radioisotopes of iodine and strontium. Diet is affected by a variety of factors
but metabolic rate and energy expenditure are both important and increase markedly with age. Intake ofwater, which also increases with age, is a universal requirement [I22].
37. Ingestion of soil by children is a common concern. Soil ingestion can be inadvertent (from handto mouth transfer) although a few children intentionally ingest soil (pica behaviour). There are only afew studies of the amount of soil eaten by children. Those studies typically use faecal analysis ofnaturally occurring stable or radioactive isotopes of elements. The estimates of ingestion of soil varysignificantly from child to child and average 20–30 mg/day for most children and 80–100 mg/day forchildren 0.5–4 years of age [U1]. There is also a significant daily variation in intake (up to 20-fold) for
any particular child [B4]. In the case of actinide contaminated lands, the critical group is likely to be
children because of potentially higher ingestion rates and higher dose coefficients [S80].
38. Transit times of material in the oesophagus, stomach and small intestine do not vary much withage. Transit time for liquids in the oesophagus is relatively fast (seconds) while in the stomach, it isabout 30–60 minutes for liquids and 75–100 minutes for solids and is affected by non-age-related
factors. Transit time in the small intestine is about 3–4 hours, increasing in the colon with age—about
8–11 hours in a child and 12–16 hours in an adult.
39. Absorption of most radionuclides occurs in the small intestine with the extent of the processdepending upon the element and chemical form. Tritiated water has essentially free passage from thealimentary tract to the blood. Caesium ions are absorbed rapidly. Small particles may enter epithelial
cells by pinocytosis (engulfment). In adults, this is not an important pathway; however it is important inneonates. There are other routes of absorption in the mouth, stomach and colon. Iodine, for example,
can be absorbed both in the mouth and in the stomach.
40. Absorption of many elements (e.g. calcium, radium, lead, cobalt, iron, plutonium, americium) is
substantially greater in infants than in adults. In general, absorption values of radionuclides after one
year of life are broadly similar to those of adults. Age-related retention of radionuclides in the small
intestine has been shown to be important for neonates owing to pinocytosis. Increased levels in the wallof the small intestine have been shown in animal studies for plutonium, thorium, uranium, americium
and other elements [F18, F19].
41. A number of elements are secreted into the alimentary tract after having been absorbed. Important
examples include iodine secreted by the salivary glands and caesium secreted by the liver into the bile.
Age does not appear to play a significant role in these secretory processes [I24].

B. Respiratory system
42. The respiratory system includes the nose, mouth, pharynx, larynx, the airways of the trachea,
bronchi and bronchioles, and the alveoli (air sacs). By the age of two, the structure of the lungs is

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

19

completely developed. The main changes that occur during childhood are in mass and size of mostpulmonary structures, which are closely related to stature. There is a significant increase in the numberof alveoli in the first two years of life. The number of alveoli at birth is estimated to be about 20 million
and a rapid multiplication of alveolated airways increases the number of alveoli to about 400 million by
the age of two. This is followed by an increase in size of the alveoli. These processes allow for a
20-fold increase in the air–tissue interface between birth and adulthood [T25].
43. The variation in mass of the respiratory system with age is shown in table 4. The limited data
available indicate that the inner diameter of bronchi is considered to be about 1.0 mm at one year ofage, about 1.5–2.0 mm from 2 to 5 years of age, and about 4.0 mm in adults. There is little change ineither the cilia length or the epithelial height with age. Before the age of five, there is a disproportion in
the peripheral airways (i.e. small children have proportionally more of them than adults do) where thediameters are narrower than those of the central airways, causing increased airway resistance comparedto that of adults. There is also a difference between children and adults relative to the larynx. Up to theage of two, the larynx is situated high in the neck to allow for simultaneous breathing and swallowing.
As a result, young children are almost entirely nose breathers. Values for the volume of air ventilated
daily (m3) increase dramatically with age as shown in table 7.
Table 7. Daily ventilation volume by age
Adapted from ICRP Publication 71 [I16]

Daily ventilation
3 months
3

Volume (m )2.8

1 year
5.1

5 years
8.8

15 years

10 years
15.2

Adult

Males

Females

Males

Females

20.1

15.8

22.2

18.2

44. Deposition of material in the respiratory tract is a function of many factors including particle size,
shape and density, method of breathing (nose versus mouth), breathing rate, and structure of the
airways. Most of the models of deposition of particles in the respiratory tract of children have been
derived from the limited empirical data available. Even so, it is known that the deposition rates inchildren are somewhat higher than those of adults. For example, the fractional deposition of 1 µm
particle varies from about 0.39 in a sleeping adult to 0.54 in a sleeping infant. In addition, deposition
increases with breathing rate. For example, the fractional deposition of a 1 µm particle increases to 0.53
in an adult at light exercise. Clearance of particles from the respiratory tract is related to mucociliarytransport and absorption. The limited data suggest that there is not a major difference in mucociliarytransport velocities or clearance rates between children and adults [I14].
45. For purposes of radiation dosimetry, the ICRP divides the respiratory tract into four parts [I14].
This is discussed in detail in appendix A (Dosimetry).

C. Neurological system
46. The mass of the brain at various ages is shown in table 4. The brain is quite large at birth relative
to other organs. It is about 10% of the body weight compared to about 2% during adulthood. More thana decade is needed after birth for its development to be completed. Maturation includes development of
supporting cells (glia), junctions between nerve cells (synapses), structural properties of the fibres(axons), and the insulation (myelin) around these fibres. Both the brain and spinal cord consist of grey

20 UNSCEAR 2013 REPORT

cell bodies, dendrites and synapses and white matter, which includes bundles of axons coated with asheath of myelin. Axon diameters and myelin grow significantly in the first two years of life—whensynaptic density increases, especially in areas of the brain devoted to vision and hearing—but are notfully mature until adulthood.
47. Many more synapses are produced than are ever needed and a process known as “pruning” refines
these connections on the basis of experience. Generally, grey matter of the cortex reaches a peak at
about one year of age and remains high until about seven, and then declines by about 40% until about
16 years of age, when the adult level is attained. Some areas (such as the frontal cortex) have peak grey
matter at about 12 years of age [G18].
48. Myelin sheaths are extensions of oligodendral cells which are wrapped in a spiral fashion arounda portion of an axon. The myelin speeds transmission of signals along the axon. Ionizing radiation caninterfere with the formation and renewal of myelin and can also damage myelin [J6]. Repair of myelin
can take weeks to months.

D. Skeletal system
49. The skeletal system consists of bone, bone marrow, periosteum, cartilage and blood vessels in
those tissues. Bones are rigid organs that support the body, provide protection, produce red and whiteblood cells and store minerals. The hard outer layer of bones is made of compact (cortical or densebone) while the interior is an open porous network of trabecular (spongy or cancellous) bone. Compact
bone makes up about 80% of total bone mass in an adult while trabecular bone is about 20% of themass but has ten times the surface area. The relative weights of the various bones differ with age. The
skull is 32% of skeletal weight in newborns but only 12% in adults. The proportion of cartilaginous
tissue in the skeleton decreases with age. The ICRP reference values for the increases in total bonemass and total skeletal calcium and cartilage with age are shown in table 8 [I15]. Cartilage is of lesser
importance as it does not concentrate long-lived radionuclides, nor does it appear to be significantly
involved in risk of radiation-induced cancer. It is also quite resistant to high doses of radiation.
Table 8. Reference values for increases in total bone mass and total skeletal calcium and cartilage at
different ages
Adapted from ICRP Publication 70 [I15]Age

Bone mass (g)Calcium (g)Cartilage (g)Newborn

370

28

130

1 year

1 170

100

360

5 years

2 430

240

600

10 years

4 500

460

820

15 years (males)

7 950

830

1 140

15 years (females)

7 180

760

920

50. Ossification of cartilage begins before birth in a primary ossification centre in the central part ofeach developing bone. By the time of birth, most of the bones have developed their primary and somesecondary ossification centres. Tubular bones grow in girth by peripheral migration of osteons forming
dense bone and owing to vigorous resorption by osteoclasts to enlarge the marrow cavity and fill it with

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

21

trabecular bone. Secondary ossification centres (epiphyses) often appear at the ends of long bones after
birth and grow towards the bone finally fusing during puberty. Longitudinal growth proceeds throughadolescence ceasing at approximately 18 years of age for females and 20 for males.
51. Bone consists of a cellularly-organized organic matrix with inorganic salts. The osteoid matrix
contains proteins (mostly collagen), carbohydrates and lipids. The inorganic material is primarily
calcium phosphate and is embedded in not only the osteoid matrix but in the collagen as well. Collagenfibres form 90–95% of the bone matrix and are aligned along lines of stress to provide support. The
mineral phase of bone provides a storage function and is composed of mostly calcium and phosphate in
the form of salts (hydroxyapatites).
52. The hydroxyapatite crystals have the ability to conjugate with different ions such as lead, sodium,
fluoride, potassium, carbon and magnesium. This makes the performance of bone scans in diagnostic
nuclear medicine possible but is also the reason for the uptake into bone of long-lived radionuclides
including barium, phosphorus, strontium, radium and plutonium.
53. The vascularity and porosity of compact bone change throughout life with more vascularity andremodelling early in infancy and childhood compared to young adulthood. The differences in reference
remodelling rates for bone at various ages are shown in table 9.
Table 9. Reference values for bone remodelling rates at different ages (annual percentage)
Adapted from ICRP Publication 70 [I15]AgeCortical bone

Trabecularbone

0–3 months

300

300

1 year105

105

5 years

56

66

10 years

33

48

15 years

19

35

22 years

927

35 years

2

10

60 years

4

20

Average after age 25 years

3

18

54. In the trabecular bone, there is a decrease in the fraction of the spongiosa which is occupied bytrabeculae. This decrease is most marked in infancy and slows thereafter.
55. The chemical composition of bone changes somewhat, but not dramatically, with age. The ash
content of the skeleton is about 23% by weight at one year of age and 26% at 35. The calcium content
of bone is about 17% by weight at one year of age and 21.5% at 35.
56. Uptake of radionuclides in bone is not uniform. The two principal factors that influence
accumulation are extraction efficiency and blood flow. Other factors include capillary permeability,
extracellular space hydrostatic pressure, electrical potential and local changes in pH. The differences inskeletal accumulation of radionuclides at various ages are readily seen in diagnostic images from a99m
Tc-metheylene diphosphonate bone scan.
57. Bone marrow is of critical interest owing to the well-documented induction of a range ofleukaemia types by radiation and also to the sensitivity of components of the bone marrow to cell

22 UNSCEAR 2013 REPORT

killing at doses of a few grays. The bone marrow is located in the trabecular bone cavities of longtubular bones and the vertebra, ribs, sternum and the flat bones of the skull and pelvis. There are twokinds of marrow—red and yellow. Red marrow contains haematopoietic stem cells and is involved in
the production of cellular blood components (red cells, several types of white cells and platelets).
Yellow marrow is mostly fat and has little function.
58. The total amount of bone marrow represents about 1.3% of total body weight in a newborn, 1.7%
at one year, 2.5% at five years, 3.8% at ten years and about 4.5% in an adult. Although the percentage
of total body weight represented by active marrow (about 2–3%) does not change much with age, there
is a significant difference in the distribution of bone marrow within the bone as an individual ages. In
the infant, all marrow is red but as the individual ages, there is transformation of red to yellow marrow
and the red marrow retreats to the more central portions of the skeleton (ribs, pelvis, skull vertebrae)and proximal portions of the femora and humeri (figure III).
Figure III. Graphical representation of change in distribution of active marrow at different ages
Adapted from [M10]E. Genitourinary system
59. The genitourinary system consists of the kidneys, urethras, bladder, uterus, vagina, ovaries,
prostate and penis. The masses of various genitourinary organs at different ages are shown in table 4.
60. At birth, the kidneys are well formed and contain the maximum number of glomeruli. After birth,
if there is injury, a kidney can hypertrophy but this is due to hypertrophy of the renal tubules and not anincrease in glomeruli. Daily excretion increases with age and body size predominantly as a function ofincreases in fluid intake (table 10).
61. The dose to the bladder and other tissues from internally-deposited radionuclides excreted in urine
is dependent on the size of the bladder and the frequency of voiding and can cause significant
differences in age-specific dosimetry. In young children, the bladder is more intra-abdominal and canlead to higher doses to other abdominal organs. In children, there is a non-linear relationship between
age and bladder capacity [K3]. In infants, the average bladder capacity is about 100 ml, increasing toabout 175 ml at age two, about 250 ml at age five, about 350 ml at age ten. The average adult bladderANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

23

capacity is about 400–500 ml. There are, however, substantial individual variations. Children typically
void every 2–3 hours. Comparison of excretion rates, bladder capacity and frequency of voiding
indicates that most children void before bladder capacity is reached. The ICRP reference bladderparameters for different ages are shown in table 11.
Table 10. ICRP Reference excretion rates per day at various ages
Adapted from ICRP Publication 89 [I22]

Excretion (ml/day)
Age
Males

Females

Newborn300

300

1 year400

400

5 years

500

500

10 years

700

700

15 years

1 200

1 200

Adult

1 600

1 200

Number of voids per day

Bladder contents (ml)3 months

20

15

1 year16

25

5 years

6

65

10 years

6

75

15 years

6

85

Adult

6

115

Table 11. Parameters of urinary bladder model
Adapted from ICRP Publication 67 [I13]Age

62. The testes are characterized by dramatic changes between birth and adulthood. The testes produce
both hormones and sperm. Sperm are produced from germ cells lining the seminiferous tubules andsupported by epithelium (Sertoli cells). The most conspicuous change in the testes takes place duringpuberty and the volume of the testes can increase by over 500% compared to their prepubertal size
(figure IV). Prior to the age of 12, the testes have a volume of less than 5 ml; by the age 17, the testes
have reached the adult size of about 31 ml. This increase in volume is due to a significant increase in
the diameter of the seminiferous tubules, proliferation of Sertoli cells and spermatogonia and sperm
production [W11]. During puberty, Leydig cells appear in the interstitium and produce testosterone.
Leydig cells are much more resistant to radiation than are the germ cells involved in spermatogenesis.
63. Just before and shortly after birth, the ovaries contain the peak number of non-growing(primordial) follicles, probably about 0.3–1 million. The number decreases with age owing to
apoptosis. The rate of recruitment to mature follicles increases from birth to about age 14 and thendeclines with age until menopause. Some primordial follicles develop during the menstrual cycle tobecome primary oocytes and then secondary oocytes. Ovaries also secrete oestrogen and progesterone.
Before puberty, the ovaries are small. At puberty, they enlarge and become more vascular. Ovarianvolume is less than 2 ml up to age eight and then there is rapid growth reaching 6 ml by age 15. Uterine
volume is less than 3 ml before age eight and then increases to about 15–20 ml by age 13 [H42].

24 UNSCEAR 2013 REPORT

Figure IV. Testicular volume/Livi index curve as the function of age
Adapted from [B14]

F. Endocrine system
64. Maturation of endocrine structures and function relevant to radiation effects predominantly
involve the thyroid gland, growth hormones and reproductive hormones.
65. The masses of the thyroid at various ages are shown in table 4. The thyroid gland is stimulated by
the thyroid-stimulating hormone (TSH), also known as thyrotropin, from the pituitary gland to produce
both thyroid hormones (triiodothyronine and thyroxine). The foetal thyroid begins to accumulate iodine
at about 10–12 weeks of gestation. After birth, there is a very rapid rise in TSH reaching a peak in
about 24 hours and declining to normal in about five days.
66. The data on the uptake of radioiodine at different ages are limited. However, after the first year oflife, it is broadly similar in children, adolescents and adults [C53, S25]. The metabolic rate ofradioiodine in children may be somewhat higher than in adults [I33]. TSH, triiodothyronine andthyroxine serum values are all highest in the first year of life and decrease slowly by about 20–40% by
the age of 16 to 20 years.
67. Growth hormone is secreted by the anterior pituitary gland. Increase in height during childhood is
the most widely known effect of growth hormone. Growth hormone levels rise steadily throughout
puberty. It has many other effects including increasing calcium retention, increasing muscle mass andprotein synthesis, stimulating the immune system and stimulating growth of all organs except the brain.
68. Puberty is initiated by the hypothalamus of the brain releasing gonadotropin-releasing hormone(GnRH). Cells in the anterior pituitary respond by secreting luteinizing hormone (LH) and folliclestimulating hormone (FSH) into the circulation. The testes and ovaries respond by growing andbeginning to produce the steroid sex hormones, testosterone and oestradiol.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

25

69. A significant portion of testosterone in boys is converted to oestradiol and this mediates bone
growth, bone maturation and epiphyseal closure. During teenage years, testosterone levels slowly rise.
In girls, during puberty the rising levels of oestradiol produce a growth spurt, bone changes, breast
growth, increased fat composition, growth of the uterus and the endometrium.

G. Female breast
70. Whereas in most other mammals breast development is minimal until pregnancy occurs, human
females develop full breast tissue before pregnancy. Small divisions of breast tissue (lobes) develop,
followed by mammary glands consisting of about 20 lobes. Mammary glands are influenced byhormones during puberty. When the ovaries start to secrete oestrogen, increased fat in the connective
tissue causes the breasts to enlarge and the duct system begins to grow. Within six–twelve months, theswelling is beyond the edges of the areola and within about another year, the breasts are approaching
mature size and shape. Once ovulation and menstruation begin, secretory glands form at the ends of themilk ducts. The density and amount of glandular tissue change during menstruation with varying
oestrogen and progesterone levels [H65].

V. DOSIMETRIC ASPECTS
71. Differences between children and adults in radiation effects and absorbed dose for the sameradiation exposure can result from some of the developmental processes mentioned in the section
above. Important factors regarding dosimetric differences between children and adults are summarizedin table 12 and a more detailed discussion on dosimetric aspects for external and internal exposures isprovided in appendix A.
Table 12. Comparison of dosimetry for exposure of children and adults
Kind of exposure

Dosimetric aspects

General differencesa

Comments and exceptions

EXTERNAL EXPOSURE
Environment

Medicine

Dose coefficients+

Exposure

o

Doses

+

Exposure parameters

-

Doses

-

Higher dose due to smaller size, organs
closerDue to lower exposure parameters

INTERNAL EXPOSURE
Inhalation

Dose coefficients+

Exposure

-

Doses

-

Depends on the radionuclide; for 137Cs, forexample, nearly “o”

Depends on the radionuclide; for 131I, forexample, “+”26 UNSCEAR 2013 REPORTGeneral differencesa

Comments and exceptions

Dose coefficients+

Depends on the radionuclide; for 137Cs, forexample nearly “o”

Exposure-

Depends on the food; for milk, for example,“+” for young children

Doses

-

Depends on the radionuclide and food; for
131
I and alkaline earths, for example, “+” andalso for milk consumption of otherradionuclides

Kind of exposure

Dosimetric aspects

Ingestion

NUCLEAR MEDICINEa

Dose coefficients+

Exposure

-

Doses

o

Less administered activity(+ = higher values for children; o = values for children and adults approximately the same; - = lower values for children).

A. External exposure
72. External exposure may be due to radionuclides in the environment (irradiation by radionuclides in
the air (submersion) or by irradiation by radionuclides deposited on the ground) or due to medical
exposure (in radiological examinations by radiographs, fluoroscopy or CT examinations or byradiotherapy). Children have smaller body diameters, meaning that for a given external exposure thedose to internal organs will be slightly greater than in an adult. They are also shorter than adults, which
results in a higher dose from radionuclides on the ground. Age-related correction factors for irradiationfrom the ground are about 1.4 for infants and 1.1–1.2 for children as compared to adults. These factors
are important when considering populations in caesium-fallout areas (such as those around theChernobyl and Fukushima Daiichi nuclear power plants). In medical exposure, children may receive
significantly higher doses than adults for the same examination if the technical parameters would not be
specifically adapted. However, in general technical parameters are adapted resulting in lower doses forchildren.
73. There are some differences between the absorbed doses incurred by children as compared toadults for given exposures. For external exposures, the midline and overall absorbed dose is somewhat
higher owing to less soft tissue attenuation. Generally dosimetric differences for external exposure areless than a factor of two- to threefold.

B. Internal exposure
74. In situations involving the intake of radionuclides, absorbed doses per unit activity may be higher
in children as a result of the organs being smaller and closer together or because there are differences inmetabolism. For selected radionuclides, the dose per unit activity can be tenfold higher for infants
compared to adults. Children, however, may have lower intakes of radionuclides than adults. Internal
exposure can also differ markedly between children and adults owing to differences in diet and physicalactivity.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

27

75. Several radionuclides are of particular concern regarding internal exposure of children. Releasesof 131I during nuclear power plant accidents have the potential for induction of thyroid cancer as theradioisotope is rapidly concentrated in the thyroid gland resulting in a very high absorbed dose to thethyroid compared to doses received by other organs. The thyroid dose per unit intake in infants may belarger by a factor of 8–9 than it is in adults. Taking account of lower breathing rates for children,
estimated inhalation doses are higher by a factor of up to two for children compared to adults exposedto the same air concentration. Because of higher consumption, doses from the ingestion of milk may be
20-fold higher in infants than in adults. For 137Cs—distributed throughout all living tissues within thebody—a shorter biological half-life in children has been observed, which compensates for the lower
body masses of children such that there is very little difference in organ dose per unit intake as afunction of age at intake. Strontium-90 is historically important as a result of fallout from nuclear tests,
with ingestion in contaminated milk and concentration of this radionuclide in the skeleton. For
ingestion and inhalation, doses per unit intake delivered to the bone surface and red marrow are highest
for infants and adolescents owing to a combination of higher intestinal absorption and increased
skeletal uptake. For inhalation, the lung dose per unit intake increases with decreasing age because of
the lower masses of children but effective doses are lower than in adults when account is taken ofbreathing rates. Ingested or inhaled 228Ra yields substantially higher doses per unit intake to systemic—principally skeletal—tissues, in infants than in adults. This is due to a combination of higher intestinal
absorption, in the case of ingestion, and increased uptake into the skeleton. However, taking account ofbreathing rates, doses to infants and children are estimated to be lower than for adults exposed to thesame air concentrations. Ingestion doses may be substantially higher than in adults, with examples of a
20-fold increase in one-year-old infants consuming vegetables and a sevenfold increase in 15-year-old
children consuming milk.
76. Radon is of importance because of the ubiquitous nature of exposure (especially in buildings) andthe long-term potential for lung cancer. The lung dose from inhalation is influenced mainly by radiationfrom daughter radionuclides. For ingestion, the dose is mainly to the stomach wall. The inhalation dosecoefficients for lung dose for a child are not more than a factor of five higher than for adults. However,owing to the lower inhalation rates, the doses are nearly the same for all ages.
77. Internal exposure of children also occurs from medical use of radionuclides. A wide variety ofradiopharmaceuticals used distribute quite differently in the body. The spectrum of examinations
performed on children is different from that performed on adults. In children, studies of the kidney andskeleton predominate. Doses per unit of administered radioactivity are often higher in children;
however, in practice, this is offset by the use of lower administered activities.

28 UNSCEAR 2013 REPORT

VI. HEALTH EFFECTS
78. Describing the effects of radiation exposure during childhood or adolescence as compared tothose incurred during adulthood is a complex matter. This section summarizes the current knowledge
on this topic. A more detailed discussion can be found in appendices B and C.

A. Malignant neoplasms
79. Data on risk of neoplasms at different ages at exposure comes from a variety of sources, but mostcommonly from studies on the atomic bombing survivors. Another major source of information istherapeutic medical exposure. The UNSCEAR 2006 Report has detailed reviews of the scientific data
for each tumour type [U12]. For some tumour types, the data showing an age-at-exposure effect arestrong while for other tumour types, the data are intermediate, weak or non-existent. In the absence ofstrong data, some researchers have combined tumour types and used various statistical models.
Assumptions used in those models have important influences on apparent age sensitivity.
80. Often the results are expressed as absolute risk versus relative risk. Relative risk assumes thatradiation-related risk is proportional to the baseline risk, which typically may vary by age, sex and otherfactors, while a measure of absolute risk assumes that the radiation-related risk does not depend on thelevel of the baseline risk. Compared to the excess absolute risk (EAR, defined as cancer rate in theirradiated group minus the rate in the corresponding unexposed group), the excess relative risk (ERR,
defined as the ratio of risk in the exposed group to that in the unexposed group), is often thought to be abetter index of the strength of a potential causal association, while the EAR is a better index of theburden of disease (number of excess cases due to the exposure). Both metrics are useful in comparing
the impact of exposure of children versus that of adults, so both will be given when available. For alimited period after exposure (e.g. the first 25 years) the EAR is lower for children than for adults sincetumours are much rarer at a young age; however, the estimated lifetime EAR for all solid cancers
combined is higher after exposure in childhood than it is after exposure in adulthood because children
have a longer remaining lifetime in which to incur risk, and at any given age at risk they have a higher
excess cancer incidence and mortality. The ERR is most often higher for children (although not for allsites). In evaluating age-at-exposure effects, a number of researchers have used attained age as the othermain variable. While this may be useful for modelling background risk, an analysis by time since
exposure is useful as a comparison and may sometimes better characterize the time course of radiation
risk. There are distinct problems and inconsistencies that arise from using a “one size fits all” model forrisk analysis. Confusion, misunderstanding and contradiction easily arise. Some published reports
which have estimated the excess number of various tumour types that would occur at different ages of
exposure indicate that the risk is 2.5–3-fold higher in infants than in 40-year-old adults for lung, colon,
bladder and prostate cancer, which is at variance with actual epidemiological data.
81. For a given radiation dose, children are generally at more risk for tumour induction than are
adults. Cancers that may be induced following radiation exposure at young ages may occur within a
few years but also decades later. In the 2006 Report to the General Assembly, the Committee stated thatlifetime cancer risk estimates for those exposed as children were uncertain and might be a factor of 2–3

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

29

times higher than estimates for a population exposed at all ages. This conclusion was based upon alifetime projection model combining all tumour types.
82. The Scientific Committee has reviewed evolving scientific material and notes that, after radiation
exposure, tumour induction in children compared to adults is quite variable and depends on the tumour
type, age and sex. The term “radiation sensitivity” with regard to cancer induction refers to the rate ofradiogenic tumour induction and does not refer to the degree of malignancy. Broadly, for about 25% of
tumour types, children are clearly more radiosensitive regardless of the model. These include
leukaemia, and thyroid, skin, breast and brain cancer. For some of these sites, depending upon thecircumstances, the risks compared to adults can be quite high. Some of the sites are very important forevaluation of accidental and medical exposures.
83. The Committee has reviewed over 23 tumour sites for age-at-exposure effects. For about 15% of
tumour types (e.g. bladder cancer), children appear to have about the same radiosensitivity as adults.
For about 10% of tumour types (e.g. lung cancer), children appear less sensitive to external radiation
exposure than adults. For about 20% of tumour types (e.g. oesophagus cancer), the data are too weak to
draw a conclusion regarding differences in risk with age at exposure. Finally, for about 30% of tumour
types (including Hodgkin’s lymphoma, prostate, rectum and uterus cancer), there is only a weak or no
relationship between radiation exposure and risk at any age of exposure.
84. At present, there are no statistically sufficient projections of lifetime risk for specific tumour sites
following exposure at young ages. Currently used estimates do not adequately capture the known
variations and additional work is needed.
85. Nevertheless, the examples above indicate that tumour induction after radiation exposure ofchildren as compared to adults is quite variable and that findings depend on the tumour type, specificassumptions and the various models used. Table 13 summarizes the relative sensitivity of children
compared to adults for the induction of various tumour types by radiation.
86. All solid cancers. In the latest report of the cancer incidence in survivors of atomic bombings,
there is a statistically significant variation in excess incidence by age at exposure for the ERR modeland even more so for the EAR model [P52]. A recent report on mortality shows a decrease in ERR by
29% per decade of age at exposure [O25]. But estimates for all solid cancers as a group do notnecessarily represent age-at-exposure risks for all individual tumour sites. When the data are combined,tumours that may not be induced by radiation (e.g. prostate and rectal cancer) appear to have a risk
which is artefactual owing to inclusion of the risk from tumours that are highly inducible by radiation.
87. Leukaemia. Most types of leukaemia other than chronic lymphocytic leukaemia can be induced byionizing radiation with a minimum latency of about two years. Acute forms of leukaemia tend to
predominate and occur more rapidly after exposure than chronic granulocytic leukaemia. A linearquadratic dose response (rather than linear non-threshold) appears to provide the best fit to the data.
From several studies covering various types of exposure, exposure in childhood appears to entail athree- to fivefold greater risk than exposure in adulthood [M1, R8].
88. Multiple myeloma and myelodysplasia. The UNSCEAR 2006 Report concluded that there wasonly weak evidence linking myeloma to radiation exposure and that the better quality of informationfrom incidence data would suggest little evidence of an association with low linear energy transfer(LET) radiation. No age-at-exposure effect has been identified [U12]. An excess of myelodysplasia has
been identified in atomic bombing survivors with an increased risk at young ages of exposure [I47].

30 UNSCEAR 2013 REPORT

Table 13. Comparison of carcinogenesis risks at age-at-exposure for children versus adults
Cancer site

More

No difference

Less

Oesophagus

Level of evidence

X

Stomach (mortality)
Small intestine

No sufficient data

ERR

EAR

Moderate

a

X

Colon
- (incidence)EAR- (mortality)

EAR & ERR

Rectum

ERR

Weak

a

Pancreas

X
a

X

Liver

X

Lung

Weak
X

b

Moderate

Skin non-melanoma

X

Moderate

BreastX

StrongUterus
Cervix

X
a

X

Ovary

X

Prostate aX

KidneyX

BladderX

Moderate

Brain

X

StrongThyroid

X

StrongParathyroid
Hodgkin’s lymphoma

XaX

Non-Hodgkin’s
lymphoma

X

MyelomaX

Leukaemia non-CLL

X

Strong

Myelodysplasia

X

Weak

a

These tumours are not definitely shown to be increased by radiation exposure.

b

The limited data on radon and lung cancer indicate approximately the same risk after exposure at pre-adult and adult ages.

89. Hodgkin’s lymphoma. With the exception of what are thought to be statistical chance associations,radiation has not been found to be associated with the development of Hodgkin’s lymphoma, following
exposure in either adulthood or childhood [U12].
90. Non-Hodgkin’s lymphoma. Examination of the atomic bombing survivor incidence data found anincrease in estimated EAR but only for males. No age-at-exposure effect was found. Studies ofchildhood cancer survivors showed an excess of non-Hodgkin’s lymphoma, but the data were notexamined for radiotherapy versus other treatment and there was no analysis by age at exposure [U12].

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

31

91. Brain and central nervous system tumours. Ionizing radiation can induce several types of nervous
system tumours. There are marked differences with age at exposure. The UNSCEAR 2006 Report
pointed out that malignant tumours of the CNS are seen mostly after high doses of radiotherapy andafter exposure in childhood [U12]. The risk of glioma is highest at the age of five years or less at
irradiation and seems to largely disappear at the age of 20 years or more at irradiation, suggesting thatsusceptibility decreases as brain development nears completion. The greatest risk of glioma is in thefirst 20 years after exposure, whereas meningiomas predominate thereafter. The risk from exposure inadulthood is more commonly for benign tumours such as meningioma, neurilemmoma andschwannoma.
92. Thyroid cancer. Children are more sensitive to induction of thyroid cancer than are adults. This istrue whether one examines ERR or EAR. The data come from a number of sources, but particularly
from radiotherapy of the head and neck (primarily for Hodgkin’s lymphoma), from the study of atomic
bombing survivors and from radioiodine exposure as a result of Chernobyl [J5, N2, P52, S65, U12].
After therapeutic radiation exposure, the risk peaks in mid-dose range (10–30 Gy) and diminishes athigher doses (possibly because of cell killing). The risk of radiation-induced thyroid cancer as a resultof adult exposure is too low to be quantified adequately.
93. Salivary gland tumours. Benign and malignant tumours of the salivary (particularly the parotid)
gland have been reported to follow external exposure in the atomic bombing survivors and in children
who have received radiotherapy. Presently, data are insufficient to assess whether there is an age-atexposure effect or not.
94. Breast cancer. Breast cancer is inducible by radiation and the difference in risk from exposure inchildhood compared to that in adulthood depends upon the model used. The increased risk in children
appears to be about three- to fivefold with most low dose studies showing minimal or no risk fromexposure after age 40. However, a pooled analysis that gave preference to attained age (age at risk)
showed no additional effect of age at exposure [P48]. Children therapeutically irradiated during the
pubertal years may have an increased risk compared to younger children or adults.
95. Lung cancer. Both low-LET and radon exposure have been shown to increase the risk of lungcancer. A recent update of the atomic bombing survivor mortality data showed that the age-at-exposure
effect was not significant and was −7% (95% CI: −35, 29) per decade. A more detailed analysis thattook into account smoking habits even suggested that risk might be greater for those exposed at older
ages [F28], which also accords with some other data [R21]. The data on underground miners with radon
exposure suggest that lung cancer risk was comparable for those first exposed at ages <15, 15-24 and>24. The findings for both external and internal lung exposures are at variance with the BEIR VII
modelling, which estimated that children are about threefold more sensitive than 40-year-old adults toradiation induction of lung cancer [N43].
96. Stomach cancer. Increased risk of stomach cancer has been shown in atomic bombing survivors
and those who have had radiotherapy for peptic ulcers. The LSS data provide weak evidence that the
ERR decrease with increasing age at exposure but the EAR does not [O25]. The very limited evidence
from other studies does not support an increased sensitivity among those exposed at young ages.
97. Colon cancer. Colon cancer is a good example of a tumour for which evaluating the age-atexposure risk is problematic. In the atomic bombing survivor data, for those exposed before age 10 the
ERR was quite high before age 40, but after age 40 the ERRs for age-at-exposure 10 and age-atexposure 30 were virtually identical. Both the incidence and mortality data showed no age-at-exposure
difference at age 70 for the ERR model, but the EAR did model higher risk for younger ages at
exposure [O25, P52].

32 UNSCEAR 2013 REPORT

98. Rectal cancer. The rectum has a relatively low sensitivity to radiation-induced cancer but astatistically significant risk is evident after extremely high radiation therapy doses. In the most recent
atomic bombing survivor cancer incidence report, the radiation risk for rectal cancer was notstatistically significant nor was there significant variation in risk by age at exposure [P52].
99. Kidney and bladder cancer. Evidence linking kidney cancer with radiation exposure is weak, andthat evidence comes only from studies where the dose is high (i.e. in the radiotherapy range). In those
few studies, there does not appear to be any significant age-at-exposure effect. Although there arepositive associations between bladder cancer and radiation exposure in radiation therapy and atomic
bombing studies, their data do not show any special radiosensitivity among those irradiated inchildhood [G26, O25, P52].
100. Prostate cancer. There is no convincing epidemiological evidence that prostate cancer is induced
as a result of radiation exposure in either adulthood or childhood. The model used by the US National
Research Council BEIR VII committee [N43] indicated that there was a 2.7-fold higher risk forchildren of having prostate cancer induced by radiation than there was for 40-year-old adults. Thismodelling is at variance with epidemiological data. The UNSCEAR 2006 Report concluded that there
was little indication of radiation effect on prostate cancer risk [U12].
101. Ovarian and uterine cancer. With the exception of the atomic bombing survivor data, not muchepidemiological evidence exists that radiation induction of ovarian cancer occurs in those exposed
either as adults or as children. The atomic bombing survivor data do not show a consistent age-atexposure effect [U12]. The epidemiological literature does not support radiation induction of uterine
cancer except, possibly, at very high doses. The absence of an association between cervical cancer andradiation is a consistent finding even after very high doses.
102. Skin cancer. A number of epidemiological studies have indicated an association between radiation
exposure and non-melanoma skin cancer, but not melanoma. The induced tumours are predominantly
basal cell type and, to a lesser extent, squamous cell carcinoma. The relative risk decreases roughly two—fivefold with increasing age at exposure [P52, S70].
103. Liver cancer. The LSS of atomic bombing survivors reported an excess of liver cancer but theanalysis did not show any statistically significant changes in risk by age at exposure. There was a nonsignificant age-at-exposure effect in the mortality data [O25]. Both are difficult to interpret owing to ahigh prevalence of infection with hepatitis C virus in that cohort, which is a major risk factor for livercancer. A number of other low-LET exposure studies do not show an increase in liver cancer incidenceor mortality.
104. Pancreatic cancer. Incidence and mortality studies of atomic bombing survivors do not show astatistically significant increase in pancreatic cancer [O25]. Some radiotherapy studies have reported anincrease in pancreatic cancer after very high doses but few contain enough patients below the age of 20
to examine an age-at-exposure effect [U12].
105. Bone and connective-tissue tumours. Studies reviewed by UNSCEAR in the past indicated thatbone sarcomas were unlikely below doses of tens of grays. A recent report on the atomic bombing
survivors suggests a dose threshold of about 0.85 Gy with a linear response above that level, but basedon small numbers and with no clear age-at-exposure effect. There was a statistically significant increasein soft-tissue sarcomas in relation to dose, but no variation by age at exposure [S13, S12, U12].

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

33

B. Deterministic effects
106. Deterministic effects —also called “Harmful tissue reactions”—occur only above a certain dosethreshold and their frequency and severity increase with dose. An example of a deterministic effect is aradiation skin burn or ulcer. Few tissues show clinically significant deterministic effects at absorbed
doses of less than a few grays.
107. Pathogenesis. Cell death, cell malfunction, perturbation of both intracellular and intercellularsignalling, and fibrosis are central to all deterministic effects. Increased mitotic activity in developing
tissues may relatively increase radiation sensitivity in these tissues during periods of rapid growth.
However, cellular damage from radiation can sometimes also occur during intervals when the cellular
activity is relatively quiescent but the injury is not expressed until development of that tissue
accelerates. The role of stem cells in response to radiation exposure at various ages is unclear. Stemcells can be depleted by radiation, with injury expressed as the patient ages. However, a greater
abundance of stem cells in some tissues at younger ages may decrease radiation sensitivity because ofcompensatory mechanisms. Conversely, limitations in cellular repair capacities at older ages cansometimes actually increase the sensitivity of some normal tissues in developed or senescing tissues.
Deterministic effects depend on the absorbed dose received, volume and type of tissue irradiated,
quality or type of radiation, time over which the dose was received and age of the individual. The
magnitude and type of effects observed depend upon the time of observation after the exposure.
108. Acute versus late effects. Acute deterministic effects are caused by injury to rapidly proliferative
stem or progenitor cells, which results in temporary or permanent lack of mature cells. Delayed lesions
are due to complex processes, including progressive fibrosis, blood vessel narrowing, disturbances incellular signalling, and immune and genetic factors. The spectrum of late responses varies with age.
Radiation-induced impairment of growth and maturation is unique to children whereas organ damage
and problems with tissue repair are common to both adults and children [P19].
109. One of the most valuable and comprehensive data sources regarding deterministic effects fromchildhood exposure is the Childhood Cancer Survivor Study (CCSS). This study followed 14,370
children diagnosed with various malignancies between 1970 and 1986 who survived for at least five
years, and compared their outcome data with that of siblings. The CCSS is somewhat complicated inthat many of the children received multimodal therapy. In spite of this, there are many conclusions thatcan be drawn regarding ionizing radiation. There are also useful epidemiological data regarding a
number of effects from the atomic bombing survivor studies.
110. Differences in deterministic effects from exposure in childhood versus that in adulthood arecomplex and often involve interaction of different tissues and pathways. In each organ (for example thethyroid), there are multiple potential effects—each with different mechanisms and different times of
expression. Similar to carcinogenesis, there are some instances in which childhood exposure poses
more risk than adult at same radiation doses (e.g. brain, cataracts, thyroid nodules). There are otherinstances where the risk appears to be about the same (e.g. neuroendocrine, kidney) and there are a few
instances where children’s tissues are more resistant (lung, marrow and ovaries). The main differences
between children and adults for deterministic effects are evident at doses only in excess of 0.5 Gy andusually at doses substantially higher associated with radiotherapy. A comparison of risks—followinginternal and external (radiotherapy) exposure of children versus that of adults—of developing
physiological abnormalities of some organ systems is given in table 14.

34 UNSCEAR 2013 REPORT

Table 14. Comparison in children and adults of risks of developing physiological abnormalities
following internal and external exposure
Most of the age-at-exposure effects are not seen at doses of less than 0.5 Gy

Organs

More

Same

Less

No sufficientdata

Levels ofevidence

Comments

Deterministic risks following radiotherapy in children versus adults
Brain

X
X

Neuroendocrine

Strong

Neurocognitive reduction

StrongConsequences greater owing to
growth hormone suppression

Cataracts

X

Weak

Cerebrovascular
accident

X

Moderate

StrokeHeart

X

StrongPrevents growth andremodelling, valvularabnormalities

Breast hypoplasia

X

StrongMost severe during puberty

Weak

Depends on end point:
maximum capacity decreased if
chest wall growth is inhibited

X

Lung

Thyroidhypofunction
Thyroid nodules

X

Weak

X

StrongX

Thyroid
autoimmune
X

KidneyWeak

Bladder

X

StrongBladder capacity reduced

TestesX

StrongMost severe during puberty.
Reduction in sperm andhormones

Moderate

Less sensitive at younger age

X

Ovaries
UterusX

Moderate

Uterine vasculature impaired

Musculoskeletal

X

StrongHypoplasia, deformity,
osteochondroma

StrongLess available marrow when
older

X

ImmuneX

Marrow wholebody

Deterministic risks following internal exposures in children versus adultsX

Thyroidhypofunction
Thyroid nodules
Thyroid
autoimmune

X

StrongX

Moderate

Insufficient evidenceANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

35

111. Neurological effects. As mentioned earlier, the brain develops over at least two decades.
Radiotherapy experience has shown that the brain is particularly radiosensitive and adverse effects are
greater at a younger age at exposure [P2, R31]. The potential for these effects is increased when certain
chemotherapeutic agents (e.g. methotrexate, cytosine arabinoside) are also administered. The brain ismost radiosensitive when rapidly developing in the first two years of life but effects also occur at a laterage at exposure. Higher doses of radiation (>20–30 Gy, depending on patient age) interfere with theprocess of myelinization of nerve axons and synaptogenesis. Also, there can be loss of brain volume[R14]. These changes can result in lethargy, poor school performance, ataxia, spasticity, progressive
dementia and even death [P4].
112. Neurocognitive effects. After fractionated doses of over 54 Gy, children over the age of 12 whohave had localized volumes of cranial radiotherapy have little reduction in intelligence quotient (IQ)
while those exposed under the age of five at treatment to similar volumes have a significant decline of
15–35% [M29]. Other neurologic sequelae can include late onset of coordination problems, seizures,
headaches, impairment in task efficiency and difficulty in emotional regulation.
113. Neuroendocrine effects. These occur as a result of hypothalamic irradiation. The most common
effect is a reduction in growth hormone secretion that, if untreated, results in short stature. Other
problems include gonadotropin deficiency, precocious puberty, hyperprolactinemia, adrenocortical
hormone deficiency and central hypothyroidism. Manifestations of damage to the hypothalamicpituitary axis depend on the hormonal axis that is affected, but can include loss or gain of weight,
altered development of secondary sexual characteristics, dry skin, slow pulse, genital atrophy andtemperature disregulation [C47, M56, S85].
114. Cataracts, cortical opacities. Changes in the lens of the eye following irradiation have beenrecorded for many decades [D23, N6, S68] and children appear to be more sensitive than adults to
induction of early lens opacities and clinically significant cataracts requiring surgery. While children
who receive low radiotherapy doses to the orbit (5–15 Gy with risk depending on their age) may sufferfrom cataracts, higher doses of >20–30 Gy are necessary to cause dry eyes, retinitis andkeratoconjunctivitis.
115. Hearing and the ear. The ear is relatively radioresistant; however, cranial radiotherapy (>30 Gy)
in children can produce late effects, including vestibular abnormalities and hearing loss. These changes
can be exacerbated when the child is also treated with select chemotherapeutic agents. Susceptibility
can be greater at a young age [M29].
116. Oral cavity and pharynx. The lining of the mouth and pharynx are more radiosensitive to acuteeffects than is the skin because of the higher renewal rate of the epithelial cells. The reactivity ofchildren is greater than that of adults but a more rapid recovery compensates for this and the end effectseems to be less Most patients receiving fractionated radiotherapy schemes totalling 60-70 Gy have
impairment in taste for several years [K45]. High radiation doses administered at young ages can causedelayed pharyngeal hypoplasia.
117. Teeth. In children, effects on teeth may occur even after >10–20 Gy therapeutic irradiation(depending on age at exposure), and also from chemotherapy. Effects are greatest in children under theage of five who had received such therapy before developing deciduous dentition [S98]. These include
increased caries, root stunting, reduced calcification, abnormal enamel, dry mouth and, occasionally,
even lack of development of the jaw bone. Tooth abnormalities are also reported in teenagers who were
injected with high activities of 224Ra.

36 UNSCEAR 2013 REPORT118. Salivary glands. Radiotherapy (>25 Gy) can reduce secretions of the parotid, submaxillary andsublingual glands with resultant dry mouth, but this is generally not pronounced below doses of 40 Gy[D31, F20]. There is little data concerning the sensitivity of these glands in children versus adults.
119. Thyroid. Effects of interest are primarily hypothyroidism, autoimmune thyroiditis and thyroid
nodule formation. After radiotherapy to the head and neck, thyroid function can be reduced; however,
the effect of age at exposure is controversial [S83, U8]. Very limited data indicate that an increased riskof hypothyroidism is observed as age at exposure decreases; however, most radiotherapy studies havefailed to confirm this. No epidemiological study has demonstrated hypothyroidism from external dosesof <1 Gy.
120. The available data indicate that autoimmune thyroiditis is unlikely to be induced by exposure toradiation in childhood. The most recent follow-up of thyroid abnormalities among survivors of theatomic bombings did not find a dose-response relationship for the presence of antithyroid antibodies orantithyroid antibody positive hypothyroidism [I34]. Most studies of populations exposed to fallout from
nuclear weapons and discharges from nuclear facilities do not show an increase in autoimmune
hypothyroidism. Multiple early studies of populations exposed to fallout from Chernobyl produced
conflicting results but the majority of recent studies do not show a relationship between thyroid doseand autoimmune thyroiditis in adults or children [T38].
121. There is a vast literature of epidemiological studies of thyroid nodules after radiation exposure.
These include studies of atomic bombing survivors, medical radiation exposure, nuclear fallout, nuclear
facility discharges and accidents. Although there is no question that the incidence of thyroid nodules
increases as a result of radiation exposure. Both the Israeli and New York tinea capitis studies foundincreased risk at thyroid doses of 100 mGy (0.1 Gy) or less. These studies have been complicated byuse of varying criteria and the high spontaneous rate of benign thyroid nodules in unexposed
populations. Most studies have demonstrated an increased risk of radiation-induced thyroid nodules
with decreasing age at exposure [N18, S71].
122. Parathyroid glands. The parathyroid glands are quite radioresistant. Although some reportssuggest, post-radiotherapy parathyroid hyperfunction or calcitonin deficiency, there is no clear evidence
of increased susceptibility of children.
123. Female breast. Adult breast tissue is quite radioresistant to deterministic effects; however, breast
development is readily inhibited by radiotherapy in infancy and severe hypoplasia has been reported inwomen who have had a history of breast irradiation in childhood. Doses reported to cause these effects
were >2 Gy.
124. Cardiovascular. There are only a few studies that allow evaluation of age-at-exposure differences
for the risk of development of cardiovascular disease. The data from survivors of the atomic bombings
do not show a clear increased risk of cardiovascular disease at doses lower than 0.5 Gy and there is noevidence of difference in risk with age at exposure [S57]. In the paediatric radiotherapy literature, there
is an increased cardiovascular risk for various cardiac injuries at doses in excess of 15 Gy, and the riskincreases slightly as the age at exposure decreases. A recent meta-analysis of low dose studies suggeststhat there is a reduction in risk with increasing age at exposure [M58]. Cardiovascular complications
from chemotherapy, particularly anthracyclines, are well described, and augment effects from radiation
therapy.
125. Pulmonary. Radiation-related respiratory effects in children can impede the formation of new
alveoli or result in skeletal deformity and smaller lungs owing to impaired chest development. Overall,however, respiratory damage in children is somewhat less than in adults at the same doses. The reasons

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

37

for this are that children have less pre-existing disease and better repair capability. In spite of this, there
can be adverse pulmonary effects in children at fractionated doses totalling 10–20 Gy [V16].
126. Gastrointestinal. There are reports of a wide spectrum of acute complications and late effects afterchildhood or adolescent radiotherapy involving the gastrointestinal track. The risk of suchcomplications is increased for children who have been treated with certain chemotherapeutic agents inaddition to radiotherapy or who have had abdominal surgery However, interestingly, children who wereyounger than three at cancer diagnosis had a 20–50% lower risk of upper and lower gastrointestinal
complications than did older children. The reason for this is unclear [G19].
127. Liver. A number of liver abnormalities may occur after high-dose hepatic irradiation. A number ofhistorical studies indicated that decreasing age was a risk factor for liver complications following
radiotherapy of children at doses >12 Gy. However, a recent analysis in the CCSS suggests thatchildren over the age of three at cancer diagnosis had a higher risk than those children who were under
three years of age [C7].
128. Pancreas. Children and young adults treated with whole body or abdominal radiotherapy withdoses in excess of 10 Gy are known to be at increased risk of insulin resistance and diabetes mellitus.
Children under two are more sensitive by about 50% than older patients [D29].
129. Testes. Radiation effects on the testes are both age and dose dependent. Germ cells are the mostsensitive. Complete sterilization can occur after fractionated doses of 2–4 Gy. Doses of 10 Gy havebeen shown to produce primary gonadal failure of various degrees in the majority of boys regardless ofpubertal status. Doses higher than 20 Gy will also affect the more resistant Leydig cells of the testes[K26].
130. Ovaries and uterus. The ovaries and subsequent fertility is an example of children being moreresistant than adults to radiation effects. Since the ovaries contain the most primordial follicles at ornear birth and there is quite a dramatic decline in number with increasing age, there is much lessreserve to allow fertility as age increases. With ovarian radiotherapy doses of 2.5–5 Gy, patients under
14 did not develop sterility compared to 30–40% for those treated at 15–40 years of age and 90% in
those who were over 40 at treatment. High doses to the uterus of girls can result in a small fibrotic
uterus, which increases the risk of spontaneous abortion or premature delivery [M36].
131. Fertility and reproduction. Fertility and reproduction can be reduced by a number of factors,
including those outlined above for the testes, ovaries and uterus. Other factors would include patency of
fallopian tubes and pituitary/hypothalamic axis endocrine problems. While there are no data indicatingthat radiation susceptibility of the neuroendocrine axis is greater at younger age, uterine development isclearly compromised by pelvic irradiation and, thus, is age dependent. Conversely, the ovaries, andperhaps the testes, may be more resistant to radiation at a younger age [K26, M36].
132. Skin. Children appear to be less sensitive than adults for the acute effect of moist desquamation,
perhaps because of faster repair by the skin cells. Otherwise, there appears to be little or no difference
between children and adults in skin sensitivity with regard to tissue reaction.
133. Musculoskeletal system. The musculoskeletal system is quite radioresistant after growth iscomplete, but radiosensitive during development. Children can experience unique late effects that do
not occur as a result of adult irradiation. Few, if any, changes are seen below fractionated doses of
10 Gy and most changes occur at doses >20 Gy. Radiation therapy can affect the musculoskeletal
system of a growing child or adolescent with inhibition of normal bone and muscle development. Lateeffects can include short stature, premature closure or slippage of epiphyses, scoliosis/kyphosis, limb
length discrepancy, and radiation-induced fractures. Exposure at less than six years of age and during

38 UNSCEAR 2013 REPORT

puberty is associated with the greatest relative impairment. Other post-radiotherapy effects can include
induction of benign bone growths (osteochondromas), increased body fat composition and metabolic
syndrome.
134. Urinary system. Radiotherapy doses above 12 Gy to the kidneys of children have been shown tocause nephritis, reduced creatinine clearance, renal insufficiency and hypertension. The urethras andbladder are more resistant to late radiation effects than are the kidneys. There are no data to suggest thata child’s urinary system is more radiosensitive than that of an adult.
135. Immune system. Studies of radiation effects on the immune system are difficult because of its
immense complexity. The results relative to age at exposure are mixed and most studies are related tolaboratory rather than clinical findings. Studies of T-cell immunity of survivors of the atomic bombingssuggest that there is increased perturbation of the immune system in those exposed at older ages. Other
studies related to genetic regulation of the immune system suggest more sensitivity among persons
exposed at less than 20 years of age. Since the data are sparse and often contradictory, there do notseem to be clinically identifiable differences in risk between children and adults.

C. Heritable effects
136. Extensive reviews of the heritable effects of radiation exposure are available in ICRP Publication
83 [I21] and in the UNSCEAR 2001 Report [U11]. The UNSCEAR 2001 Report contained a section
reviewing two studies on genetic disease in the offspring of long-term survivors of childhood andadolescent cancer and in the offspring of those treated for haemangioma in infancy. As with adults,
there is no evidence that radiation exposure in childhood confers any measurable risk of heritableeffects in offspring.
137. Over the past decade, there have been additional studies that have focused on survivors ofchildhood and adolescent cancer. Gonadal doses from radiotherapy often range from tenths of a gray up
to twenty grays. There has been little evidence in the offspring of irradiated parents of chromosomal
instability, minisatellite mutations, transgenerational genomic instability, change in sex ratio ofoffspring, or congenital anomalies. A number of papers have been published using data from the CCSS
and the atomic bombing survivor LSS, and there is no apparent increase in cancer in the offspring.
138. Many studies in the last decade have been directed at searching for possible heritable effects afterchildhood exposure, the vast majority of which involve the offspring of persons who received
radiotherapy as children or adolescents. The results of such studies are important as the survivors ofchildhood cancer reach the age of fertility. Winther et al. [W33] studied female cancer survivors andfound only a minimally higher incidence of induced abortion. There is also an increased risk of lowbirth weight and pre-term delivery of babies for those females who received pelvic radiotherapy. This ispresumably the direct effect of radiation on the uterus and ovaries.
139. Curwen et al. [C57, C58, C56] investigated the possible association between G2 chromosomal
radiosensitivity in Danish survivors of childhood and adolescent cancer and their offspring. There wasstrong evidence of heritability of the radiosensitive phenotype but not a statistically significant
relationship between the chromosomal radiosensitivity and cancer predisposition.
140. Tawn et al. [T8] examined chromosomal instability among 25 adult survivors of childhood
cancer, their 26 partners and 43 offspring. Frequencies of all aberration categories were significantly
lower in the offspring group. Genomic instability was not associated with radiotherapy nor was it foundANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

39

to be a transgenerational radiation effect. Tawn et al. [T9] also studied germ line minisatellite mutations
in survivors of childhood and young adulthood cancer who had been treated with radiation. No
significant difference was observed in the paternal mutation rate of 5.6% in exposed fathers with amean preconceptional dose to the testes of 1.23 Gy and that of 5.8% in unexposed fathers. The maternalmutation rate of 1.6% in cancer survivors with a mean preconceptional dose to the ovaries of 0.58 Gy
was lower than that of unexposed mothers (2.1%).
141. Winther et al. [W30] studied chromosomal abnormalities among 2,630 live-born offspring of thesurvivors of childhood cancer compared with 5,504 offspring of their siblings. The proportion withabnormal karyotypes was identical at 0.21%. Thirty-seven per cent of the group had received
radiotherapy.
142. Winther et al. [W35] also performed a case–cohort study of 472 survivors of childhood andadolescent cancer and their 1,037 pregnancies. Adverse outcomes included 159 congenital
malformations, six chromosomal abnormalities, seven stillbirths and nine neonatal deaths. The risk ofgenetic disease was similar among the children of irradiated survivors when compared with nonirradiated survivors (relative risk (RR) = 1.02; 95% CI: 0.59, 1.44; p = 0.94)). However, a statisticallysignificant association between abdomino-pelvic irradiation and malformations, stillbirths and neonatal
deaths was not seen in the children of female survivors overall (p = 0.07) or in the children of mothers
receiving high uterine doses (mean 13.5 Gy, max 100 Gy) (RR = 2.3; 95% CI: 0.95, 5.56). An earlier
population-based cohort study by the same authors [W32] found a slightly higher, non-significant
increase in congenital malformations which was unrelated to gonadal dose.
143. A recent retrospective cohort analysis was performed by Signorello et al. [S77] of 4,699 childrenof 1,128 male and 1,627 female childhood cancer survivors within the CCSS. Neither the dose to theovaries (mean dose 1.19 Gy; odds ratio (OR) = 0.59; 95% CI: 0.20, 1.75), nor the dose to the testes(mean dose 0.48 Gy; OR = 1.01; 95% CI: 0.36, 2.83) was related to congenital anomalies.
144. Additional studies have been conducted on reproductive outcomes, cancer incidence andhospitalization of offspring. Green et al. [G31] studied patients in the CCSS, including 1,227 malesurvivors who sired 2,323 pregnancies and 1,915 female survivors who had 4,029 pregnancies.
Offspring of women who had received doses to the uterus of more than 5 Gy were more likely to besmall for gestational age. There was no difference in proportion of offspring with simple
malformations, cytogenetic syndromes or single-gene defects. In another study of the same data base,Signorello et al. [S75] also reported low birth weight and pre-term delivery in those who had received
high doses to the uterus from pelvic irradiation. Another study by Signorello et al. [S76] examined theoccurrence of stillbirth and neonatal death. There was no increase in these in the offspring of men
exposed to gonadal irradiation. However, uterine and ovarian irradiation had serious adverse effects
probably related to uterine damage (and not heritable causes).
145. The possibility of sex ratio alterations after childhood radiotherapy has been studied by Winther et
al. [W29] in a Danish study of 1,100 survivors of childhood cancer who became the parents of 2,130
children. The sex ratio for male (0.99) and female (1.00) offspring did not differ significantly from thatfor the Danish population as a whole (1.06) and there was no evidence of a radiation dose effect. The
authors point out that sex ratio may not be a good or even valid indicator of genetic effects in humans.
A study of hospitalization of offspring of survivors of childhood cancer has been conducted by Wintheret al. [W34]. This was done on the basis that hospitalization might be an indicator of multifactorial
genetic disease. Once heritable cancer syndromes had been eliminated, there were no significant
associations.

40 UNSCEAR 2013 REPORT146. The risk of cancer in offspring of the survivors of the atomic bombings has been studied by Izumi
et al. [I48, I49]. They did not find an increase in the mortality or cancer rates of offspring from exposedparents. They indicated that most parents were between 10 and 30 years of age at the time of thebombings with the mean age for males being 24.4 years and that for females 19.8 years. Owing to thenegative findings and small numbers of deaths in offspring, their reports do not allow a distinction
between risks at the younger and older ages of the parents at the time of the bombings.
147. There are several recent studies of potential heritable effects in populations living in areas of highnatural background radiation, particularly in Kerala, India. These studies have been negative formultiple end points, so they are not able to elucidate differences between radiosensitivity of children
compared to adults [D12, D13, J9, R6].
148. A recent review by Little et al. [L31] of transgenerational effects in the offspring of irradiatedparents included both radiotherapy patients, atomic bombing survivors, and occupationally andenvironmentally exposed groups. The authors concluded that human health was not significantly
affected by transgenerational effects of radiation, perhaps because these effects might be restricted torelatively short times post-exposure and because conception shortly after exposure was rare.

VII. FUTURE RESEARCH
149. The Committee recognizes that continued research is needed to identify the full scope andexpression of effects, mechanisms, differences in radiosensitivity and risk of exposure in children ascompared to adults. This is necessary because for a number of studies (such as those on the atomic
bombing survivors, on children exposed after the Chernobyl accident to radioiodine and on patients
who have had CT scans), the lifetime results remain incomplete. Future long-term studies following
childhood exposure will face significant difficulties owing to unlinked health records, administrativeand political barriers, as well as ethical and privacy considerations.
150. There also is a need for development of statistically sufficient projections of lifetime risk forspecific cancer types following exposure at young ages. Current ERR and EAR estimates do notadequately capture the subtleties of both attained age and time since exposure.
151. Important areas of future research include evaluation of potential radiation effects on children (a)in areas of high radon and other natural background exposure; (b) after CT scans and high dose medical
interventional fluoroscopy; and (c) after cancer radiotherapy (including potential interaction with othertherapies). Moreover, the Committee identified other areas of research that may prove useful, including
development of radiation dose databases for children who can be tracked in the long term, andevaluation of juvenile organ-specific and partial organ-volume effects. Studies at the molecular,
cellular, tissue and juvenile animal level are likely to be informative and should include considerationof developmental effects on the cellular organization of tissues, the response of tissues and cells toradiation damage, and identification of cells at risk. Application of the range of available proteomic,
genomic and metabolomic technologies may be beneficial.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

41

VIII. SUMMARY AND CONCLUSIONS
152. The effects of radiation exposure during childhood or adolescence as compared to those during
adulthood is a complex matter. The commonly held notion that children might be two–three times moresensitive to radiation than adults is true for some health effects but certainly not for all. Publishedmodels assuming that after radiation exposure, the same increased relative risk of carcinogenesis inchildren as in adults applies to nearly all tumour types are overly broad generalizations without clear
scientific support. In fact, for a few effects (e.g. lung cancer), children are more resistant than adults.
153. While there are clear instances of increased risk of some tumours (e.g. leukaemia, breast and brain
cancer) in children compared to adults, there are other tumour types (e.g. bladder cancer) for which
there appears to be little or no difference in risk by age at exposure, and some in which the publishedmodels are not supported by the data. Similar conclusions regarding age dependency for adverse healthrisks can be drawn from the data on deterministic effects. For many of these effects, there are
significant variations in magnitude during the span from infant, through childhood and intoadolescence. Thus, in a discussion of effects of childhood radiation exposure, generalizations are best
avoided and attention should be directed to the specifics of the exposure, age at exposure, absorbed
dose to certain tissues, attained age at the time of assessment, and the particular effects of interest.
(a) The reason for these differences is easy to explain for some effects (e.g. the developmental andphysiological status of the brain) while in many other instances, the reason for different effects inchildren versus adults is not known. An accurate assessment of risks to children would involve
identifying the specifics of the exposure, the situation in which the exposure occurred, andvariables relating to the host. More knowledge will be obtained with longer follow-up of thesurvivors of the atomic bombings and childhood cancer. It also is recognized that, currently, anumber of epidemiological studies are under way—which may yield information in the next
decade—regarding exposure from CT scans in childhood and possible induction of neoplasms. For
a given radiation dose, children are generally at more risk for tumour induction than are adults.
Cancers that may be induced following radiation exposure at young ages could occur within a few
years but also decades later. In the 2006 Report to the General Assembly, the Committee stated thatlifetime cancer risk estimates for those exposed as children were uncertain and might be a factor of
two–three times higher than estimates for a population exposed at all ages. This conclusion was
based upon a lifetime project model combining all tumour types.
(b) The Scientific Committee has reviewed evolving scientific material and notes that, afterradiation exposure, tumour induction in children compared to adults is quite variable and depends
on the tumour type, age and sex. The term “radiation sensitivity” with regard to cancer inductionrefers to the rate of radiogenic tumour induction and does not refer to the degree of malignancy.
Broadly, for about 25% of tumour types, children are clearly more radiosensitive regardless of themodel. These include leukaemia, and thyroid, skin, breast and brain cancer. For some of these sites,
depending upon the circumstances, the risks for children compared to adults can be quite high.
Risks may also vary significantly at different ages during childhood. Some of the tissue sites arevery important for evaluation of exposures from accidental and medical situations.
(c) For about 15% of tumour types (such as bladder cancer) children appear to have about thesame radiosensitivity for tumour induction as adults. For about 10% of tumour types (e.g. lungcancer), children appear less sensitive to external radiation exposure than adults. For about 20% of
tumour types (including oesophagus cancer), the data are too weak to draw a conclusion regarding
differences in risk with age at exposure. Finally, for about 30% of tumour types (including42 UNSCEAR 2013 REPORT

Hodgkin’s lymphoma, prostate, rectum and uterus cancer), there is only a weak or no relationshipbetween radiation exposure and risk at any age of exposure.
(d) At present, there are no statistically sufficient projections of lifetime risk for specific tumoursites following exposure at young ages. Currently used estimates do not adequately capture theknown variations and additional work is needed.
154. For direct effects (deterministic) that occur after high acute or high fractionated doses, thedifferences between exposure in childhood and in adulthood are complex and can be explained by theinteraction of different tissues and pathways. These effects may be seen after radiation therapy or
following accidental exposure. “Radiation sensitivity” of children versus adults for deterministic effects
in a specific organ is often different from that for tumour induction. There are some instances in whichchildhood exposure poses more risk than adulthood exposure (e.g. for cognitive defects, cataracts andthyroid nodules). There are other instances where the risk appears to be about the same (e.g.
neuroendocrine and kidney) and there are a few instances where children’s tissues are more resistant(e.g. lung function, marrow and ovarian failure).
155. Because of the above considerations, the Committee recommends that in a discussion of effects ofchildhood radiation exposure, generalizations are best avoided and attention should be directed to thespecifics of the exposure, age at exposure, absorbed dose to certain tissues, attained age at assessment,
and the particular end points of interest.
156. There have been many human studies of possible heritable effects following radiation exposure;these studies were reviewed by the Committee in 2001. It has been generally concluded that noheritable effects in humans due to radiation exposure have been identified (specifically in studies ofoffspring of atomic bombing survivors). Over the past decade, there have been additional studies thathave focused on survivors of childhood and adolescent cancer, and gonadal doses from radiotherapy areoften very high. There is essentially no evidence of an increase in chromosomal instability, minisatellite
mutations, transgenerational genomic instability, change in sex ratio of offspring, congenital anomalies
or increased cancer risk in the offspring of parents exposed to radiation.
157. Heath effects and risks depend upon a number of physical factors. Regarding external radiation
exposure, because children have smaller body diameters and there is less shielding by overlying tissues,
for a given external exposure the dose to children’s internal organs will be higher than for an adult.
Also, because they are shorter than adults, children may receive a higher dose from radioactivity
distributed on the ground. These factors are important when considering doses to populations in someareas (such as those around the Chernobyl and Fukushima-Daiichi nuclear power plants, areas of highnatural background) with elevated levels of radionuclides on the ground. In medical exposure, children
may receive significantly higher doses than adults for the same examination if the technical parameters
are not specifically adapted.
158. Regarding exposure from sources of radiation inside the body (internal exposure), because of thesmaller size of infants and children—and, therefore, because their organs are closer together—there ismore opportunity for radionuclides concentrated in one organ to irradiate other organs. There are also
many other age-related factors with regard to metabolism and physiology that make a substantial
difference in dose with age. Several radionuclides are of particular concern regarding internal exposureof children. In a nuclear power plant accident, radioiodines are significant sources of exposure, whichhave potential to induce thyroid cancer. The dose to the thyroid for infants is larger by a factor of eightor nine than it is for adults. For a dose from 137Cs, there is very little difference between children andadults. Internal exposure of children also occurs in the medical use of radionuclides. The spectrum of
examinations normally performed on children is different from that performed on adults. Potentially

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

43

higher doses in children, in practice, are offset by the use of a lower amount of administeredradioactivity.
159. Developmental processes and mechanisms give rise to differences between children and adults
both for the absorbed dose from a given exposure to a source of ionizing radiation and for the resulting
effects on health. The Scientific Committee recognizes that continued research is needed to identify thefull scope and expression of effects and risk from exposure in childhood as compared to adulthood.
This is necessary because for a number of studies (such as those on the atomic bombing survivors, onchildren exposed after the Chernobyl accident to exposure from radioiodine and on patients who have
had CT scans), the lifetime results remain incomplete. Future long-term studies following childhood
exposure will face significant difficulties because of unlinked health records, administrative andpolitical barriers and ethical and privacy considerations.
160. Important areas of future research and work include evaluation of potential radiation effects onchildren in areas of high radon and other natural background exposure, effects of high dose medical
interventional fluoroscopy procedures, and effects of cancer radiotherapy (including potential
interactions with other therapies), development of radiation dose databases that can be combined andtracked long term, and evaluation of juvenile organ-specific and partial volume effects. Studies at themolecular, cellular, tissue and whole organism level are likely to be informative and should include
consideration of developmental effects on the cellular organization of tissues, the response of tissues
and cells to radiation damage, and identification of cells at risk. Application of the range of available'omics technologies may be beneficial.

ACKNOWLEDGEMENTS
The Committee would like to acknowledge F. Mettler (United States) and the consultants for theirintensive work on this annex.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN45

APPENDIX A. DOSIMETRYI.

INTRODUCTION

A1.
This appendix gives a short overview on dosimetric quantities and describes differences
between children and adult doses for external and internal exposure from environmental and medical
sources. The differences in radiation effects and absorbed dose for the same radiation exposure canresult from some of the developmental processes and anatomical differences. This appendix deals withfactors regarding dosimetric differences between children and adults, and discusses the dosimetricaspects for external and internal exposures.

A. Dose quantities and units
A2.
The absorbed dose, D, is defined as the quotient of d by dm, where d is the mean energy
imparted to matter of mass dm by ionizing radiation, that isdε
D = dmThe SI unit is joules per kilogram (J kg-1) and its special name is gray (Gy).
A3.
In calculations for radiation protection purposes, the absorbed dose is generally averaged overa target region rT, either a target organ (e.g. liver or kidneys) or a target tissue (e.g. muscle), D(rT). In
some cases, averaged doses to radiosensitive regions of an organ or tissue instead of doses to the wholeorgan or tissue are considered. Examples for this are the walls of the human respiratory tract [I14] andthe human alimentary tract [I24], the skeleton (consideration of a 10 µm thin layer at the surface of thebone), and the skin (a thin layer at a depth of 70 µm from the skin surface) [I7].
A4.
Some types of radiation are biologically more effective than others in causing cancer orcancer-related end points [I25]. For radiation protection purposes, ICRP makes simple adjustments toreflect these differences using radiation weighting factors, wR, and by the introduction of the term
equivalent dose. The equivalent dose to a target organ or target region rT, H(rT), is defined by

H ( rT ) = ∑ wR ⋅ DR ( rT )R

where DR(rT) is the mean dose to the target organ or tissue rT due to radiation type R and wR theradiation weighting factor. Because wR is dimensionless, the SI unit of the equivalent dose is also joules
per kilogram (J kg-1), but its special name is sievert (Sv).
A5.
The radiation weighting factors used by the ICRP are 1 for photons and electrons, and 20 foralpha particles [I11, I25]. It should be noted that these simple adjustments made in the calculation of

46 UNSCEAR 2013 REPORT

equivalent dose for protection purposes do not fully reflect the extent of scientific knowledge, withevidence, for example, for differences in low-LET radiation (photons and electrons) according to theirenergies [I25]. For alpha particle irradiation, there is evidence for different relative biologicaleffectiveness (compared with low-LET radiation) for different biological end points, including different
cancer types.
A6.
In internal dosimetry, the committed equivalent dose, i.e. the equivalent dose delivered over adefined period, TD, is considered:TD⋅

H ( rT , TD ) = ∫ H ( rT , t ) dt
0⋅

where H ( rT , t ) is the equivalent dose rate in the target organ or tissue rT at time t. In general, TD istaken to be 50 years for adults and the time until the age of 70 years for infants, children andadolescents. Because of the rather short half-lives of the radionuclides used in nuclear medicine, TD istaken to be infinite in those applications.
A7.
The effective dose provides a measure for the radiation-induced detriment like cancer andhereditary effects. It is a weighted mean value of the tissue doses with tissue weighting factors wT thatreflect contributions to total cancer detriment. The sum over all tissue weighting factors is 1 with, forexample, values of 0.12 for lung and colon. The tissue weighting factors of ICRP Publication 60 havestill been used in this report [I11].
A8.

In the methodology of ICRP Publications 26 and 60 [I7, I11] the effective dose E is:

E = ∑ wT ⋅ H ( rT )T

A9.
The tissue weighting factors are mean values for the whole population of both sexes and allages. Therefore, the same tissue weighting factors are applied to children and adults. Furthermore,tissue weighting factors are simplified rounded values in which organs/tissues are grouped and assigned
one of a few weighting factors. For these reasons, the effective dose cannot be used to quantify theradiation risk to individuals and specific groups such as children. For the assessment of the radiation
risk for individuals or groups of children, organ-absorbed doses have to be used in combination withdata on the biological effectiveness of the respective ionizing radiation and tissue-specific risk
coefficients.

B. Dose coefficients
A10.
Dose coefficients give the (organ or effective) dose per unit intake for internal exposure and,for example, per unit activity concentration in air or per unit activity on a unit area on the ground forexternal environmental exposure.
A11.
For internal exposure, age-dependent effective dose coefficients for members of the public are
given in ICRP Publication 119 [I30] for ingestion and inhalation. For the application ofradiopharmaceuticals, organ and effective dose coefficients are given in ICRP Publications 53, 80 and
106 [I9, I20, I27]. All these dose coefficients give the committed absorbed organ dose (for patients), theANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

47

committed equivalent organ dose (for members of the public) or the committed effective dose per unit
intake. For a known intake, the doses can be calculated by multiplication of the intake and the dosecoefficient. The dose coefficients for internal exposure also take into account the contribution from any
daughter radionuclides that are formed within the body.
A12.
For external exposure, dose rate coefficients are given for adults in ICRP Publication 74 [I19]and for environmental sources in air, water, and soil in Eckerman and Ryman [E6]. For the calculationof dose, these dose coefficients must be multiplied by the amount of exposure (e.g. the activity per unit
area on the ground) and the exposure time.

II. EXTERNAL EXPOSURE
A13.
External exposure may be due to radionuclides in the environment (irradiation byradionuclides in the air, i.e. submersion, or by radionuclides deposited on the ground) or to medical
exposure (in radiological examinations by radiography, fluoroscopy or CT, or by radiotherapy).

A. Environmental exposure
A14.
Doses to children from submersion or by irradiation from the ground are larger because of thesmaller distances between organs and body surface and, in the case of irradiation from the ground,
additionally by the shorter distances between the organs and the radiation source (table A1).
Table A1. Age-related correction factors for submersion and irradiation from ground dependent on
gamma energy
Adapted from [B19]Age-related correction factors≤1 year1–2 years

2–7 years

7–12 years

12–17 years>17 years

Submersion>200 keV

1.4

1.4

1.3

1.2

1.1

1.0

Submersion≤200 keV

1.8

1.7

1.5

1.3

1.1

1.0

Irradiation from theground; >200 keV

1.6

1.5

1.3

1.2

1.1

1.0

Irradiation from theground; ≤200 keV

1.7

1.6

1.4

1.3

1.1

1.0

A15.
Drexler et al. [D47] and Petoussi et al. [P28] noted that the dose to organs from externalradiation increases with decreasing body size. This effect is more pronounced at low photon energy,
and for organs located near the middle of the body, which are shielded by overlying tissues. Petoussi etal. [P28] also noted that doses to the organ of an infant may be about 40% higher for energies larger
than 100 keV. Below 100 keV the difference may approach a factor of three for deeper organs such as
the ovaries and colon.

48 UNSCEAR 2013 REPORT

A16.
Yamaguchi [Y3] calculated dose rate coefficients for six age groups (newborn, 1-, 5-, 10-, 15year-old and adult) under five irradiation geometries. For isotropic radiation fields, effective dosecoefficients for newborns and one-year-old infants normalized to kerma in free air were about 20–30%
higher than those for adults at energies above 115 keV.
A17.
Recently, calculations of external dose rate coefficients have been performed for various
individuals whose CT images were segmented to voxel models. For the daughter nuclide 137mBa of
137
Cs, a correction factor of 1.3 for an eight-week-old infant was derived for submersion and irradiationfrom the ground [P27].

B. Medical radiation uses
A18.
External doses received during medical examinations depend on the examination type, theequipment used, the dose settings applied, and the patient’s size and the illness. In order to monitor theamount of radiation imparted during an examination, most modern equipment is equipped withdosimetric devices. This enables the assessment of patient dose, and the comparison with diagnostic
reference levels (DRLs) that have been introduced by ICRP Publication 73 [I18]—as an indication
whether, in routine conditions, the patient dose from a specified procedure is unusually high or low forthat procedure.
A19.
However, the dose quantities used for this purpose are given in terms of air kerma or absorbed
dose to standard phantoms only. In order to assess patient-related dose quantities—such as organ doseand effective dose—appropriate conversion factors have to be applied, which have to take into accountdifferences in patient size and organ position between adult and paediatric patients. The assessment oforgan doses is quite cumbersome and can best be achieved using appropriate dose calculation software.
A20.
For conventional X-rays imaging techniques, i.e. radiography and fluoroscopy, the dosequantities used are the same, but the dose levels in fluoroscopy are significantly higher. Cross-sectional
imaging techniques, such as CT, require different dose quantities for monitoring radiation exposure.
Contrary to radiation protection aspects in diagnostic radiology, application of the prescribed dose to
the target volume is intended in radiotherapy, necessitating dedicated therapy planning.
A21.
All computational methods and software solutions presented in this appendix refer to standard
patients of the specified age and size. Depending on the actual anatomy, individual doses—in particulardoses to organs that are not or not fully covered by the X-rays beam—may deviate from the calculated
values.

1.

Radiography

A22.
In radiography, the most common dose descriptor used for dose monitoring is the air kermaarea product (KAP). The KAP is an integral dose quantity that combines both the incident air kerma(IAK), i.e. “intensity”, and the extension of the irradiation. As long as backscatter from the patient to
the KAP meter can be neglected, the KAP is independent from the distance between the radiation
source and the patient and it can conveniently be measured using flat ionization chambers attached to or
integrated into the beam-limiting device. Alternatively, the KAP can also be calculated from theexposure and collimator settings. KAP values are displayed at or close to the operator’s console and are
documented in the dose report or in the structured report that is provided on modern equipment.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

49

A23.
The measurement of local dose—i.e. IAK or entrance surface dose (ESD), includingbackscattered radiation—requires dose meters attached to the patient’s surface. Either
thermoluminescent dosimeters (TLDs) or small semiconductor probes can be used for this purpose.
Owing to the inconvenience associated with this procedure (time and cost), the assessment of local doseis not routinely applied, but rather restricted to dedicated studies.
A24.
To illustrate typical dose levels in paediatric radiography, recommendations for the mostfrequent types of examination from a number of European countries are listed in table A2. DRLs for
paediatric radiographs were established in the United Kingdom [N44] as ESD values, in Germany[B21] as KAP values and in Austria [H64] as both ESD and KAP values.
Table A2. Comparison of European recommendations for DRLs in paediatric radiography

Examination

Age (years)

EuropeUK

Austria

Germany

[E4]

[N44]

[H64]

[B21]

ESD (mGy)
AbdomenThorax AP/PA

0

0.10

1

0.70

0.40

0.172

0.035

0.20

5

1.00

0.50

0.511

0.110

0.25

10

0.80

0.966

0.360

0.35

15

1.20

0

0.08

0.05

0.055

0.017

0.005

1

0.135

0.05

0.069

0.023

0.015

5

0.10

0.07

0.082

0.026

0.025

0.12

0.108

0.037

0.035

15

0.112

0.073

0

0.379

10

Skull AP/PA

Skull lat

KAP (Gy cm2)

1

1.69

0.80

0.69

0.10

5

1.54

1.10

0.880

0.19

0.20

10

1.10

0.998

0.31

0.30

15

1.10

1.123

0.37

0.294

0.08

0.50

0.70

0.23

0.20

0.80

0.506

0.20

0.25

10

0.80

0.557

0.25

15

0.80

0.676

0.33

0
1
5

1.078

A25.
A rough estimate of the effective dose (E) can be made by multiplying the KAP with anappropriate conversion factor (normalized value of effective dose per unit KAP) k:

E = KAP × k

50 UNSCEAR 2013 REPORTThe conversion factor must at least account for differences in radiation sensitivity between different
body regions (head, neck, chest abdomen, pelvis and extremities) and also for size- or age-related
effects (adults, children of different age). An example of conversion factors for three common
examinations (chest, abdomen and pelvis/hips) and different age groups (adults and five paediatric age
groups from newborn to 15 years old) is shown in table A3. Depending on the patient’s size, theconversion factors vary by one order of magnitude, with the highest values for newborn.
Table A3. Normalized values of effective dose per kerma-area product (“k factors”) for estimation ofeffective dose to children and adults for three frequent types of radiographic examinations
Adapted from [W8] using ICRP Publication 60 [I11] for the estimation of effective dose; total beam filtration used is 3 mm Al

k factors
Examination
Newborn

1 year

5 years

10 years

15 years

AdultsVoltage (kV)

70 a

73

75

80

80

86

K (mSv/Gy cm2)

2.2 a

0.58

0.41

0.28

0.16

0.15

Voltage (kV)

60

60

80

80

85

75

K (mSv/Gy cm2)

2.0

0.91

0.64

0.40

0.28

0.20

60

60

70

75

80

71

2.2

1.1

0.60

0.28

0.21

0.22

CHEST PAABDOMEN APPELVIS/HIPS AP
Voltage (kV)2

K (mSv/Gy cm )a

AP: Anterior-posterior.

A26.
For the purposes of estimating effective dose in radiography, this quick method has two major
drawbacks: (a) because the KAP is based on IAK, the conversion factors are strongly dependent on
beam quality, i.e. on differences in tube voltage settings and total beam filtration [G23, S116]; (b)although with units of µGy m2, meanwhile, a standardized unit for the KAP exists, other combinationsof dose and area units (Gy cm2, dGy cm2, cGy cm2, mGy cm2) are also used on dose displays, in dose
reports and conversion factor tables, which can easily lead to errors of one order of magnitude or even
more.
A27.
Assessment of organ doses requires tables with conversion factors for various types of
examinations, different combinations of tube voltage and total beam filtration, and different age groups.
The most commonly used source that serves for both adult and paediatric patients has been published inreport NRPB-R279 [H26]. In order to calculate organ dose HT, either ESD or the IAK, depending on
the input requirements of the conversion factor table, has to be multiplied with the appropriate
conversion factors kT:

H T = ESD ⋅ kT or H T = IAK ⋅ kT
Some of the required input dose quantities are interrelated, namely:(

ESD = IAK ⋅ BSF or IAK = KAP ⋅ FID
A
FSD

)

2

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

51

with BSF = backscatter factor, FSD = focal spot-to-skin distance, FID = focal spot-to-image receptor
distance, and A = irradiated field size at the image receptor. Backscatter factors for various conditionsof irradiation (field size, object thickness, beam quality) are tabulated in [D40].
A28.
Organ and effective dose assessment is greatly facilitated when making use of dedicatedsoftware. Comprehensive software solutions have been released such as CalDose_X online, which is a
web-based Monte Carlo application [K48] and PCXMC, a versatile Monte Carlo program [T5]. The
latter program calculates organ and effective doses according to both ICRP 60 and ICRP 103 tissue
weighting factors. The anatomical data are based on mathematical hermaphrodite phantom models[C51], representing patients in six different age groups: newborn, 1-, 5-, 10-, 15-year-old and adultpatients. These phantoms were modified to some extent in order to make them more realistic forexternal irradiation conditions. PCXMC allows a free adjustment of the X-rays beam projection andother examination conditions of projection radiography and fluoroscopy. A considerable advantage ofthis program is that the phantom sizes are adjustable at will to a patient’s weight and height.

2.

Fluoroscopy

A29.
As in radiography, the most common dose descriptor used for dose monitoring in fluoroscopy
is the KAP, representing the integral dose. To illustrate typical dose levels in paediatric fluoroscopy,
KAP values for three common paediatric fluoroscopic examinations are given in table A4. However,owing to new technical developments during recent years, the KAP values given in table A4 may now
be much lower. For micturating cysto-urethrography in the first year of life, for example, KAP values
lower by more than a factor of 10 have been reported recently by Schumacher and Allmendinger [S42]when pulsed digital fluoroscopic equipment was used.
A30.
As the dose levels in fluoroscopy are significantly higher than those in simple radiographic
examinations, particularly during interventional procedures, local dose is of interest, too, to prevent
deterministic skin injuries. For this purpose, a patient entrance reference point is defined by the
manufacturer in relation to the mechanical construction of the system. According to the relevant IEC
standard [I31], the interventional reference point (IRP) is located from the isocentre towards the X-rays
tube for any source-to-image receptor distance. The IRP is intended to represent the location where the
X-rays beam enters the patient’s skin surface, but seldom coincides with the patient’s actual skinposition. Dose rate and cumulative dose at the IRP are displayed where the operator can see themduring the performance of the procedure and are documented in the examination report after theprocedure has been finished.
A31.
Methods for the assessment of effective and organ doses are identical to those used inradiography. However, as fluoroscopy is a dynamic imaging procedure, the varying irradiation
conditions during the procedure (beam quality, field size, X-rays beam projection, dose rate) make dose
calculations more complex. Under these circumstances, even the use of dedicated software programs
will result in only rough estimates, particularly for the doses to organs that are not fully covered by the
X-rays beam.

52 UNSCEAR 2013 REPORT

Table A4. Different KAP values for three common paediatric fluoroscopic examinations
Adapted from [H27]

Examination

Age (years)

KAP per examination(Gy × cm2)

Micturating cystourethrography

0

0.43

1

0.81

5

0.94

10

1.64

15

3.41

0

0.76

1

1.61

5

1.62

10

3.19

15

5.67

0

0.56

1

1.15

5

1.01

10

2.40

15

3.17

Barium meal

Barium swallow

3.

Computed tomography

A32.
In CT, volume computed tomography dose index (CTDIvol) and dose-length product (DLP) areroutinely used as descriptors for dose monitoring. Contrary to the situation with the KAP, the units used(mGy and mGy cm, respectively) are unequivocal. While CTDIvol represents the local dose, DLP serves
an integral dose quantity that combines both the “intensity” (CTDIvol) and the scan length (L), i.e. theextension of the irradiation (analogue to the KAP in conventional X-rays imaging). Both quantities arecalculated from the exposure settings (“scan protocol”) and are displayed on the operator’s console anddocumented in the examination report.
A33.
Contrary to IAK and KAP, which are measured free-in-air, CTDIvol and DLP refer to absorbed
dose in standard PMMA phantoms: a “head phantom” with 16 cm diameter representing the patient inhead examinations of adults (CTDIvol–16), and a “body phantom” with 32 cm diameter for
examinations in the trunk region of adults (CTDIvol–32). For the same exposure settings, CTDIvol–16
amounts to approximately twice the corresponding CTDIvol–32.
A34.
While CTDIvol–16 is better suited to represent the smaller size of paediatric patients up to
10 years, the CTDIvol displayed on the console and in the examination report up to now depends on theapplied scan mode only. As a consequence, CTDIvol-32 and DLP-32 are used regardless of the patient’s
size for scans in the trunk region (abdomen, chest) performed in body scanning mode.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

53

A35.
In order to avoid misinterpretation, newer scanners (or those updated with a newer scanner
software) explicitly state the underlying standard phantom diameter. In cases where no statement of theunderlying phantom diameter is given, CTDIvol and DLP for examinations in the trunk region usuallyrefer to the 32 cm standard phantom. However, this may not be valid for scanners that apply a different
beam shaping filter that better fits to smaller patient diameters.
A36.
To illustrate typical dose levels in paediatric CT examinations, the German DRLs [B21], basedon a nationwide survey on paediatric CT practice in 2005/2006 [G2], are given in table A5. For patients
up to 10 years, CTDIvol and DLP values are stated for both standard phantom sizes. These values, which
are orientated to the relatively high corresponding German DRLs for adults, can be significantly
lowered if scan protocol optimization is applied as the current Swiss DRLs showed [B1].
Table A5. German dose reference levels for paediatric CT examinations
CTDIvol and DLP are based on both 16 cm and 32 cm standard phantom measurements; adapted from [B21]

Examination
Cranium

Mid-face

Chest

Abdomen w.
pelvisAge or weight group

CTDIvol-16(mGy)

CTDIvol-32(mGy)

DLP-16(mGy cm)

DLP-32(mGy cm)

Newborn

27

n.a.

300

n.a.

≤1 year

33

n.a.

400

n.a.

2–years

40

n.a.

500

n.a.

6–10 years

50

n.a.

650

n.a.

11–15 years

60

n.a.

850

n.a.

>15 years

60

n.a.

950

n.a.

Newborn

9

n.a.

70

n.a.

≤1 year

11

n.a.

95

n.a.

2–5 years

13

n.a.

125

n.a.

6–10 years

17

n.a.

180

n.a.

11–15 years

20

n.a.

230

n.a.

>15 years

20

n.a.

250

n.a.

Newborn (≤5 kg)

3

1.5

40

20

≤1 year (6–10 kg)

4

2

60

30

2–5 years (11–20 kg)

7

3.5

130

65

6–10 years (21–30 kg)

10

5

230

115

11–15 years (31–50 kg)

n.a.

8

n.a.

230

>15 years (51–80 kg)

n.a.

12

n.a.

400

Newborn (≤5 kg)

5

2.5

90

45

≤1 year (6–10 kg)

7

3.5

170

85

2–5 years (11–20 kg)

12

6

330

165

6–10 years (21–30 kg)

16

8

500

250

11–15 years (31–50 kg)

n.a.

13

n.a.

500

>15 years (51–80 kg)

n.a.

20

n.a.

900

54 UNSCEAR 2013 REPORT

A37.
Like in conventional X-rays imaging, a rough estimate of the effective dose E can be made bymultiplying the integral dose quantity (i.e. DLP) with an appropriate conversion factor k:

E = DLP ⋅ k
As the DLP refers to absorbed dose in phantoms (unlike the KAP, which refers to IAK), differences inbeam quality are almost negligible in CT. The most widely used set of conversion factors for paediatric
CT examinations has been published by Shrimpton et al. [S73] and has subsequently been adopted by
AAPM report 96 [A1]. The corresponding values are listed in table A6. Special attention is required
when applying these conversion factors for paediatric examinations of the neck and trunk region ofpatients up to 10 years, as the factors assume DLP–16. If the scanner’s dose display and examination
report are given in terms of DLP-32 in these cases, the dose values have to be multiplied by two—thus
converting DLP–32 into DLP-16 values—before applying the conversion factors.
Table A6. Normalized values of effective dose per DLP (“k factors”) over various body regions andstandard patient ages
Adapted from [A1]. Conversion factors for adult head and neck and paediatric patients assume use of the head CT dose
phantom (16 cm). All other conversion factors assume use of the 32-cm diameter CT body phantom

k factors (mSv mGy-1 cm-1)
Body region
Newborn

1 year old

5 year old

10 year old

Adult

Head and neck

0.013

0.00850.00570.00420.0031

Head

0.011

0.00670.00400.00320.0021

Neck

0.017

0.012

0.011

0.00790.0059

Chest

0.039

0.026

0.018

0.013

0.014

Abdomen and pelvis

0.049

0.030

0.020

0.015

0.015

Trunk

0.044

0.028

0.019

0.014

0.015

A38.
The conversion factors given in table A6 refer to the organ-weighting scheme of ICRP 60. As
the subdivision into body regions is fairly rough, the differences between that scheme and the neworgan-weighting scheme of ICRP 103 are normally small (up to ±10%) except for pelvis where ICRP
103-based k factors are lower by about 25% [D30]. For more restricted scan regions with a few highlyweighted organs (e.g. the mamma in cardiac CT examinations), the difference between ICRP 60- andICRP 103-based assessment of effective dose is significantly larger.
A39.
Assessment of organ doses requires tables with conversion factors for different age groups anddifferent types of scanners. Zankl et al. [Z2] provide a full set of conversion coefficients for paediatricpatients which are based on Monte Carlo simulations using voxel phantom data, but for an eight-weekold infant (“BABY”) and a seven-year-old child (“CHILD”) and for one specific type of scanner only.
Although newer Monte Carlo based data for mathematical phantoms representing more refined age
groups (newborn, 1, 5, 10, 15 years, and adults) have been calculated later for a total of three types ofscanners [K29], the full set of these data has not been made available up to now.
A40.
The conversion factors k (organ z) in the tables of Zankl et al. [Z2] are listed in increments of
1 cm along the patients longitudinal axis (“z axis”) for various organs. In order to calculate organ doseHT, the contributions from all slices along the scan range (from position z− to z+) have to be summed
up, multiplied with the CTDIfree-in-air and corrected for pitch-related effects if the pitch factor p differsfrom 1:

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

55z+

H T = 1 ⋅ CTDI free −in − air ⋅ ∑ k ( organ, z )pz−
As CTDIfree-in-air is neither displayed on the scanner’s console nor documented in the examination report,
it has to be deduced from CTDIvol using the equations:PH =CTDI w, H
CTDI free −in − air, PB =

CTDI w, B
CTDI free −in − airand CTDI w = p ⋅ CTDI volwhere PH and PB are the phantom factors for either the standard head (H) or body (B) phantom, andCTDIw is the weighted CTDI. And as the conversion factors apply to one particular type of scanner
only, appropriate corrections for different beam qualities and beam shaping filters have to be applied byusing scanner-specific correction factors kCT. These factors and also phantom factors have been
published for a large number of scanners by Nagel et al. [N3].
A41.
The calculation of organ doses is significantly facilitated by using dedicated CT dose
calculation software. For paediatric CT, the CT-Expo software serves these purposes [S109]. This
Excel-based program provides sex-specific organ and effective dose calculation for a large number ofexisting scanners. However, as the software is based on the tabulated conversion coefficients from
Zankl et al. [Z2], dose assessment is possible only for eight-week-old infants and seven-year-old
children. The software requires selection of age group and sex, input of the upper and lower scan range
limits, selection of the type of scanner and input of the exposure settings. The calculation yields all
relevant dose quantities (CTDIw, CTDIvol and DLP), all referring to the 16 cm standard phantom andalso effective dose (according to both ICRP 60 and ICRP 103 [I11, I25]) and organ doses.
A42.
For CT examinations such as those for other external medical exposure, the dose distribution
within the body is quite inhomogeneous. Table A7 gives some age-dependent examples for organ andeffective doses for chest CT examinations on the basis of exposure parameters specified as German
reference levels (see table A5). It can be seen that all doses decrease with decreasing age. However, thedecrease for the dose to the lungs is much more pronounced than for the dose to adjacent organs likespleen and thyroid because these are located closer to the direct beam for younger ages.
Table A7. Different organ and effective doses resulting from a chest CT examination
Calculated with CT-Expo [S109] on the basis of German diagnostic reference levels

Infant (six week)

Child (seven years)

Male adult

Lungs

3.6

11

19

Endosteal surfaces

3.7

7.7

13

Spleen

3.4

7.2

7.4

Thyroid

1.7

12

8.0

Effective dose (mSv)

1.5

4.2

5.7

Organ dose (mSv)

A43.
As a consequence of the increased awareness of radiation exposure arising from CT
examinations, it can be anticipated that other software solutions for a comprehensive paediatric dose
assessment in CT, including organ doses, will become available in the next years. These might comeeither as stand-alone PC software, as applications for mobile devices or as web-based applications. For
dose assessment of adults, these solutions are already available. Owing to the increased computational

56 UNSCEAR 2013 REPORT

power of today’s hardware, Monte Carlo programs like PCXMC for conventional X-rays imaging
should also be feasible, provided that the characteristics of the beam shaping filters, which differ fromscanner to scanner, will be made available by the manufacturers.
A44.
In epidemiological studies, in order to assess the risk of cancer as a function of radiation doses
received from CT examinations in childhood and adolescence, individual doses to specific relevantorgans need to be estimated from birth to 20 years of age. It is therefore necessary to generate a CT
organ dose database with phantoms with smaller age gaps (from newborn to adults) with a realistic
anatomy. In addition to the application to a wide range of patient ages for both sexes, an ongoing large
European epidemiological study to quantify risks for paediatric computerized tomography and to
optimize doses (EPI-CT) will include improvements in CT dosimetry [T17].

4.

Radiotherapy

A45.
The goal of radiotherapy is to deliver a prescribed dose to the target tissue and to keep the doseto the surrounding healthy tissues as low as possible. This goal can be achieved only by using dedicatedtherapy planning software systems that also calculate organ doses. The dose to be delivered to the target
tissues is considered to be independent of age. The treatment parameters are assessed by computerizedalgorithms taking into account tumour location and size, patient size, and tissue density and shape, andare not specifically age dependent.
A46.
Children treated with radiation therapy for malignancies are at risk for a spectrum of normal
tissue injuries, and these toxicities are dependent on the specific region, volume, and dose delivered tothe tissues, and also the developmental status of those tissues. Modern techniques attempt to reduce thehigh dose volumes and the most sensitive subsections of the exposed tissues in order to minimize
potential damage. Techniques such as intensity modulated radiation therapy using modern treatment
algorithms accomplish this but at the expense of delivering lower radiation doses to larger tissue
volumes, which may pose an increased risk for induction of cancer. This requires research into (a) the
dose-volume dosimetry in order to quantify this exposure and (b) long term tracking of patients in orderto determine outcome.
A47.
In addition, incidental radiation is delivered to the various normal tissues through (a) internalradiation scatter, (b) radiation leakage from the accelerator “head”, (c) verification methodologies
including beam films and image-guidance techniques that often involve CT and (d) the radiation dosefrom CT that are used in the simulation (treatment planning) procedures.

III.

INTERNAL EXPOSURE

A48.
In this section, the behaviour of incorporated radionuclides within the body and their age
dependence will be described. For the quantification of the effects of this age dependence of models on
doses, biokinetic and dosimetric models used by the ICRP to calculate dose coefficients [I30] will be
used for illustration purposes. Some relevant examples of age-dependent dose coefficients and doses
from environmental sources will be presented.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

57

A. Models in internal dosimetry
A49.
Internal doses cannot be measured; they can only be assessed using biokinetic and dosimetricmodels. Biokinetic models describe the deposition of radionuclides within the body, their transfer toother internal body regions and their excretion from the body. They are used to calculate the number ofnuclear transformations in the various regions within the body (“source regions”). Dosimetric models
are used to calculate the doses to relevant organs and tissues (“target tissues”) caused by these nuclear
transformations.
A50.
For radiation protection purposes, the ICRP specifies the committed equivalent dose to a target
tissue rT, calculated by:TD

H ( rT , TD ) = ∑ ∫ A ( rS , t ) ⋅ S w ( rT ← rS , t ) dt
rS0

where A(rS,t) is the activity in the source region rS at time t and the weighted S coefficient Sw(rT←rS,t)
is the equivalent dose rate in rT per unit activity in rS. For adults, the weighted S coefficient is
considered to be independent of time (age). However, age dependence applies for infants, children andadolescents because of growth and changing organ masses and distances.
A51.

The weighted S coefficients are calculated by:

S w ( rT ← rS , t ) = ∑ wR ∑ ER ,i ⋅ YR ,i ⋅R

iφ (rT ← rS , ER ,i , t )M (rT ,t )where ER,i is the (mean) energy of the ith nuclear transition of radiation type R, YR,i is the number of the
ith nuclear transitions per nuclear transformation of radiation type R and φ (rT←rS,ER,i,t) is the absorbed
fraction—the fraction of energy ER,i emitted in the source region rS at time t which is absorbed in thetarget organ or tissue rT—and M(rT,t) is the mass of the target organ or tissue rT at time t.
A52.
The quotient from the absorbed fraction and the target mass is called the specific absorbed
fraction:Φ (rT ← rS , Ei , t ) =φ (rT ← rS , Ei , t )M (rT , t )The methods to calculate absorbed fractions are described in [C51]. While the methodology describedhere applies to the calculation of equivalent dose, the same principles apply to the calculation ofabsorbed doses to organs/tissues, the primary scientific dosimetric quantity.

B. Biokinetic models and their age dependence
A53.
In general, biokinetic models are first-order compartment models. This means that the
movement of a radionuclide within the body is described by compartments that represent (parts of) the
source regions where the radionuclide accumulates. The retention of the radionuclide within such a
compartment is described by first-order differential equations; this means that the retention (without
consideration of the physical decay) can be characterized by a biological half-time (i.e. a time at which

58 UNSCEAR 2013 REPORT

half of the radionuclide present in such a compartment is moved to other compartments). There arebiokinetic models for the alimentary tract, the respiratory tract, systemic circulation and excretion
developed by the ICRP. These models and their age dependence for infants, children and adolescentsare described here. It is not within the scope of this report to comment on the reliability of the models
used by the ICRP. Rather, their biological basis is briefly addressed and they are used to illustratedifferences in doses as a function of age at intake.

1.

Models for the alimentary tract

A54.
Biokinetic models for the alimentary tract describe the transfer from the input compartment(the oral cavity for ingestion of a radionuclide, the oesophagus for a radionuclide mechanicallytransferred to the alimentary tract from the respiratory tract or, for example, the small intestine for aradionuclide secreted from systemic circulation) to faecal excretion, and also the absorption from thealimentary tract to systemic circulation.
A55.
For transit through the upper part of the alimentary tract, the transit times are largely
independent of age. However, for infants, shorter transit times have been observed because of theirconsumption of a more liquid diet. For colonic transit, an increase in transit time with age has been
observed, particularly for the first year of life [A22, C50].
A56.
Absorption from the alimentary tract to blood is greatest for infants [O6] and, for someelements, higher fractional absorption values have also been observed for children and adolescents thanfor adults, e.g. for alkaline earth elements as shown by animal experiments [T12] with limited support
from human studies [M60].
A57.
The biokinetic model for the alimentary tract described in ICRP Publication 100 [I24]supersedes the gastrointestinal tract model of ICRP Publication 30 [I8], which was based on a model by
Eve [E15].
A58.
The gastrointestinal tract model of ICRP Publication 30 [I8] is a four-compartment model(stomach, small intestine, upper large intestine and lower large intestine). Absorption from thegastrointestinal tract to blood is considered to occur only from the small intestine and the fraction ofingested material that is absorbed to blood is called f1. Transit between the stomach and small and large
intestine compartments was considered to be independent of age and sex.
A59.
The more recent ICRP model [I24] has more compartments within the tract (oral mucosa,
oesophagus, three instead of two colon compartments). Transport rates through the tract are age- andsex- dependent. Table A8 shows the mean transit times according to the ICRP. Faster transit times for
infants and young children are partly due to different food composition.
A60.
Table A9 shows examples of age-dependent f1 values [I13, I17], which quantify the fraction ofingested material absorbed from the small intestine to blood. This fraction can be very small (10-5 forinsoluble plutonium compounds) but can also be very large. For example, iodine and caesium areassumed to be essentially completely absorbed. In table A9, it can be seen that there are higher
fractional absorption values at younger ages for some elements.
A61.
On the basis of recommendations of an OECD/NEA expert group [O6], the ICRP [I10]assumed as a default that the f1 value for an infant in the first year of life is higher than that for adults bya factor of 2–10 if no specific information is available. As a default, the assumption made was:

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN−

f1 (infant) = 1−

f1 (infant) = 2 ⋅ f1 (adult)

if 0.01 ≤ f1 (adult) ≤ 0.5−

f1 (infant) = 0.02

if 0.001 < f1 (adult) < 0.01−

f1 (infant) = 10 ⋅ f1 (adult) if f1 (adult) ≤ 0.001.

59

if f1 (adult) > 0.5

However, it must be considered that the use of the default rule involves inherent uncertainties.
Table A8. Age-dependent mean transit times through alimentary tract
Adapted from ICRP Publication 100 [I24]

Mean transit times
Region3 months

1 year

5–15 years

Male adultFemale adult

2s

12 s

12 s

12 s

12 s

4 / 30 s

7 / 40 s

7 / 40 s

7 / 40 s

7 / 40 s

75 min70 min70 min70 min95 minSmall intestine

4h

4h

4h

4h

4h

Right colon

8h

10 h

11 h

12 h

16 h

Left colon

8h

10 h

11 h

12 h

16 h

Rectosigmoid

12 h

12 h

12 h

12 h

16 h

Oral cavity
OesophagusaStomacha

Fast/slow compartment.

Table A9. ICRP age-dependent f1 values for different elements
Adapted from ICRP Publications 67 and 69 [I13, I17]

f1 values
Element
3 months

1 year

5 years

10 years

15 years

Adults

Iron

0.6

0.2

0.2

0.2

0.2

0.1

Cobalt

0.6

0.3

0.3

0.3

0.3

0.1

Strontium

0.6

0.4

0.4

0.4

0.4

0.3

Barium

0.6

0.3

0.3

0.3

0.3

0.2

Lead

0.6

0.4

0.4

0.4

0.4

0.2

Radium

0.6

0.3

0.3

0.3

0.3

0.2

2.

Model for the respiratory tract

A62.
Inhaled aerosols containing radionuclides are partly deposited within the respiratory tract
while the rest is exhaled. The fraction of the inhaled aerosol deposited in the lung depends on thephysical properties of the inhaled aerosol—mainly the particle size—and on age, sex and breathing
behaviour, which itself is also age-dependent.
A63.
The ICRP [I14] has developed a biokinetic and dosimetric model for the human respiratory
tract. While the deposition of aerosols in the various regions of the respiratory tract is age dependent,

60 UNSCEAR 2013 REPORTthe mechanical transfer rates (to the environment by extrinsic means, to lymph nodes and to the upper
airways by mucociliar clearance) and absorption to blood are considered to be independent of age andsex. For absorption to blood, the ICRP has proposed standard absorption rates dependent on thesolubility of the inhaled aerosol: there are default absorption Types F, M, and S for material that isabsorbed at rates classified as fast, moderate, or slow.
A64.
The fraction of an inhaled aerosol deposited in the respiratory tract depends on its physicalproperties and on the anatomy and physiology of the person who inhales the aerosol. It therefore also
depends on the breathing pattern, which depends on the physical activity of the person, whether
sleeping, sitting, or undertaking light or heavy exercise. ICRP defined the daily mix of physicalactivities for the age-dependent reference persons (see table A10) [I14].
Table A10. Daily distribution of time
Adapted from ICRP Publication 66 [I14]

Daily distribution of time (h/d)
Activity
3 months

1 year

5 years

10 years

15 years

AdultsSleeping

17

14

12

10

10

8

Sitting

—

3.33

4

4.67

5.5

6

Light exercise

7

6.67

8

9.33

7.5

9.75

Heavy exercise

—

—

—

—

1

0.25

A65.
Assuming an aerosol size with the default activity median aerodynamic diameter (AMAD) of
1 µm for the members of the public, the ICRP [I16] derived age-dependent deposition values for the
extrathoracic region, in the bronchiolar, the bronchioles and in the alveolar interstitial region. These arelisted in table A11. It can be seen that the total amount deposited in the respiratory tract is larger for
younger age groups. The deposition in the extrathoracic region is higher for these age groups while thedeposition in the alveolar region is highest for adults.
Table A11. Age-dependent deposition values in different regions of respiratory tract
Adapted from ICRP Publication 66 [I14]. The calculated values are for an activity median aerodynamic diameter of 1 μm andmay be more precise than the underlying data would support

Region ofrespiratory tract

Deposition values
3 months

1 year

5 years

10 years

15 years

AdultsExtrathoracic

0.482

0.484

0.397

0.406

0.320

0.339

Bronchiolar andbronchioles

0.031

0.027

0.029

0.029

0.037

0.023

Alveolar interstial

0.086

0.096

0.099

0.095

0.107

0.115

Total

0.599

0.607

0.525

0.530

0.464

0.477

3.

Systemic activity

A66.
Systemic biokinetic models describe the behaviour of radionuclides injected or absorbed intoblood. For several elements, a shorter retention in children is known: e.g. for iodine a shorter retention
time for younger ages in the thyroid, where iodine mainly accumulates, has been observed [D50, S110]

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

61

by up to a factor of about six; for caesium there is a shorter retention time in the whole body by up toalmost a factor of ten [L18] which may be related to different body masses and/or potassium content.
For elements with a long accumulation in the skeleton such as the alkaline earth elements, strontium
and radium, a higher skeletal uptake at younger ages was observed in beagle studies [B68] which isassumed to be proportional to the calcium addition rate to bone [L19], with peaks for infants andadolescents. However, the retention time in the skeleton is lower for younger ages in relation to thebone resorption rates [L19]. There are many elements for which no age-dependent information isavailable.
A67.
ICRP has developed age-dependent systemic models for tritium, carbon, strontium, iodine,caesium, barium, lead, radium, thorium, uranium, neptunium, plutonium, americium, and curium [I13,
I17, I16].

4.

Excretion

A68.
The main excretion routes are via kidneys and urinary bladder to urine and via liver, gall
bladder and the intestinal tract to faeces. For faecal excretion, in the generic ICRP models it is assumed
that the radionuclide is transferred to the upper large intestine or to the right colon and is thentransported to faecal excretion [I8, I13, I24]. It would be physiologically more correct to consider
secretion into the small intestine but this would imply consideration of possible re-absorption from thesmall intestine, which would complicate the modelling.
A69.
For urinary excretion, for infants and young children, a higher frequency of bladder voiding
compared to adults has been observed [G17]. For the calculation of the activity in the contents of theurinary bladder of a member of the public, the ICRP made the simplifying assumption of first-orderkinetics with a transfer rate of 12 d-1 for adults, which corresponds to a bladder voiding interval of fourhours or to six voids per day. For young children, a more frequent bladder voiding was assumed: abladder voiding interval of 1.5 hours for a one-year-old child and of 1.2 hours for a three-month-old
infant [I13].
A70.
In radiopharmaceutical dosimetry, however, because of the shorter half-lives of theradioisotopes used, a more realistic biokinetic model is used by the ICRP [I27] for urinary excretion,
which takes the kinetics of filling and voiding of the urinary bladder into account. An age-dependent
bladder-voiding interval is considered, which is 3.5 hours for adults and 10- and 15-year-old children,
3 hours for five-year-old children and 2 hours for one-year-old children and three-month-old infants.

C. Dosimetric models and their age dependence
A71.
Dosimetric models are used to calculate energy deposition in target organs, tissues and regions
within tissues as a result of radioactive disintegration occurring in source organs, tissues or regions. The
weighted S coefficients Sw(rT←rS;t) are calculated for source regions rS and target tissues rT at age t.
These coefficients include physical decay data of the radionuclide considered as listed—for example,
by the ICRP in Publication 107 [I26]—and the specific absorbed fraction, which takes anatomical
characteristics into account. The ICRP calculates SAFs for reference persons, for which the agedependent masses of target tissues are given by ICRP Publication 89 [I22]. Then, for the calculation ofweighted S coefficients, it is necessary to derive the absorbed fractions φ (rT←rS,ER,i,t) for a given
energy ER,i of radiation type R and the age t.

62 UNSCEAR 2013 REPORT

A72.
In general, for non-penetrating radiation (alpha and, to a lesser extent, beta radiation), it isassumed that the absorbed fractions are 1 for rT = rS and 0 for rT ≠ rS; that is, all energy from radioactive
disintegration is deposited in the region in which the disintegration occurred. This is an adequate
approximation for larger regions rT and rS and in these cases, the age dependence of the weighted
S coefficients is related only to the age dependence of the target tissue masses. This assumption is notadequate, however, for small target regions as in the skeleton and in content/wall pairs of walled organs
like the respiratory tract, the alimentary tract and the urinary and gall bladders, for which more explicit
calculations have been performed to account for irradiation between regions.
A73.
For penetrating radiation (mainly gamma radiation), the absorbed fractions can be derived
using Monte Carlo calculations, which describe the photon transport within an anatomical phantom. For
these calculations, the activity is assumed to be homogeneously distributed within the source regions,and the average doses to the target tissues are calculated.
A74.
For these calculations, a family of mathematical phantoms that describe the human body—
including its organs—by geometrical figures has been used. These mathematical phantoms are being
replaced by more realistic voxel phantoms, which have been developed on the basis of images of real
persons. The ICRP has adapted such phantoms to the anatomical characteristics of its reference persons[I22]. New ICRP reference voxel phantoms for male and female adults have been published [I28] andreference paediatric phantoms are being developed.

D. Age dependence of dose coefficients and doses to public
A75.
This section provides some examples of age-dependent dose coefficients as published by the
ICRP and resulting doses from environmental sources that take age-dependent intake rates into account.
Table A12 shows the air inhaled per day by the reference persons of different age, according to the
ICRP [I14] and the annual intake of different kinds of foodstuff by different age groups presented by
the IAEA [I4]. These data are used below to compare doses for different age groups.
Table A12. Age-dependent intake rates for members of public
Inhalation values are adapted from ICRP Publication 66 [I14] and ingestion values from [I4]Intake rates
3 months
Inhalation rate (m3/d)

a

2.86

1 year

5 years

10 years

15 yearsa

Adults22.2 a

5.16

8.72

15.3

20.1

Consumption of leafy
vegetables (g/d)

58

74

79

86

94

Consumption of milk (g/d)

560

140

180

210

230

For males.

1.

Iodine-131

A76.
Extensive human data are available on which to base biokinetic model structures andparameter values [I10]. The current ICRP biokinetic model for iodine [I10] is similar to that given
earlier [I8]. In this model, 30% of the iodine in blood is transferred to the thyroid; the rest is excreted inANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

63

urine. Iodine is assumed to be retained in the thyroid of adults with a biological half-time of 80 days.
From the thyroid, it is transported to all other tissues as organic iodine where it is retained with abiological half-time of 12 days. Twenty per cent of this organic iodine is excreted into faeces via theupper and lower large intestine while the remaining 80% is recycled to blood. The iodine is once again
available to be taken up as inorganic iodine in the thyroid or excreted in urine [I13]. For children, theavailable human data show that iodine is retained in the thyroid and other tissues with shorter retention
times (see table A13) [I10].
Table A13. Age-dependent biological half-times of iodine in thyroid and other tissues
Adapted from ICRP Publication 67 [I13]

Biological half-times (d)3 months

1 year

5 years

10 years

15 years

AdultsThyroid

11.2

15

23

58

67

80

Rest of body

1.12

1.5

2.3

5.8

6.7

12

A77.
Table A14 shows dose coefficients for the intake of 131I for different age groups. For
inhalation, absorption Type F has been used as a default [I16]. Because even the shorter biological halftimes of iodine in the thyroid are longer than the physical half-life of 131I (8 d), they do not have a great
impact on dose. The ingestion and inhalation dose coefficients for children are higher than those for
adults because of the higher specific absorbed fraction values for children, which is a consequence of
their smaller organ masses. In the case of 131I, the effective dose coefficient is almost exclusively
determined by the dose to the thyroid. Both the dose coefficient for the thyroid and the effective dosecoefficient are larger by a factor of 8–10 for infants than those for adults.
Table A14. Dose coefficients and age-dependent doses in relation to adult doses for 131I
Adapted from ICRP Publications 67 and 71 [I13, I16]

Age
3 months

1 year

5 years

10 years

15 years

Adults

Dose coefficients (Sv/Bq)Thyroid dose coefficientfrom ingestion-6

3.7 × 10

3.6 × 10-6

2.1 × 10-6

1.0 × 10-6

6.8 × 10-7

4.3 × 10-7

Effective dose coefficientfrom ingestion

1.8 × 10-7

1.8 × 10-7

1.0 × 10-7

5.2 × 10-8

3.4 × 10-8

2.2 × 10-8

Thyroid dose coefficientfrom inhalation

1.4 × 10-6

1.4 × 10-6

7.3 × 10-7

3.7 × 10-7

2.2 × 10-7

1.5 × 10-7

Effective dose coefficientfrom inhalation

7.2 × 10-8

7.2 × 10-8

3.7 × 10-8

1.9 × 10-8

1.1 × 10-8

7.4 × 10-9

Effective dose relative to the adult effective dose
Inhalation

1.1

1.9

1.8

1.6

1.4

1

Ingestion of leafy
vegetables

5.2

3.8

2.0

1.4

1

Ingestion of milk

20

3.0

1.8

1.4

1

64 UNSCEAR 2013 REPORT

A78.
Because of the lower inhalation rates for children, inhalation doses from contaminated air are
higher only by up to a factor of two for children. Doses from the ingestion of milk may be 20-foldhigher for young children than for adults because of their higher milk consumption rate.

2.

Caesium-137

A79.
Caesium behaves similarly to potassium in body tissues, being taken up actively by living
cells. Differences in concentration between tissues are small and systemic caesium is therefore assumed
to be distributed homogeneously in the whole body in the current ICRP biokinetic model [I10]. On thebasis of human data, it is assumed to be retained in the body of adults with biological half-times of 2 d(10%) and 110 d (90%). Eighty per cent of the systemic caesium is taken to be excreted in urine, andthe other 20% in faeces. There is good evidence that the rates of loss of caesium from the body are
greater in children than in adults and these data are reflected in ICRP model assumptions (table A15).
Table A15. Biokinetic model for caesium
Adapted from ICRP Publication 67 [I13]Age
3 months

1 year

5 years

10 years

15 years

AdultsLong biological half-time (d)

16

13

30

50

93

110

Short biological half-time (d)

—

—

9.1

5.8

2.2

2

Fraction of whole body activity which iscleared with the long biological half-time

1

1

0.55

0.7

0.87

0.9

A80.
For ingestion and for inhalation of soluble compounds of caesium, the organ dose coefficientsare quite similar because of the homogeneous distribution of caesium within the body. Table A16
shows effective dose coefficients for different age groups for ingestion and inhalation. For inhalation,
absorption Type F has been used as a default [I16]. The dose coefficients are quite similar for children
and adults, although greater for infants, because in general the shorter retention times in younger ages
are compensated by the higher SAF values.
Table A16. Dose coefficients and age-dependent doses in relation to adult doses for 137Cs
Adapted from ICRP Publications 67 and 71 [I13, I16]

Age
3 months

1 year

5 years

10 years

15 years

Adults

Dose coefficients (Sv/Bq)
Effective dose coefficientfrom ingestion

2.1 × 10-8

1.2 × 10-8

9.6 × 10-9

1.0 × 10-8

1.3 × 10-8

1.3 × 10-8

Effective dose coefficientfrom inhalation

8.8 × 10-9

5.4 × 10-9

3.6 × 10-9

3.7 × 10-9

4.4 × 10-9

4.6 × 10-9

Effective dose relative to the adult effective dose
Inhalation

0.25

0.27

0.31

0.55

0.87

1

Ingestion of milk

0.57

0.58

0.65

0.91

1

Ingestion of vegetables

2.2

0.45

0.60

0.91

1

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

65

A81.
As a consequence, the actual doses from the inhalation or ingestion of environmental caesium
are lower for children than for adults because of lower intake rates, except for the ingestion of milk by
young (one-year-old) children.

3.

Strontium-90

A82.
Strontium is an alkaline earth element and, for this group of elements, the ICRP has developed
a generic biokinetic model [I13] with skeleton (cortical and trabecular bone surfaces and volume), liver,kidneys and other soft tissues as specified source regions. A simplified model is used for strontium
without red blood cells as a separate source compartment and without liver and kidney compartments,
because strontium is retained principally in the mineralised bone of the skeleton. The parameters of themodel are age dependent—the main differences being in the kinetics of uptake and retention in theskeleton—and are based on knowledge of bone metabolism and a large quantity of data on the agespecific behaviour of strontium in humans [I10]. There is a larger skeletal uptake for infants andadolescents of age 15 years and a lower retention in the non-exchangeable bone volume compartments
for younger ages. Moreover, the absorption from the gastrointestinal tract is higher for younger ages
(see table A8).
A83.
Table A17 shows dose coefficients for ingestion and inhalation (with absorption Type M) of90
Sr for different age groups. The doses to bone surfaces and red marrow from ingestion are highest forthree-month-old infants and for 15-year-old adolescents; the same is true for the effective dose. For
inhalation, the dose to the lung (and the effective dose) increases with decreasing age mainly because of
the lower masses of children.
A84.
The ingestion and inhalation doses for 90Sr from environmental sources are highest for
15-year-old adolescents, except for the ingestion of milk when the dose to one-year-old children ishighest.
Table A17. Dose coefficients and age-dependent doses in relation to adult doses for 90Sr
Adapted from ICRP Publications 67 and 71 [I13, I16]

Age
3 months

1 year

5 years

10 years

15 years

Adults

Dose coefficients (Sv/Bq)
Red bone marrow dosecoefficient from ingestion

1.5 × 10-6

4.2 × 10-7

2.7 × 10-7

3.7 × 10-7

4.9 × 10-7

1.8 × 10-7

Bone surfaces dosecoefficient from ingestion

2.3 × 10-6

7.3 × 10-7

6.3 × 10-7

1.0 × 10-6

1.8 × 10-6

4.1 × 10-7

Effective dose coefficientfrom ingestion

2.3 × 10-7

7.3 × 10-8

4.7 × 10-8

6.0 × 10-8

8.0 × 10-8

2.8 × 10-8

Red bone marrow dosecoefficient from inhalation

3.1 × 10-7

1.2 × 10-7

7.7 × 10-8

1.0 × 10-7

1.3 × 10-7

7.0 × 10-8

Bone surfaces dosecoefficient from inhalation

4.8 × 10-7

2.1 × 10-7

1.8 × 10-7

2.9 × 10-7

5.0 × 10-7

1.6 × 10-7

Lung dose coefficient frominhalation

8.2 × 10-7

7.0 × 10-7

4.3 × 10-7

2.9 × 10-7

2.3 × 10-7

2.1 × 10-7

66 UNSCEAR 2013 REPORT

Age
3 months

1 year

5 years

10 years

15 years

Adults5.1 × 10-8

5.0 × 10-8

3.6 × 10-8

Dose coefficients (Sv/Bq)
Effective dose coefficientfrom inhalation-7

1.5 × 10

1.1 × 10-7

6.5 × 10-8

Effective dose relative to the adult effective dose
Inhalation

0.71

0.71

0.98

1.3

1

Ingestion of milk

1.6

1.3

1.8

2.6

1

Ingestion of vegetables

6.3

1.0

1.7

2.6

1

4.

0.54

Radium-228

A85.
Radium is also an alkaline earth element and the ICRP alkaline earth model [I13] applies. The
ICRP model is based on consideration of similarities between the alkaline earth elements and also on an
extensive literature on the behaviour of strontium in adult humans, together with more limited humandata for children, supplemented by animal data [I13]. In contrast to the approach used for strontium, itconsiders liver explicitly as a source organ.
A86.
Radium-228 is used here as an illustrative example because, for this radioisotope, the infant
dose coefficients are very high compared to those for adults. The age distribution of dose coefficients issimilar to that for 90Sr, except that there is a larger peak dose for infants, which is caused partly by ahigher f1 value. The dose coefficients are highest for infants by up to a factor of almost 60 (ingestion
dose coefficient for the red bone marrow) compared to those for adults. The ingestion effective dosecoefficient for infants is a factor of about 40 higher than for adults. Because of the smaller variation inlung dose, for inhalation the corresponding factors are about 9 for red marrow and 6 for effective dose.
A87.
Inhalation doses from environmental sources are highest for 15-year-old adolescents; ingestion
doses for children of all ages are higher than for adults, up to a factor of seven for ingestion for leafy
vegetables and up to a factor of 20 for milk (table A18).
Table A18. Dose coefficients and age-dependent doses in relation to adult doses for 228Ra
Adapted from ICRP Publications 67 and 71 [I13, I16]

Age
3 months

1 year

5 years

10 years

15 years

Adults

Dose coefficients (Sv/Bq)
Red bone marrow dosecoefficient from ingestion

1.3 × 10-4

2.1 × 10-5

1.2 × 10-5

1.3 × 10-5

1.8 × 10-5

2.3 × 10-6

Bone surfaces dosecoefficient from ingestion

8.5 × 10-4

1.6 × 10-4

1.1 × 10-4

1.4 × 10-4

2.3 × 10-4

2.2 × 10-5

Liver dose coefficient fromingestion

4.3 × 10-5

9.6 × 10-6

5.3 × 10-6

4.7 × 10-6

5.4 × 10-6

1.0 × 10-6

Effective dose coefficientfrom ingestion

3.0 × 10-5

5.7 × 10-6

3.4 × 10-6

3.9 × 10-6

5.3 × 10-6

6.9 × 10-7

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

67

Age
3 months

1 year

5 years

10 years

15 years

Adults

Dose coefficients (Sv/Bq)
Red bone marrow dosecoefficient from inhalation-5

4.2 × 10

2.4 × 10-5

1.4 × 10-5

1.0 × 10-5

1.0 × 10-5

4.7 × 10-6

Bone surfaces dosecoefficient from inhalation

2.7 × 10-4

1.6 × 10-4

1.2 × 10-4

1.1 × 10-4

1.3 × 10-4

5.6 × 10-5

Liver dose coefficient frominhalation

1.5 × 10-5

9.2 × 10-6

5.3 × 10-6

3.6 × 10-6

3.4 × 10-6

2.4 × 10-6

Lung dose coefficient frominhalation

4.2 × 10-5

3.6 × 10-5

2.2 × 10-5

1.4 × 10-5

1.2 × 10-5

9.7 × 10-6

Effective dose coefficientfrom inhalation

1.5 × 10-5

1.0 × 10-5

6.3 × 10-6

4.6 × 10-6

4.4 × 10-6

2.6 × 10-6

Effective dose relative to the adult effective dose
Inhalation

0.89

0.95

1.2

1.5

1

Ingestion of milk

5.1

3.9

4.8

7.0

1

Ingestion of vegetables

20

3.0

4.4

7.0

1

5.

0.74

Radon-222

A88.
For 222Rn inhalation, by far the highest dose is the lung dose—caused mainly by the radon
progeny—while for ingestion the dose to the stomach wall—caused mainly by the radon gas itself—ishighest. Harley [H25] calculated inhalation 222Rn absorbed dose coefficients for lung regions for theone- and ten-year-old children and for adults. The dose coefficients for one- and ten-year-olds wereabout a factor of two higher than those for adults. Age-dependent dose coefficients for 222Rn were
published in NRC reports for one-, five,- ten-, and fifteen-year-olds and adults. The dose coefficientsfor children were higher by a factor of two to three compared to those for adults for ingestion [N40]
while the dose coefficients were similar for all age groups for inhalation [N39].
A89.
Age-dependent dose coefficients for 222Rn and its short-lived decay products have been
derived by Kendall and Smith [K23] for children aged one and ten years, and for adults. The inhalationdose coefficient for young children was higher by a factor of four to five compared to that for adults,
and higher by a factor of about seven for ingestion. However, because of the lower breathing rates andwater consumption rates that apply to children, the effective dose from inhalation is similar for all ages
for exposure to the same air concentrations of radon and progeny.

68 UNSCEAR 2013 REPORT

E. Age dependence of dose coefficients and doses forpatients in nuclear medicine
A90.
In almost all cases, no age-dependent biokinetic parameters are known forradiopharmaceuticals [E2]. Therefore, the adult biokinetic parameters are usually applied to all ages.
For radiopharmaceuticals, the ICRP published age-dependent dose coefficients in its Publications 53,
80, and 106 [I9, I20, I27]. In these publications, the ICRP uses adult biokinetic parameters for all ages
with the exception of the urinary bladder for which a generic assumption for the bladder-voiding
interval was applied. This is 3.5 hours for adults and ten- and 15-year-old children, three hours for fiveyear-old children and two hours for one-year-old children and three-month-old infants [I27].
A91.
Most nuclear medicine examinations of children are kidney scintigraphies followed byscintigraphies of the skeleton and the total body. Table A19 shows the effective doses for theradiopharmaceuticals that are most frequently used for kidney scintigraphies. While for 99mTc-MAG3
and 99mTc-DTPA, the effective dose to a one-year-old child is higher by a factor of about threecompared to that for adults, it is higher by a factor of about four for 99mTc-DMSA. This is because forMAG3 and DTPA, the urinary bladder receives the highest dose and the retention in the urinary bladderis shorter for young children while for DMSA, the kidneys receive the highest dose and the contributionof the urinary bladder to the effective dose is less.
Table A19. Effective dose coefficients for radiopharmaceuticals used for kidney scintigraphies
Adapted from ICRP Publication 106 [I27]

Effective dose coefficients (mSv/MBq)
1 year

5 years

10 years

15 years

Adults

99m

0.022

0.012

0.012

0.009

0.007

99m

0.016

0.009

0.00820.00620.0049

99m

0.037

0.021

0.015

0.011

0.0088

Tc-MAG3
Tc-DTPA
Tc-DMSA

A92.
However, the higher doses to children are partly compensated by the lower activities
administered to children. There are European recommendations [L10, L9, P32] for the fractions of theradionuclide activities used for adults that should be administered to children depending on their bodyweight. The latter recommendations are based on a publication by Jacobs et al. in which fractions ofadult administered activities were recommended for children, which were intended to result inapproximately the same effective dose for children as for adults [J7]. Recommendations foradministered activities in paediatric nuclear medicine have also been issued in the United States ofAmerica [G6]. Age-dependent administered activities and the resulting effective doses are shown intable A20. It can be seen that, in most cases, the higher dose coefficients for the younger ages arecompensated by lower administered radionuclide activities, resulting in quite similar doses for all ages.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

69

Table A20. Age-dependent administered activities for radiopharmaceuticals used for kidney
scintigraphies and resulting effective doses
The determined age-dependent effective doses were obtained using the German DRLs for adults [B20, B22] as a basis(100 MBq for MAG3, 150 MBq for DTPA and 70 MBq for DMSA) and the total body weights of the ICRP reference persons [I22]and the age-dependent ICRP dose coefficients [I20]

Administered activities (MBq)a
Radiopharmaceutical99m

Tc-MAG3

Reference
[P32]

[L9]

[G6]

99m

Tc-DTPA

[P32]

[L9]

99m

Tc-DMSA

1 year

5 years

10 years

15 years

Adults

15

27

45

65

92

100

(0.59)(0.54)(0.78)(0.83)(0.70)

23

33

45

62

(0.51)(0.40)(0.54)(0.56)

37

70

118

148

148

(0.81)(0.84)(1.40)(1.30)(1.00)

41

68

98

138

150

(0.66)(0.61)(0.80)(0.86)(0.74)

38

65

102

150

(0.61)(0.59)(0.84)(0.93)

15

37

20

20

[G6]

-

-

-

-

-

-

[P32]

15

19

32

46

64

70

(0.70)(0.67)(0.69)(0.70)(0.62)

33

48

64

70

(1.20)(1.00)(0.96)(0.77)

18.5

35

59

104

135

(0.68)(0.74)(0.89)(1.10)(1.20)

[L9]

[G6]

a

Newborn18

18.5

The values in parentheses are effective doses (mSv).

F. Nuclear medicine therapy
A93.
Especially in children, therapeutic applications of open radioactive sources are usually basedon individual calculations of tumour, organ and tissue doses before and during therapy. This requires
the delineation of tissue masses out of imaging procedures and the evaluation of individually measured
biokinetic data. In some clinical units, the internal dosimetry models described above are individually
adjusted to the patient. Software programs are being developed to provide dosimetric data fromtomographic imaging procedures [S46].

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN71

APPENDIX B. MALIGNANT NEOPLASMSI.

INTRODUCTION

B1.
It has commonly been thought that radiation exposures in childhood cause two–three times asmuch excess cancer as exposures in adulthood. While this may be true on average, it is an
overgeneralization: for some cancers the risk is higher for exposure in childhood than in adulthood, forothers it is equal and for some others it is even lower. Greater lifetime risk from exposure duringchildhood than from that during adulthood has two aspects. In part, it reflects greater risk per unit doseat comparable ages at risk or times since exposure for childhood exposures, but it also reflects thelonger period of risk for those irradiated at younger ages since excess risk continues throughout theremaining lifetime. Radiation-induced cancers at early ages also have a long-term impact on quality oflife and may induce anxiety about recurrences or other health detriments.
B2.
Risks associated with age at radiation exposure may be correlated with other cancer risk
factors or genetic susceptibility factors, especially in studies of risk after initial childhood cancer
radiotherapy, although little is known about this possibility. A limited but growing body of datasuggests that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic
susceptibility syndromes confer an increased risk of cancer, such as the Li-Fraumeni syndrome.
Table B1 below summarizes the spectrum of neoplasms, affected genes, and Mendelian mode ofinheritance of selected syndromes of inherited cancer predisposition.
Table B1. Selected syndromes of inherited cancer predisposition
Affected gene

Mode ofinheritance

Syndrome

Major tumour types

Adenomatous
polyposis of the colon

Colon, hepatoblastoma, intestinal cancers,
stomach, thyroid cancer

APC

Dominant

Ataxia telangiectasia

Leukaemia, lymphoma

ATM

Recessive

Beckwith-Wiedemannsyndrome

Adrenal carcinoma, hepatoblastoma,
rhabdomyosarcoma, Wilms’ tumour

CDKN1C/NSD1

Dominant

Bloom’s syndrome

Leukaemia, lymphoma, skin cancer

BLM

Recessive

Fanconi anaemia

Gynaecological tumours, leukaemia,squamous cell carcinoma

FANCA, FANCB, FANCC,FANCD2, FANCE,FANCF, FANCG

Recessive

Juvenile polyposis
syndrome

Gastrointestinal tumours

SMAD4/DPC4

Dominant

Li-Fraumeni syndrome

Adrenocortical carcinoma, brain tumour,breast carcinoma, leukaemia, osteosarcoma,
soft tissue sarcoma

TP53

Dominant

72 UNSCEAR 2013 REPORT

Syndrome

Major tumour types

Affected gene

Mode ofinheritanceMultiple endocrine
neoplasia 1

Pancreatic islet cell tumour, parathyroid
adenoma, pituitary adenoma

MEN1

Dominant

Multiple endocrine
neoplasia 2

Medullary thyroid carcinoma,pheochromocytoma

RET

Dominant

Neurofibromatosis
type 1

Neurofibroma, optic pathway glioma,
peripheral nerve sheath tumour

NF1

Dominant

Neurofibromatosis
type 2

Vestibular schwannoma

NF2

Dominant

Nevoid basal cell
carcinoma syndrome

Basal cell carcinoma, medulloblastoma

PTCH

Dominant

Peutz-Jeghers
syndrome

Intestinal cancers, ovarian carcinoma,
pancreatic carcinoma

STK11

Dominant

Retinoblastoma

Osteosarcoma, retinoblastoma

RB1

Dominant

Tuberous sclerosis

Hamartoma, renal angiomyolipoma, renal
cell carcinoma

TSC1/TSC2

Dominantvon Hippel-Lindau
syndrome

Hemangioblastoma, pheochromocytoma,renal cell carcinoma, retinal and central
nervous tumours

VHL

Dominant

WAGR syndrome

Gonadoblastoma, Wilms’ tumour

WT1

Dominant

Wilms’ tumour
syndrome

Wilms’ tumour

WT1

Dominant

Xeroderma
pigmentosum

Leukaemia, melanoma

XPA, XPB, XPC, XPD,
XPE, XPF, XPG, POLH

Recessive

II. ALL SOLID TUMOURS
B3.
Although the biology of cancers differs by organ site and even by subtype within site, forpurposes of radiation protection it is common to examine the cumulative radiation risk for all types ofsolid cancers as an overall index of radiation risk, so it will be considered here. When examining
differentials by age, sex or other modifying factors, however, caution needs to be taken not toovergeneralize, as for example in applying overall age-at-exposure effects to individual tumour sites.

A. Atomic bombing Life Span Study (LSS) modelling of risk
B4.
In the latest LSS report of cancer incidence, for total solid cancers there is statisticallysignificant variation in excess incidence by age at exposure for the ERR model and even more so for
the EAR model (figure B-I) [P52]. The ERR was estimated to decrease by 17% (90% CI: 25, 7) per
decade of age at exposure, and the EAR by 24% (90% CI: 32, 16) per decade of age at exposure.
Table B2 shows estimated ratios of the risks for those young at exposure compared to ones older at

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

73

exposure for representative ages. Similarly, the recent summary of cancer mortality reports a decreasein ERR by 29% (95% CI: 41, 17) per decade of age at exposure [O25].
Table B2. Ratios of excess risk by age at exposure (AAE) for total solid cancer in LSS of atomic
bombing survivors
ERR ratio,
cancer incidencea

EAR ratio,
cancer incidencea

ERR ratio,
cancer mortalityb

AAE 5 / AAE 30

1.6

2.0

2.4

AAE 5 / AAE 40

1.9

2.6

3.3

AAE 10 / AAE 40

1.7

2.3

2.8

Ratio by AAEaCancer incidence estimates based on [P52].

b

Cancer mortality estimates based on [O25].

B5.
Though a large fraction of tumour sites are thought to be compatible with a common doseresponse slope, subject to variation because of statistical imprecision [P21], the degree of consistency
across those sites in variation in risk due to age at exposure is unclear. Recent analyses of the atomic
bombing data have tended to feature primarily ERR estimates that emphasize attained age (age at risk),based on modelled risk at age 70 after exposure at age 30 (figure B-I). Those comparisons intermix
time and attained age effects (e.g. for those exposed at age 50 the risk represents risk 20 years after
exposure, whereas for those exposed at age five it would be 65 years after exposure. Temporal variationin risk by time since exposure appears to be important biologically. Given that, a comparison based onsome specific attained age irrespective of time since exposure would tend to confound time-sinceexposure and age-at-exposure effects and, therefore, may not represent latter well. The EAR may vary
less by time since exposure than the ERR does, though that has not been rigorously addressed. If so,then EAR comparisons of age-at-exposure effects at age 70 may be preferable to ERR comparisons(figure B-I). It would be especially desirable for research to report presented analyses by time since
exposure and age at exposure, as well as by attained age and age at exposure, which would tend to givea different picture of age-at-exposure effects.
Figure B-I. Excess risks for all solid cancers at various attained ages, after exposure at ages 10, 30 or
50 years
Adapted from [P52]. The curves represent sex-averaged risks after exposure to 1 Gy

74 UNSCEAR 2013 REPORT

B6.
From a public health perspective lifetime risk probably represents a better index by which tocompare risks by age at exposure. However, because of the complexities of computing lifetime risks
and the fact that lifetime risk calculations based on most studies would involve uncertain projections of
future risk, research reports have tended not to calculate lifetime risks at all, or at least not in sufficientdetail to show age-at-exposure variations for particular tumour sites. The recent UNSCEAR report[U12] did present lifetime risks for total solid cancers for selected ages at exposure (see table B3), but
not for specific tumour sites. The table shows, for a representative population, that the lifetime risk after
exposure at ages 0–9 is about 2.6 times as great as that at ages 40–49 for the ERR model and 2.1 times
as great for the EAR model comparison. Part of the difference is due to variations in risk estimates andpart by the fact that those younger at exposure have a longer remaining lifetime to express risk, albeit
the absolute number of excess cases would be relatively small at young ages. A further considerationfrom a public health viewpoint is that the average years of life lost per cancer case is greater for those
exposed at young ages (table B3, last column) which, of course, is attributable to the fraction of excess
deaths at early ages for those who were young at exposure.
Table B3. Lifetime risk estimates for solid cancer mortality by age-at-exposure group, projected tothe current United Kingdom population (using LSS mortality risk estimates [P51])
Extracted from UNSCEAR 2006 Report (annex A, table 61) [U12]

ERR: Per cent excess cancer
deaths at 1 Sva

EAR: Per cent excess cancer
deaths at 1 Svb

ERR: Years of life lost perradiation-induced cancer death

0−9

12.77

10.35

16.2

10−19

10.64

9.17

14.9

20−29

8.65

7.89

13.9

30−39

6.73

6.52

12.8

40−49

4.87

5.07

11.4

50−59

3.18

3.62

9.6

60−69

1.78

2.28

7.7

≥70

0.56

0.90

5.5

Age at exposurea

ERR model includes dose (linear), sex, attained age, years since exposure.

b

EAR model includes dose (linear), attained age, years since exposure.

B7.
Keeping in mind the caveats for ERR and EAR analyses based on limited attained ages andthat any lifetime projections from those models are based on expectations and not actual observed data
for those who were young at exposure, the estimated variation and confidence intervals by age at
exposure are shown in table B4 for both the ERR and EAR models from the latest report of cancer
incidence among atomic bombing survivors. The ERR and EAR models show a fair degree ofconcordance with regard to age-at-exposure effects. Both show greater risk for younger age at exposurefor total solid cancers, non-melanoma skin cancer and, more recently, thyroid cancer [F29]; and bothmodels show no significant difference by age at exposure for stomach, liver, lung, bladder andmiscellaneous other solid cancers. However, the EAR shows greater risk for younger age at exposurefor colon cancer and female breast cancer, but the ERR model indicates no significant difference in risk
by age at exposure.
B8.
It would be of interest to see whether age-at-exposure differences are seen for various tumoursites using other models (e.g. models including age at exposure and time since exposure) and forlifetime risk estimates, but such analyses are generally not available. However, for breast cancer analternative analysis [L5] was conducted that included age at exposure and attained age, but had certain

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

75

variations from the Preston et al. [P52] modelling approach, for instance, not limiting the risk projection
to an attained age of 70. They found a higher ERR for age at exposure of subjects under age 20
compared older subjects with their parametric model approach and also with a non-parametric model.
These results differ from the breast cancer results in table B4 and highlight the importance that different
assumptions or constraints chosen in the course of modelling can have for the estimation of age-atexposure effects.
B9.
In summary, the finding that people exposed to radiation when young are more susceptible tototal solid cancer than those exposed at older ages does not imply that all solid cancers show age-atexposure effects. To broadly summarize the results in table B4, of the nine tumour sites listed(including the grouping of “other cancers”), for the ERR model only five had negative coefficients(central estimates) of change by age at exposure, implying greater risk after exposure in childhood thanafter exposure in adulthood. For the EAR model, eight of the nine had negative coefficients. For
various other cancer sites not listed in that table, the direction and degree of change by age at exposure
were not reported in the original paper [P52], but may possibly help account for the overall negative
age-at-exposure effect for total solid cancers.

Age-specific estimates are taken from [P52] (table 11)

ERRa
Tumour site

a

EARa

Age 10 (%)

Age 30 (%)

Age 50 (%)

Age-at-exposure
coefficientb (%)

Age 10 (%)c

Age 30 (%)

Age 50 (%)

Age-at-exposure
coefficientb (%)

All solid

67(52, 85)47(40, 54)

32(24, 42)−17(−25, −7)

90
(68, 113)

52(43, 60)

30(22, 39)−24(−32, −16)

Stomach44(20, 83)34(22, 47)25(12, 44)−13(−35, 15)9.9
(4.5, 18)

9.5
(6.1, 14)9.2
(4.2, 16)

−2(−26, 29)

Colon

52
(21, 120)

54(30, 81)55(15, 120)

1(-36, 45)

41
(17, 91)

8.0(4.4, 12)1.6
(0.3, 3.9)

−56(−74, −34)

Liver

28
(6, 78)30(11, 55)

32(7, 85)

3(−37, 68)

6.8
(0.0, 22)4.3
(0.0, 7.2)

2.6
(0.5, 6.4)

−21(−57, 378)

Lung

56
(26, 110)81(56, 110)

115(69, 180)

20(−7, 54)7.3(3.4, 14)7.5
(5.1, 10)7.8
(4.6, 12)2(−20, 28)

Non-melanoma skin228
(4, 780)17(0.3, 55)

1
(0, 8)−73(−85, −55)

2.3
(0.2, 7)0.35
(0.03, 1.1)

0.05
(0.0, 0.29)−61(−75, −42)

Breast (females)

86(47, 150)

87(55, 130)87(44, 150)

0(−19, 24)

23
(15, 34)

9.2(6.8, 12)3.7
(2.1, 5.9)−37(−48, −24)

Bladder

132(28, 410)

123(59, 210)

115(34, 250)−3(−42, 56)

4.8
(0.7, 16)

3.2
(1.1, 5.4)

2.1
(0.5, 4.5)

−19(−54, 41)

Thyroid

121(43, 290)57(24, 110)27(5, 77)−31(−59, 4)4.0
(1.7, 7.8)

1.2
(0.5, 2.2)

0.4
(0.0, 1.3)

−46(−68, −12)

Other solidd

165(69, 350)

91(50, 140)

51(14, 110)−26(−51, 4)7.7
(3.3, 16)

5.0
(2.7, 7.7)

3.3
(1.1, 6.5)

−19(−44, 9)90% CI in parentheses.

b

Per cent change in ERR or EAR coefficients by decade of year of age at exposure.

c

Estimated sex-averaged excess absolute rate at 1 Gy for attained age 70 after exposure at the indicated ages with units of excess cases per 10,000 PY Gy.

dIncludes cancers of small intestine, certain other parts of the digestive and respiratory tracts, nasal cavity, larynx, thymus, bone and connective tissues, melanomas, male breast cancers, female and male genital organs,parts of urothelial and endocrine systems, and ill-defined sites.

76 UNSCEAR 2013 REPORT

Table B4. Changes in cancer-incidence risk estimates by age at radiation exposure in LSS of atomic bombing survivors

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

77

III. LEUKAEMIA
B10.
An increased incidence of leukaemia was first suspected of being caused by exposure toradiation as early as 1911. The most substantial human data on radiation-induced leukaemia come fromstudies of three major population groups: the survivors of the atomic bombings in Japan, persons
exposed to high doses of pelvic radiation therapy, and those treated with X-rays for ankylosing
spondylitis or other diseases. Several of these populations included children.
B11.
Age at exposure is a significant modifying factor of the risk estimates. The incidence andmortality data for the survivors of the atomic bombings in Japan suggest that ERRs were highest for the
youngest survivors.

A. External exposure
1.

Background radiation

B12.
A recent study analysed childhood leukaemia risk in relation to natural residential backgroundexternal radiation levels and radon levels in the United Kingdom [K24]. The study included over
27,000 leukaemia cases in the National Registry of Childhood Tumours during 1980−2006 along with
36,000 matched (on sex and date of birth) controls drawn from the same birth register as the cases.
Radiation doses were based on estimated mean exposure levels for the county district in which themother resided at the child’s birth, and information on socioeconomic status was based on the mother’s
census ward or the father’s reported occupation. The main measure of radiation was cumulative
exposure to the red bone marrow (RBM) which was basically the imputed external exposure rate plus
radon dose rate, based on the geographic location of the mother’s domicile, times the age at diagnosis.
The mean RBM cumulative dose at diagnosis was about 4.0 mSv (range 0 to 31 mSv), with about 10%of the RBM dose contributed by radon on average. The analysis using that metric produced a highly
significant trend, with an estimated risk of ERR mSv-1 of 12% (95% CI: 3, 22) (i.e. ERR of 120 Sv-1).
The study should be interpreted with caution because of the large uncertainties associated with using an
ecological measure of dose. The major studies of high-background radiation areas have not examinedchildhood leukaemia risk [N4, T4].

2.

Atomic bombing survivors

B13.
Between 1950 and 1987, a total of 237 leukaemia cases were reported to have occurred among
the survivors with estimated doses [P47]. The effect of age at exposure was unclear with an EAR
model, but the tabled data suggested that radiation exposure accounted for greater fractions of theleukaemia cases occurring among those who were young at the time of exposure, namely, 60%, 43%
and 46% for those who were <20, 20–39 and ≥40 years of age, respectively, with similar dose
distributions. A clear age-at-exposure effect was seen for acute lymphocytic leukaemia.

78 UNSCEAR 2013 REPORT

B14.
Mabuchi et al. [M1] reported on leukaemia risk on a scale of ERR per gray based on
essentially the same data, and found an age-at-exposure effect such that those young at exposure had
the highest risk (figure B-II). Richardson et al. [R20] reported on leukaemia mortality among thesurvivors of the atomic bombings for the period 1950–2000. Their modelling clearly showed a greaterrisk among those who were young at the time of exposure (figure B-III).
B15.
The data on leukaemia incidence were recently updated through 2001 and included 312
pathologically reviewed cases with estimated doses after excluding chronic lymphocytic leukaemia andadult T-cell leukaemia [H70]. It was found that a concave upward linear-quadratic dose-response curve
fitted the data better than pure linear or pure quadratic curves. They reported that models incorporating
attained age and age at exposure or attained age and time since exposure fit the data about equally well.
Basing their estimates on risk at the attained age of 70 years, they reported only a small age-at-exposure
effect: the ERRs at 1 Gy were 6.5 (95% CI: 4.0, 10.3), 3.9 (2.3, 6.1) and 4.0 (2.1, 6.9) for exposures atages 0–19, 20–39 and ≥40, respectively (figure B-IV). However, the highest ERRs were seen shortly
after exposure among those exposed early in life, as the earlier reports also had shown (figure B-III), so
a comparison at age 70 may be misleading. Furthermore, a substantial excess of childhood leukaemia
cases has been observed in the atomic bombing survivor study: 10 observed against about 1.6 expected[W6]. Examination of the age- and temporal patterns for the broad subtypes of acute myeloid
leukaemia, acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia showed complex
variations from which it was difficult to draw conclusions regarding variation in risk by age at
exposure. A recent paper found an association of atomic bombing exposure and the incidence of
myelodysplastic syndromes, with an indication that the risk was greater for those who were young at
exposure [I47].
Figure B-II: Excess relative risk at 1 Gy for all types of leukaemia, incidence, 1950–1987
Adapted from [M1]

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

Figure B-III. Predicted city-averaged ERR at 1 Gy for leukaemia mortality (all types as a function ofage at exposure and time since exposure)
Adapted from [R20]

Figure B-IV. Leukaemia risk at 1 Gy in LSS according to age at exposure and temporal pattern: ERR
and EAR estimates, 1950–2001
Adapted from [H70]79

80 UNSCEAR 2013 REPORT

3.

Persons exposed to fallout

B16.
Fallout from nuclear weapon testing in the Marshall Islands caused a substantial bone marrowdose to some of the islanders. However, acute myelogenous leukaemia subsequently developed in only
one inhabitant [C41]. This single case may be due to chance, although the possibility of it being
induced by radiation cannot be excluded.
B17.
A study in French Polynesia [V14] indicated higher rates of childhood leukaemia in the period
1985–1989 compared to the period 1990–1995 but these rates were similar to those in Hawaii.
Furthermore, given the time lag between atmospheric weapon testing and these higher rates, aconnection is not likely. A case-control study of leukaemia in Utah following testing of nuclear
weapons showed a small increase of acute leukaemia in the decade following the major fallout events
among those who were under age 20 at exposure [S114]. The estimated median red bone marrow dosewas 3.2 mGy, with a maximum dose of 26 mGy.
B18.
To date, studies on the populations exposed to fallout from the Chernobyl accident have shownno increase in incidence of leukaemia [U10, U15]. Studies of adults living in the Bryansk area of theRussian Federation have been published by Osechinsky et al. [O17] and [G4], with negative results.
Studies in the most contaminated areas of the Kaluga oblast by Ivanov [I45, I43] also yielded negative
results. Both Bebeshko [B10] and Prisyazhniuk [P56] found no increased incidence of leukaemia in thecontaminated areas of Ukraine and Belarus. However, Noshchenko et al. [N33] reported an increased
incidence of leukaemia but only among children born in 1986. Steiner et al. [S113] and Parkin et al.
[P10, P11] have also observed an increase in the incidence of infant leukaemia in western Europe but it
was not related to the radioactive contamination of the ground, which was used as a surrogate forradiation exposure. Furthermore, no increased incidence of infant or childhood leukaemia has beenfound in Belarus, the Russian Federation or Ukraine related to the Chernobyl accident according to
UNSCEAR [U10, U15]. While Noshchenko et al. [N35, N33, N34] indicated an increase in leukaemia
among children exposed at ages 0–5 to more than 10 mSv, there are questions about possible biases incontrol selection, and these results have not been confirmed in several other studies summarized in thereport of the Chernobyl Forum [W21]. A subsequent paper examining leukaemia risk in Ukraine,
Belarus and the Russian Federation concluded that an apparently elevated risk in Ukraine may havebeen at least partially due to sampling bias and was not generally supported by the results from theother two countries. However, the combined data from the three countries did show a significant dose–
response trend [D19].
B19.
Studies of the incidence of leukaemia at greater distances from Chernobyl are unlikely to yieldadditional useful information because of the lower doses received by the populations. Studies in
Hungary have shown no increased incidence of leukaemia [T31]. A suggested increase in the incidence
of infant leukaemia in Scotland and Wales [B71] was not confirmed in a larger study of the United
Kingdom [C9]. Two further studies, conducted in Finland [A28] and Sweden [H51], did not find astatistically significant excess risk of childhood leukaemia in relation to fallout exposure levels. Cardis
et al. [C4] have estimated the potential impact of Chernobyl fallout in Europe. They estimated that theaccident might result in 2,400 excess leukaemia cases and 1,650 excess leukaemia deaths or an
attributable fraction of 0.04%. However, the epidemiological data to date do not indicate a measurable
increase in risk and the small hypothetical percentage increase would probably not be possible to detect.
The UNSCEAR 2000 and 2008 Reports [U10, U15], the 2005 Chernobyl Forum report [W21] and also
the 2006 BEIR VII report [N43] have summarized the studies of leukaemia incidence in children andadults living in areas contaminated by the Chernobyl accident. On balance, these studies indicate thatthe existing evidence does not support the conclusion that incidence of either childhood or adulthoodleukaemia has increased as a result of radiation exposure, at least not to a degree that is detectable.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

81

B20.
The incidence of leukaemia in the population downwind of the Semipalatinsk nuclear testingsite—who were estimated to have received an effective dose of 2 Sv or more—was nominally, but notstatistically significantly, elevated (OR = 1.9; 95% CI: 0.4, 9.7) [A3]. No information was presented on
the incidence of leukaemia according to age at exposure. A study of residents near the Three Mile
Island nuclear power plant did not find an increase in leukaemia incidence after the nuclear accident,
either for childhood leukaemia [H28] or leukaemia at all ages [H29].

4.

Persons living near nuclear facilities

B21.
Studies of the risk of leukaemia in populations living around nuclear power plants in the
United States have been discussed in detail by Jablon et al. [J2]. To date, no consistently significant
increase in leukaemia incidence attributable to radiation has been found in the United States ofAmerica, Canada [M20] or Israel [S96]. There are several articles concerning the possibility ofincreased incidences of leukaemia around a number of specific nuclear installations in Europe,
including Sellafield, Dounreay and La Hague. Apart from Sellafield and Dounreay, no other sites in the
United Kingdom have shown an excess incidence of leukaemia among the local populations [C39].
Reviews of these findings have been presented by Laurier et al. [L12, L14, L13, W20] and UNSCEAR[U12, U13]. They have all concluded that there is no relationship between the increased incidences ofleukaemia and radiation exposure; however, an infectious aetiology could not be excluded. A review ofleukaemia incidence around Japanese nuclear power plants by Yoshimoto et al. [Y9] also does notsupport an association. Boice et al. [B41] examined childhood leukaemia rates in a county with anuclear power station, but found no excess compared to control counties. A study of leukaemia amongchildren below five years of age in the vicinity of French nuclear power plants also showed no effect[L15].
B22.
However, the recent KiKK study, prompted by an apparent excess of childhood leukaemia
near the German Krümmel nuclear power plant, examined the incidence of leukaemia diagnosed at ages
0–5 years among residents in the vicinity of the 16 German nuclear power plants [K1]. They reported
an odds ratio of 2.2 (90% CI: 1.5, ~3.2) for children within 5 km of a plant compared to those living
further away. For those within 10 km compared to those living further away, the odds ratio was 1.3(90% CI: 1.1, ~1.7). Both German [S108] and British [C40] reviewers have examined this study indetail and pointed out certain methodological limitations, though not fatal flaws. The KiKK study
prompted a nationwide cohort study in Switzerland of cases of cancer among children aged 0–15 years[S106]. For children born within 5 km of a nuclear power plant compared to those born 15 or morekilometres away, they found an odds ratio of 1.2 (95% CI: 0.6, 2.4) for leukaemia diagnosed at ages
0-4 years, and 1.05 (95% CI: 0.6, 1.9) for those diagnosed at ages 0–15 years.
B23.
There are several papers concerning potential uranium contamination and incidence ofleukaemia among members of the public. The papers by Boice et al. [B39, B40] indicated a nonsignificant elevation of leukaemia incidence with a relative risk (RR) of 1.15 (95% CI: 0.9, 1.6) arounda uranium mining and milling facility in Texas and a non-significant decrease near a uranium facility in
Pennsylvania. A study in a uranium mining and milling area in New Mexico found no association withleukaemia incidence: a standardized incidence ratio (SIR) of 1.3 (95% CI: 0.95, 1.7) for all non-CLL
cases, and an SIR of 1.6 (95% CI: 0.91, 2.7) for childhood leukaemia (ages 0–19 years) [B43]. Also,
the mortality data did not indicate an association with the incidence of childhood leukaemia; thestandardized mortality ratio (SMR) was 1.06 (95% CI: 0.7, 1.6). No difference in the incidence ofleukaemia was found by Boice et al. [B42] in a study of persons residing near the Hanford site, UnitedStates of America. A paper by Bithell et al. [B27] examined contamination by 235U and found noevidence of an association with childhood leukaemia. Leukaemia incidence has also been studied by

82 UNSCEAR 2013 REPORT

Grosche et al. [G36] around two nuclear facilities that discharge tritium. The results did not support anassociation. For the facility with the higher discharges, there was a non-significantly decreased rate ofchildhood leukaemia while for the other facility with discharges several orders of magnitude smaller,
there was a significant increase in the incidence of childhood leukaemia.

5.

Diagnostic radiology

B24.
Several case–control studies have been performed of the incidence of leukaemia anddiagnostic radiation exposure. A New Zealand study of 590 leukaemia cases diagnosed during 1958–
1961, along with age–sex matched hospital controls, reported an association between leukaemia
incidence and therapeutic radiation exposure, but not with diagnostic irradiation. No breakdown by age
at exposure or diagnosis was given [G38].
B25.
In a case–control study of the incidence of childhood leukaemia (>300 cases and >800
controls), Graham et al. [G25] reported a relative risk of 1.14 (p >0.5) for post-natal diagnostic
irradiation received at least one year prior to diagnosis.
B26.
Bartley et al. [B6] studied 711 cases of childhood ALL and 116 childhood cases of acute
myeloid leukaemia (AML) in relation to reported post-natal diagnostic X-rays administered one ormore years prior to diagnosis. For ALL they found a statistically significant association (OR = 1.85;
95% CI: 1.12, 2.79) for three or more diagnostic X-rays, but not for AML (OR = 1.05; 95% CI: 0.90,1.22).
B27.
Infante-Rivard [I36] similarly studied reported post-natal diagnostic X-rays among childhoodcases of ALL and found an increasing risk with number of X-rays—odds ratio = 1.48 (95% CI: 1.11,
1.97) for two or more X-rays. On the other hand, at least three studies have reported no significant
statistical association between diagnostic X-ray exposure and childhood leukaemia risk [M25, R3,
S74].
B28.
A recent cohort study examined leukaemia incidence following CT scans given to over
178,000 juveniles at ages 0–21 [P22]. For a dose-response analysis they estimated average red bonemarrow doses for various CT procedures during two time periods and summed estimated doses across
CT scans for each individual. From 74 observed cases of leukaemia, they found an ERR Gy-1 of 36(95% CI: 5, 120). However, they included myelodysplastic syndrome (MDS) with the leukaemia cases,
and the MDS cases had an extremely high relative risk. Without the MDS cases, the estimated risk was
still high, but no longer statistically significant (ERR Gy-1 of 19 (95% CI: −12, 79)).
B29.
Mathews et al. [M9] reported a very large paediatric CT study in Australia, based on about
680,000 children who received CT scans during the period 1985-2005 and 10,000,000 with no record ofsuch exposures. It included about 147,000 who received CT scans before age 10, and 533,000 whose
first CT scan was in the age range 10–19. On the basis of type of examination, age at examination, andtime period (1985–2000 or 2001-2005), they estimated effective doses (mean of 4.5 mSv per scan), redbone marrow doses and brain doses and conducted a record-linkage follow-up through 2007. It was
concluded that overall cancer incidence was 24% (95% CI: 20, 29) greater in the CT group, with astatistically significant trend by recorded number of CT scans. They reported excesses in the CT groupfor digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, thyroid, leukaemia,
myelodysplasia, Hodgkin’s lymphoma and ill-defined/unspecified sites. The risk estimate for “allcancers, excluding brain cancer after brain CT” risk was statistically incompatible with the data at
comparable ages from the Japanese LSS study on atomic bombing survivors [M9] (ERR Sv-1 of 27(95% CI: 17, 37); LSS, 3 (95% CI: 2, 6)). On the basis of a total of 211 leukaemia cases in the exposed

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

83

group, they reported a relative risk of 1.19 (95% CI: 1.03, 1.37; excess of 34 leukaemias) compared tothe unexposed group. For leukaemias plus myelodysplasias, the excess was 48 out of 246 total cases
and a RR of 1.23 (95% CI: 1.08, 1.41). On the basis of the estimated doses and a dose lag of one year,
the ERR Gy-1 for leukaemias plus myelodysplasias was 39 (95% CI: 14, 70).
B30.
Concerns about possible biases and the interpretation of the study arise for several reasons.
Reverse causation (cancers were caused by the medical conditions prompting the CT scans rather thanby the CT dose) as a potential bias could not be examined in the study since no documentation wasavailable on the indications for the CT scans. The choice of focusing on cancers that occurred at leastone (rather than five or ten) year after the initial CT scan amplified the potential for reverse causationand is biologically implausible. The finding of generally stronger associations if they included years
one–four after the CT scan than if they included only later years reinforces this concern. Missing
subsets of CT exposures included those due to unrecorded repeat CT scans (e.g. because of patient
movement) and those occurring outside the age or time ranges of the study. Missing doses would tend
to inflate the estimates of risk per unit dose. Implausible CT and tumour associations included radiation
excesses seen for melanoma and Hodgkin’s lymphoma, neither of which is known to be associated withradiation, but not for breast cancer, a radiosensitive site. No clear excess of leukaemia was seen for
those exposed before age ten but it appeared for those exposed at later ages, unlike other studies ofradiogenic childhood leukaemia, which tend to show the greatest leukaemia risk for exposure at early
ages.
B31.
Lundell and Holm [L42] studied 14,624 infants who were given radiotherapy in infancy totreat skin haemangiomas. There were no significant associations between incidence of childhood
leukaemia and radiation dose, but the mean marrow dose was estimated to be only about 0.13 Gy. A
small excess incidence of leukaemia was reported in children who had been treated with radiotherapy
for tinea capitis. In a report on ~10,800 tinea capitis patients, Ron et al. [R37] assumed a dose of 0.3 Gy
averaged across all the bone marrow. For 14 leukaemia cases in the exposed group and 9 among
unexposed controls, the ERR was marginally elevated at 4.3 (95% CI: 0, 15) Sv-1 with an EAR of 9(95% CI: 0, 33) (104 PY Sv)-1. They reported that the relative risks for leukaemia were 3.3, for 0–5year-old group, 2.6 for the 6–8-year-old group, and lower for the 9–15-year-old group (the ages being
the ages at exposure), but the comparison was based on a very small number of cases [R35].
B32.
In a group of ~2,200 children given X-rays therapy for tinea capitis, eight leukaemia patientswere observed (SIR = 3.2; 95% CI: 1.5, 6.1) associated with a dose of about 4 Gy to the cranial bonemarrow [S41, S71]. If one assumes that the mean bone marrow dose was 0.3 Gy, as in the Ron et al.
report, then the ERR would have been 7.3 (95% CI: 1.7, 17) Sv-1. Damber et al. [D3] reported a cohort
follow-up study of ~20,000 patients treated for benign lesions of the locomotor system. The ERR for
leukaemia was non-significant, but only 115 patients were treated before the age of 20.

6.

Radiotherapy

B33.
There have been reports of an increased incidence of acute leukaemia in patients after
treatment of Hodgkin’s lymphoma, multiple myeloma, breast cancer, and other neoplasms [G37, R55,
Z3]. The aetiology of the increased risk is unclear, and it is likely multifactorial, including radiation,
chemotherapy, the primary disease, or even an underlying immunodeficiency.
B34.
A number of studies have examined the risk of second tumours after treatment for childhood
cancers [T46, T47]. There was a strong dose–response relationship between leukaemia risk and thedose of alkylating agents. The relative risk of leukaemia reached 23 in the highest chemotherapy dose

84 UNSCEAR 2013 REPORT

group. A lower risk was seen for doxorubicin. The radiation dose had no influence on leukaemia risk.
In another study, Rosenberg and Kaplan [R54] found an increased leukaemia risk after MOPP
chemotherapy, but this was largely independent of radiation dose. A report by Hawkins et al. [H33]—in
which over 16,000 survivors of childhood cancer were studied—indicated that radiation, and also
specific chemotherapy involving alkylating agents or epipodophyllotoxins, can induce secondary
leukaemia. A follow-up of survivors of Hodgkin’s disease and leukaemia by Kaldor et al. [K5] found a
marginally significant increase in ERR of 0.24 (95% CI: 0.04, 0.43) Sv-1. A recent report on the followup of 14,359 patients in the CCSS by Friedman et al. [F17] found an observed over expected ratio of
41/7 and an SIR of 6.1 (4.5, 8.2) for leukaemia.

B. Internal exposure
B35.
A number of studies have examined the relationship between radon exposure and leukaemia
incidence. Most of the studies have been negative or non-significant. Kaletsch et al. [K7] concluded
that there was no association between indoor residential radon exposure and incidence of childhood
leukaemia. Lubin et al. [L36] conducted a case–control study of indoor radon exposure and incidenceof ALL. There was no evidence for an association. A similar conclusion was reached by Law et al.
[L16] in the United Kingdom regarding adult acute leukaemia. Steinbuch et al. [S112] studied the riskof childhood acute myeloid leukaemia and radon exposure and concluded there was no association.
However, Raaschou-Nielsen et al. [R2] examined domestic radon levels and childhood leukaemia
incidence in Denmark and reported a statistically significant dose response with a 56% increase in therate of ALL per 103 Bq/m3-years. Kendall et al. [K24], in a large case-control study of childhood cancer
and background radiation in the United Kingdom, examined the influence of radon upon childhood
leukaemia risk and did not find an association.
B36.
Residents along the Techa River were exposed to effluent releases from the Mayak nuclear
production facility. The main source of exposure to the red bone marrow was from 90Sr, a bone seeking
radionuclide. Red bone marrow doses ranged up to over 1 Gy. For non-chronic lymphocytic leukaemia,
Krestinina et al. [K52] observed an approximately linear dose response with an ERR of 4.9 (95% CI:
1.6, 143; n=53) Gy-1 but the age-at-exposure effect was not statistically significant.

C. Summary
B37.
There is little doubt that non-CLL is induced by radiation, with a minimum latency ofapproximately two years. The tumours induced are either acute forms or chronic granulocytic
leukaemia, with the acute forms tending to predominate. The ICRP [I11] estimates the lifetime fatal
probability coefficient to be 50 (10-4 Sv-1) among a population of all ages from non-CLL after exposure
to low doses. The risk at low doses is based on mathematical models since the studies have not shown astatistically significant increase in leukaemia incidence at marrow doses of less than about 400 mSv. A
linear–quadratic dose–response model appears to be more appropriate than a linear non-thresholdmodel and this has been used by the ICRP [I11], BEIR [N38, N43] and UNSCEAR [U12, U13] withallowances for dependencies on sex, age at exposure and time since exposure. The estimates made bythese different groups of the excess leukaemia deaths in a population of 100,000 of all ages and both
sexes exposed to a dose of 0.1 Gy are quite similar. The studies that have sufficient statistical power topermit the derivation of risks of radiation-induced leukaemia are shown in table B5. Overall, the risk toANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

85

children appears to be three to fivefold greater than that to adults. A number of epidemiological studies
of children who have undergone CT scanning are currently under way and these may yield more
information on the risks of radiation-induced leukaemia over the next several years.
Table B5. Estimates for leukaemia incidence and mortality rate from radiation exposure in children
Adapted from UNSCEAR 2006 Report (annex A, table 44) [U12]; only studies are listed for which quantitative estimates of risk
were possible

Average ERR a at 1 Sv

Study

Average EAR (104 PY Sv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
LSS [P47]
Sex

Age at exposure

Males

4.66 (3.07, 6.88)

4.14 (3.06, 5.39)

Females

5.05 (3.24, 7.61)

2.41 (1.71, 3.23)<20 years

8.27 (4.95, 13.66)

2.79 (1.99, 3.74)

0–40 years

3.59 (2.01, 5.97)

2.69 (1.70, 3.90)>40 years

3.98 (2.32, 6.45)

4.68 (3.10, 6.57)<20 years

6.5 (4.0, 10.3) bn.a

3.9 (2.3, 6.1)bn.a

4.0 (2.1, 6.9)bn.aLSS [H70]
Age at exposure

20–39 years≥40 years
Paediatric CT examinations [P22] b

36 (5, 120) d

Paediatric CT examinations [M9]39 (14, 70) d

Hodgkin’s disease [K5]c

UK childhood cancers [H33]eInternational childhood cancer [T47]

n.a
n.a

0.24 (0.04, 0.43)

b

n.a.

0.24 (0.01, 1.28)

b

n.a.

0.0 (0.00, 0.004)

n.a.

Mortality rate
LSS [P51]
Sex

Age at exposureMales

4.07 (2.75, 5.84)

3.23 (2.41, 4.18)

Females

3.96 (2.57, 5.87)<0 (<0, 291.33)<20 years

6.63 (4.21, 10.26)<0 (<0, 271.86)

20–40 years

3.07 (1.81, 4.87)

2.39 (1.56, 3.39)>40 years

3.15 (1.74, 5.24)

3.46 (2.12, 5.09)

4.44 (1.7, 8.7)

0.95 (0.4, 1.9)

Israeli tinea capitis [R37] e
Stockholm skin haemangioma [L42]f

1.6 (−0.6, 5.5)

b

n.a.

86 UNSCEAR 2013 REPORT

Average ERR a at 1 Sv

Study

Average EAR (104 PY Sv)-1

INTERNAL LOW-LET EXPOSURES
Incidence
Chernobyl-related exposure in Belarus,
Russian Federation and Ukraine [D19]32.4 (9.78, 84.0)

n.a.

Chernobyl-related exposure in Ukraine [N34]2.5 (1, 5.4) b,g,hn.a.

Chernobyl-related exposure in Ukraine [N35]2.1 (1.2, 3.7)

b,d,g

n.a.

4.4 (1.3, 15)a

90% CI in parentheses.

b

95% CI in parentheses.

cRisk estimates based on [L29].

d

ERR Gy-1 for leukaemia plus myelodysplasia.

e

Risk estimates based on the UNSCEAR 2000 Report [U9].

fBased on those with doses above 0.1 Sv.

g

Odds ratio, not ERR at 1 Sv.

hRelative risk among those with doses of 10 mSv or more relative to those with less than 2 mSv.

IV. THYROID CANCER

A. General
B38.
Thyroid cancer represents about 1–2% of all cancers. It is approximately twice as common infemales as in males, with the incidence increasing with age. The association of ionizing radiation
exposure with thyroid cancer risk was first noted in a case–control study by Duffy and Fitzgerald [D49]
and was confirmed within a few years by several other studies [C30, S81, W28], including that of thesurvivors of the atomic bombings in Japan [S95, W40]. Since then, the thyroid has been the subject ofmany investigations concerning the induction of neoplasms, both malignant and benign. X-rays andgamma radiation, and also internally deposited radionuclides (particularly radioiodines), may induce
thyroid carcinoma.
B39.
Robbins et al. [R30] have estimated that 9% of thyroid cancers in the general population may
be attributable to radiation. In Western Europe, the incidence of thyroid cancer has also been risingwhich prompted some to question whether the Chernobyl accident was a cause; however, this
supposition has not been borne out. The reason for the increased incidence may be improved diagnosisof clinically “occult” lesions. Studies ranging from the early case–control study by Astakhova et al.
[A27] to the Ukrainian and Belarusian cohort studies [B60, T39, Z1] have confirmed radiation as theprimary cause of the large increase in thyroid cancer rates among juveniles in Belarus and Ukraine.
B40.
Radiation-induced thyroid cancer does not appear to have a different survival rate from that ofsporadic thyroid cancer [B69]. In the United States of America, the five- and 10-year survival rates ofthyroid cancer patients are 97% and 95%, respectively. In general, most thyroid cancers induced byradiation are well-differentiated papillary adenocarcinomas, with a small percentage being follicularANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

87[N13]. Radiation-induced thyroid cancers do not usually include the anaplastic and medullary types;
thus, the fatality rate of radiation-induced thyroid tumours may be even lower than for sporadic cancers.
B41.
Although several cases of anaplastic thyroid tumours have been reported following radiation
exposure [G8, K43], it is uncertain whether these were fortuitous or whether they were indeed
radiation-induced. It is possible that they may have resulted from the degeneration of betterdifferentiated radiogenic tumours.
B42.
The risk factors derived in various epidemiological studies are not always easy to compare
because they include different age groups, ethnic backgrounds, primary diseases, and ratios of males tofemales in the population examined. Sources of information regarding radiation-induced thyroid cancer
include the NCRP [N17, N18], BEIR [N38, N43] ICRP [I11], the UNSCEAR Committee [U10, U12],
Shore [S65], and Nagataki [N2].
B43.
The occult carcinoma, which is usually of a non-sclerosing papillary type, is not considered inradiogenic risk estimates because these occult tumours are of doubtful clinical significance and areusually discovered incidentally by pathologists. Martinez-Tello et al. [M8] have indicated that in an
autopsy study of a non-exposed Spanish population, about 22% of completely sectioned thyroids
contained occult papillary carcinomas. A prevalence of 8.8% occult papillary carcinoma has beenreported by Furmanchuk et al. [F24] in a Belarussian autopsy series, and 18% in autopsies of nonirradiated persons in the Japanese atomic bombing study [S14].
B44.
Since the Chernobyl accident, there has been great interest in a possible genetic or mutationalsignature (a genomic fingerprint) that might be associated with radiation-induced thyroid cancers. A
large proportion of the childhood thyroid cancers occurring after Chernobyl were reported to beaggressive. Initial reports indicated that rearrangements of the tyrosine kinase domain of the RET protooncogene were found at a higher than expected rate of these rearrangements in thyroid tumours in thegeneral population [B54, E3, T20]. The most frequently observed were RET/PTC1 and RET/PTC3
rearrangements; however, 30–50% of the papillary cancers did not have these findings. Currently, it
appears that the genomic differences and aggressive nature of the tumours reported may represent thetype of thyroid cancer that occurs in childhood rather than a radiation signature per se (but see [H43]).
The mortality rate from these cancers is very low [S23, T19, W24]. An indication of EML4-ALK fusion
gene rearrangements has also been seen in irradiated thyroid cancer cases [H13].
B45.
The cell type of the childhood thyroid cancers occurring after the Chernobyl accident was also
initially felt to be rather specific with a solid-follicular variant of papillary cancer being predominantfrom 1990 to 1995. This cell type, however, has decreased with time since exposure, and the proportionof papillary cancers composed mainly of papillae has been increasing with time [T41]. As of 2000–
2001, the percentage of each type of papillary cancer was almost equal. It also appears that RAS, p53,
BRAF, B-raf and NTRK1 mutations are not characteristic of the radiation-associated tumours [B12,
H12, H50, L25, N32, S117].

B. Modifying factors
B46.
The latent period from radiation exposure to the clinical development of thyroid neoplasms
varies widely among studies. Following exposure to external radiation, the latent period has beenreported to be anywhere between four–five years and up to 60 years, the maximum length of follow-up
of relevant cohorts [A7]. The reported latent periods appear to be a function of the follow-up time of

88 UNSCEAR 2013 REPORT

the particular study, with several authors indicating an excess number of cancer cases occurring 40 or
more years after irradiation [A7, F29, S7]. Any epidemiological study not conducted with a longenough follow-up period will estimate the mean latent period as likely to be short. There is also asuggestion that the latent period may increase with age at irradiation [C37, R10], although that study
was based on a large series of clinical cases rather than systematic follow-up and time-to-event analyses
of well-defined cohorts. Schneider et al. [S33] have reported that for children who received
radiotherapy to the head and neck for benign conditions, the ERR at 10 mGy was about 0.02 at lessthan 10 years post-exposure, 0.04 at 10–25 years post-exposure, rose to a maximum of 0.08 at 25–29
years post-exposure and then declined to about 0.04 at 40 or more years post-exposure. On the basis ofpooled data from five irradiated cohorts, including the Schneider cohort, Ron et al. [R43] reported thatthyroid cancer risk peaked at about 15–19 years after irradiation but was still elevated beyond 40 years,
as was also noted by another temporal modelling method [S69].
B47.
The effect of dose fractionation or a low dose rate is difficult to evaluate because there is no
major study with appreciable intrastudy variation in dose rate/fractionation. Therefore, comparisons
have to be made between studies, and variation in a number of factors can affect such comparisons. The
pooled analysis by Ron et al. [R43] systematically attempted to evaluate dose-fractionation effects andreported a factor of 0.7 for the risk from fractionated exposures compared to single exposures.
However, the degree of fractionation was relatively small in most of the included studies. Studies of therisks associated with the use of 226Ra applicators for skin haemangiomas by Lundell et al. [L40] andLindberg et al. [L26] tend to suggest that a lower dose rate confers essentially as much risk as acuteexposures. However, a study of the risks associated with the administration of 131I for diagnostic
purposes suggests little effect after a low-dose-rate exposure [H7]. Nevertheless, the substantial
Chernobyl data generally indicate approximately the same risk as for comparable brief external
exposures. This is discussed later in the section on internal exposure.
B48.
Various studies reviewed later indicate that the thyroid is more radiosensitive in children andadolescents than in adults. For radionuclides, it is unknown whether this is due to differences inmetabolism or concentration of radionuclides. Certainly, inhalation of a fixed amount of radioiodine
results in a greater concentration in the infant thyroid than in the adult thyroid [B47]. Moreover, there issubstantial evidence that the younger a person is at the time of exposure, the higher the risk ofdeveloping radiation-induced thyroid cancer in the future. Except at high therapeutic doses, exposuresover the age of about 30 years from external radiation have not been found to significantly increase therisk of thyroid cancer.
B49.
The best estimate of risk for persons exposed under 20 years of age to external radiation comesfrom a pooled analysis of five large cohort studies by Ron et al. [R43]. The ERR at 1 Gy was estimatedto be 7.7 (95% CI: 2.1, 29) following exposures in childhood, although if the one study with a very highrisk was excluded, or if exposure status was adjusted for in that study, the ERR was reduced to 3.8(95% CI: 1.4, 9.9).
B50.
Sex also appears to be a modifying factor. Several epidemiological studies indicate thatfemales are more sensitive than males to radiation-induced thyroid adenomas and cancers. The EAR infemales may be two–four times that in males [D15, M11, M47], but the ERR per unit dose is about thesame for both sexes or only slightly higher in females. In the United States population, spontaneous
thyroid carcinoma occurs in females approximately two and a half times more commonly than in males.
B51.
Ethnic background may also be a significant modifying factor. This has been notedparticularly in the studies of persons of Jewish ancestry [R33, S65]. Radiation risk for those with
Jewish ancestry may be several times higher than that for non-Jewish populations [R39, S65] although
not all reports have confirmed that [A7]. Persons of Jewish ancestry from North Africa, especially

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

89

Morocco and Tunisia, appear to be five or more times more sensitive than non-Jewish populations, andtwice as sensitive as the Jewish children native to Israel or other Middle East countries. Whether this isdue to a high prevalence of ataxia telangiectasia heterozygosity from an ataxia-telangiectasia mutated(ATM) founder mutation in the North African Jewish population is unknown [S7]. A report of Momani
et al. [M47] involving a United States hospital study of siblings who were irradiated did not identify
familial factors that modified the effects of radiation exposure, nor did a study of infants irradiated forenlarged thymus [S66], although there seems to be some radiation-associated familial clustering [P24].
B52.
As to other risk factors, various studies have reported mixed results with regard tomodification of the radiation-induced risk by age at menarche or first childbirth, gravidity, parity, oral
contraceptive use, menopausal hormone use and obesity [A7, F12, K42, M21, P44, R36, S32, S66].
B53.
Several authors have suggested that iodine deficiency may be a promoting factor in radiationinduced thyroid carcinogenesis because of a reduction in the level of thyroid hormone and its
stimulatory effect on the cells. While this has been suggested in animal studies, at least two humanstudies indicate the opposite—that thyroid cancer can be associated with a high normal intake of iodine[F13, K42]. Some authors believe that Graves' disease influences the development and behaviour of
thyroid carcinoma [M14]. Whether there is an association between thyroid cancer and goitre is not fully
clear [R32].
B54.
In Ukraine, Tronko et al. [T39] observed a higher thyroid cancer risk among those with goitre,
but not in relation to low levels of iodine in the urine. Similarly, in Belarus, diffuse goitre or thyroid
enlargement increased the radiation risk estimate, but low levels of iodine in the urine did not [Z1].
However, a study in the Russian oblast of Bryansk found that low iodine excretion levels wereassociated with a twofold greater thyroid cancer risk from radioiodine exposure [S48].
B55.
A study by Cardis et al. [C3], discussed below, indicates that in areas of iodine deficiency, theradiation-related risk of cancer may be three times higher than in areas of normal iodine levels and thatwith iodine prophylaxis, the risk can be reduced by about a factor of three, but replication of thoseresults would be desirable. On the other hand, the cohort study in Ukraine did not find a statisticallysignificant modification of radiation risk in the case of either low iodine excretion levels or the use of
stable iodine prophylaxis [B60].
B56.
Researchers have suggested that one reason for the sensitivity of the thyroid to radiation
carcinogenesis may be that TSH enhances the effect of exposure to ionizing radiation [R28]. They havealso suggested that patients at risk be given prophylactic exogenous thyroxine. In at least a few cases,
however, this treatment seems to have had little effect [S24]. Even if the thyroid hormone did affect thesensitivity of the thyroid gland to cancer induction, this would be unlikely to explain an age-at-exposure
effect since serum thyroid hormone levels in children and adults are similar.

90 UNSCEAR 2013 REPORT

C. External exposure
1.

Atomic bombing survivors

B57.
Thyroid cancer was the first type of solid cancer to be found in excess among the survivors of
the atomic bombings in Japan [P8, S95, W40]. The LSS mortality studies have not reported on thyroid
cancer because of the rarity of death from thyroid cancer. The incidence of thyroid cancer increased
with decreasing age at exposure and attained age. In the 1994 LSS incidence report, there were 225
thyroid cancer cases. The ERR at a dose 1 Sv was 1.2 (95% CI: 0.5, 2.1) with an EAR of 1.6 (95% CI:
0.8, 2.5) (104 PY Sv)–1 [T23]. There was no significant difference in the ERR between males andfemales, although the risk decreased with age at exposure. At 0–9 years of age at exposure, the ERR
was 9.5 Gy-1; at 10–19 years of age, it was 3.0 Gy-1; at 20–29 years of age, it was 0.3 Gy-1; and at over
40 years of age, it was 0.2 Gy-1. For the population 0–19 years of age at exposure, the ERR was 6.3(95% CI: 5.1, 10.1) Gy-1 whereas for the population exposed over the age of 20, the ERR was notstatistically significant at 0.3 (95% CI: <0, 12) Gy-1.
B58.
A more recent report of thyroid cancer incidence from 1958 to 1998 among the survivors of
the atomic bombings was based on 471 thyroid cancers and showed a strong dose response with an
ERR of 0.57 (90% CI: 0.24, 1.1) Gy-1 [P52]. The dose–response function indicated a radiation-related
excess of 63 cancers. There was a negative age-at-exposure effect of -31% (90% CI: -59, 4) per decadeof age at exposure, which implies that the risk is about 2.5 times higher for exposure at age 5 than atage 30. They did not report whether the radiation effect was statistically significant for exposures atages 30 years and beyond. There also was a diminution in the ERR with attained age (age at risk), but
the radiation risk was still elevated 40 or more years after exposure. The difference in risk between thesexes was not statistically significant: ERR ratio for females to that for males was 1.3 (90% CI: 0.6,
3.9). However, the EAR was greater for females than males, the EAR ratio being 3.6 (90% CI: 1.8,
9.5). This occurs because females have a higher baseline risk of thyroid cancer than males, so
multiplying both the male and female baseline risks by about the same factor yields a greater absolute
excess for females. The EAR averaged over the sexes was 1.2 (90% CI: 0.5, 2.2) (104 PY Sv)–1, and it
declined by 46% (90% CI: 68, 12) per decade of age at exposure, which indicates that the EAR would
be about 4.7 times greater following exposure at age five compared to that at age 30. The change in
EAR with attained age was not statistically significant.
B59.
A pathological review of thyroid cancers in the LSS of atomic bombing survivors from 1958
through 2005 has now been reported [F29], including 371 thyroid cancers, but excluding
microcarcinomas <10 mm in diameter. The ERR at 1 Gy, modelled for those exposed at age 10 andobserved at age 60, was 1.28 (95% CI: 0.59, 2.70) and the EAR was 3.0 (95% CI: 1.4, 5.0)(104 PY Sv)-1. The radiation risk decreased markedly with increasing age at exposure, such that there
was little evidence of a radiation effect for those exposed at >20 years of age as the ERR was 0.27
(95% CI: <0, 1.07). They estimated that the ERR decreased by 53%, while the EAR decreased by 70%,
per decade increase in age at exposure. The excess thyroid cancer risk among those <20 years old at
exposure has persisted for over 50 years since exposure (figure B-V).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

91

Figure B-V. Radiation and thyroid cancer incidence
Adapted from [F29]2.

Diagnostic radiology

B60.
Inskip et al. [I39] conducted a study based on 484 thyroid cancers recorded in cancer registries
covering the Uppsala region of Sweden for a 13-year period. The study included a search of hospitalrecords for all diagnostic medical radiation procedures more than five years before diagnosis of thyroid
cancer for the cases and a comparable period for the matched controls. For diagnostic exposures to theupper part of the trunk after age 20, there was a small (non-significant) diagnostic radiation-associateddeficit of cases while for exposures before age 20, there was a small non-significant excess of cases.

3.

Radiotherapy

B61.
The external radiation doses to the thyroid in several major epidemiological studies were a few
tens of milligrays to a few grays. Hempelmann et al. [H38] compared 2,872 patients who had received
X-ray therapy for presumed thymic enlargement. The treatment was given in infancy, and the study
population was compared to 5,055 non-irradiated siblings. The mean thyroid dose was 1.19 Gy with awide range of doses (from 0.01 Gy up to >6 Gy for a few). The absolute risk derived was 2.7 cases
annually per million persons exposed per 10 mGy. With Jewish subjects excluded, the absolute risk was
lower, being 1.7 cases annually per million persons per 10 mGy (48 cases per million persons per
10 mGy). In 1993, Shore et al. [S66] reported on a study of this group with a mean follow-up time of
37 years. There were 37 thyroid cancers in the exposed group and five in the sibling controls. In theirradiated group, 33 cancers were papillary and four were follicular. The earliest cancer in this group
was found six years after exposure, and the latest was at 49 years after irradiation. A linear dose–
response model fit the data well, and the ERR at 1 Gy was 9.5 (95% CI: 6.9, 12.7). Jewish subjects

92 UNSCEAR 2013 REPORT

were noted to be at higher risk, as were women who were older at menarche or at first childbirth. In a
recent update [A7], 50 thyroid cancers were identified in the irradiated group and 13 in the larger nonirradiated comparison group. After adjustment for several other risk factors, the ERR was 3.2 (95% CI:
1.5, 6.6) Gy-1, with an EAR of 2.2 (104 PY Sv)–1. Although the ERR declined in longer periods, it was
still elevated 58 years after irradiation.
B62.
Maxon et al. [M11], examined 1,266 patients who had received external radiotherapy for anassortment of benign diseases in childhood. The mean thyroid dose was approximately 2.9 Gy. The
male–female ratio in those who developed thyroid cancer was 0.6. The absolute risk factor derived
from this study was 1.5 cases annually per million persons per 10 mGy.
B63.
Ron and Modan [R32] examined Israeli patients who had been treated for tinea capitis with
X-rays between 1949 and 1960; the estimated mean thyroid dose was 90 mGy. During irradiation, partsof the head, face, and neck were shielded with lead rubber sheeting, and the estimate of the dose
depended critically on the children's maintaining a constant position. Nevertheless, statistical modellingof uncertainties suggested that the risk estimates would not be greatly affected by potential dosimetric
uncertainties [L37, S26]. The ethnic background of this group was almost exclusively Jewish, and theabsolute risk determined in this study was 13 cases annually per million persons per 10 mGy. A higher
radiation risk was found in patients of Moroccan or Tunisian descent. There were 5,420 such subjects
included. The absolute risk in the Moroccan and Tunisian subjects was 15 cases annually per million
persons per 10 mGy and a lifetime risk of 140 cases per million persons per 10 mGy. Subjects from
Israel, Asia, and other countries in North Africa had an absolute risk factor of seven cases annually per
million persons per 10 mGy and a lifetime risk of 70 cases per million persons per 10 mGy. In an
update of the Israeli tinea capitis group, Ron et al. [R39] estimated the ERR as 27 (95% CI: 15, 42) Gy-1
for childhood exposure. The absolute excess risk was 13 (104 PY Gy)-1. The risk was about twice ashigh among those irradiated before the age of five compared to those irradiated at ages 5–15 years. A
statistically significant excess risk for thyroid cancer was found at doses between 50 and 100 mGy.
B64.
In the most recent report on the Israeli tinea capitis patients, the median length of follow-up
was 46 years [S7], with 103 thyroid cancer cases in the 10,834 irradiated subjects and 56 in thecomparison group of 16,226 siblings or matched population controls. Nearly 10% of the irradiatedsubjects received more than one course of radiation treatment. The estimated doses ranged from 45 to
495 mGy, with a median of 87 mGy. A linear dose–response model provided an adequate fit to the data
which was not improved significantly by adding a quadratic term, although there was some evidence of
upward curvature. The ERR was 20 (95% CI: 12, 32) Gy-1 overall, and was about twice as high for
those from North Africa as those from Israel or the Middle East. There was an age-at-exposure effect(p = 0.02), with the ERR of 34, 13 and 21 Gy-1 for irradiation at ages <5 years, 5–9 years and >9 years,
respectively. The EAR was 9.9 (95% CI: 5.7, 15) (104 PY Sv)–1 overall, but was four times as highamong females as males (p = 0.001). The risk coefficients were higher than those obtained in manyother studies. It is unclear whether that was due to an underestimation of dose because of patient
movement during radiotherapy, statistical fluctuations, an unusual sensitivity of this particular
population, or undocumented X-ray treatments for scalp ringworm prior to immigration to Israel.
B65.
A report by Shore et al. [S71] compared a group of 2,224 patients irradiated for tinea capitis ata mean age of eight in New York with 1,380 non-irradiated tinea capitis patients. The study, with a
median follow-up of 39 years and an average thyroid dose of about 60 mGy [H24], found two thyroid
cancers in the exposed group and none in the controls. A comparison of the two cancers in irradiatedgroup with rates of thyroid cancer among the general population showed an SIR of 1.0 (i.e. 2.04
expected cancers). The comparison of irradiated and non-irradiated tinea capitis patients yielded an
EAR estimate about six times lower than the Israeli study, so at face value the two tinea capitis

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

93

irradiation studies seem incompatible. However, the small number of cases in the New York study
precludes a definite conclusion.
B66.
A group of over 1,100 patients who were treated in Boston for lymphoid hyperplasia at an
average age of seven years was located and asked to complete a questionnaire. A subset was clinicallyexamined [P40]. The average length of follow-up was 29 years and the estimated mean thyroid dose
was about 240 mGy. The analysis showed an ERR of 5.9 (95% CI: 1.8, 12) Gy-1 for thyroid cancer,
based on 13 thyroid cancers (detected either by history or by screening and diagnostic examination) in
the irradiated group and 2 in the unexposed group.
B67.
A study performed in Chicago at Michael Reese Hospital initially followed up 2,189 persons
who had received external radiotherapy to the head, neck, or chest prior to or during adolescence,
predominantly for tonsillar hypertrophy [S31]. The absolute risk of cancer in this group was determined
to be three–four cases annually per million persons per 10 mGy. The population included in this group
may have contained a relatively high proportion of Jewish patients. The study was expanded to 4,296
X-irradiated subjects, including 2,634 for whom thyroid dose estimates and follow-up were possible.
The mean age at treatment was four years, with an upper limit of 16 years, and the mean follow-up timewas 33 years. The mean dose was 590 mGy. They documented 1,043 with thyroid nodules, including
309 with thyroid cancer [S33] of which 52% were <10 mm in diameter [B69]. When the estimates ofthyroid cancer risk were compared for the time before screening and the time during which there were
multiple screenings, there was no significant difference in the dose–response slopes, although the lattergave a smaller numerical risk estimate. The estimated ERR was 2.5 (95% CI: 0.6, 26) Gy-1 and theEAR was 3.0 (95% CI: 0.5, 17) (104 PY Sv)–1 [R43]. They reported estimates of ERR of 3.6, 2.8 and
1.4 Gy-1 for treatments at ages <1 year, 1–4 years and 5–15 years, indicating a more than twofold
gradient of risk over the age range 0–15 years.
B68.
DeGroot et al. [D33] examined 416 patients who were irradiated at a mean age of seven years
with a mean thyroid dose of 4.51 Gy. The study subjects volunteered for screening or were referredbecause of a suspected thyroid abnormality. Mean age at examination was 33.5 years and 41 thyroid
carcinomas were detected. The average size was 1.7 cm, with 37% being less than 1 cm in size. Fiftynine per cent of the tumours were multifocal, and 10 of 38 patients with cancer had normal radionuclide
thyroid scans. Carcinoma occurred in 37% of single nodules and in 18% of multinodular glands in thispopulation.
B69.
Several studies reported on thyroid cancer incidence among patients who volunteered forthyroid screening because of a history of head and neck irradiation. Refetoff et al. [R15] reported theresults of approximately 100 patients who had been irradiated during childhood or adolescence. Fifteenof these patients were subsequently subjected to operation, and seven cases of thyroid carcinoma were
found. None of these were of the occult sclerosing papillary type; all were either papillary follicular or
mixed in character. Paloyan et al. [P6] reported histological findings in 38 cancers found during
operation on 70 such patients. Thirteen of the carcinomas were papillary, 8 were follicular and 17 weremixed papillary and follicular. DeGroot and Paloyan [D32] reported that among 50 patients seen forthyroid cancer, 20 had a prior history of neck irradiation. In addition, two thirds of patients who had
had a history of neck irradiation and who had clinical thyroid abnormalities were later shown to havecancer. The ERR for the Chicago tonsillar radiation study was 3.0 (95% CI: 2.6, 3.5) and an excess
incidence of cancers was seen at doses of about 0.5 Gy and above.
B70.
Lundell et al. [L40] followed up a cohort of 14,351 infants given 226Ra (81%) or X-ray (19%)
treatment for skin haemangiomas during the 1920s through 1950s. On average, children had 1.5
treatments and received 260 mGy to the thyroid. The average age at treatment was six months, with amean follow-up of 39 years. They found 17 thyroid cancers, which yielded an SIR of 2.3 (95% CI: 1.3,

94 UNSCEAR 2013 REPORT

3.7). Sixteen of the 17 cancers were among those treated with 226Ra. A dose–response analysis showed
an ERR of 4.9 (95% CI: 1.3, 3.7) Gy-1 and an EAR of 0.9 (95% CI: 0.2, 1.9) (104 PY Sv)-1.
B71.
Lindberg et al. [L26] followed up another cohort of 11,800 infants treated with 226Ra for skinhaemangioma between 1930 and 1965. Their median age at treatment was five months and the mean
length of follow-up was 31 years. The estimated median thyroid dose was 120 mGy. Fifteen cases ofthyroid cancer were observed, giving an SIR of 1.88 (95% CI: 1.05, 3.1). The ERR was 7.5 (95% CI:
0.4, 18) Gy-1; the EAR was 1.6 (104 PY Sv)–1.
B72.
For comparison, a Swedish study of over 8,100 adults who received cervical spine
radiotherapy (with an average thyroid dose of about 1 Gy) had a much lower risk estimate: an ERR of
0.6 (95% CI: 0.0, 1.4) Gy-1 [D4]. Most (15 out of 22) of the thyroid cancers were diagnosed more than
15 years after exposure.
B73.
Radium applicators were used in some countries for nasopharyngeal irradiation to reduce thesize of adenoid tissue. This was often used in children to reduce the incidence of otitis media and forsubmariners to reduce the potential for barotraumas [K36]. A report by Ronckers et al. [R48] on cancer
incidence among 4,339 (89% under age 20) who received nasopharyngeal irradiation found an
estimated thyroid dose of 15 mGy. After a mean follow-up of 31 years, they reported four thyroid
cancers, giving an SIR of 2.8 (95% CI: 0.8, 7.2). A study of 904 children treated with radium foradenoid hypertrophy by Yeh et al. [Y5] found a non-significant excess of thyroid cancer based on twocases with a relative risk of 4.2 (95% CI: 0.4, 45).
B74.
Thyroid nodules, both benign and malignant, have been reported after high-dose external
radiotherapy. Hallquist et al. [H10] reviewed 1,056 cases of thyroid cancer. Thirty-seven of these had
had a previous cancer and ten of these had received radiotherapy. The odds ratio was non-significantly
increased at 1.1 (95% CI: 0.5, 2.8) and the thyroid doses ranged from 3 to 40 Gy. Van Daal et al. [V1]have followed up 605 persons treated with radiotherapy for benign diseases of the head and neck 16 to
46 years earlier. Seven thyroid carcinomas were found in this group, with a mean latency of 37 years.
The mean dose to the thyroid was 11.1 Gy. The female–male ratio was 2.5, and average age at
irradiation was ten years.
B75.
De Jong et al. [D25] reported a retrospective analysis of thyroid surgery of 110 persons who
had received childhood radiotherapy for acne. Of this highly select sample, 31% were found to havethyroid cancer. Such studies, unfortunately, cannot be used to develop risk estimates, owing to patient
selection by a number of unknown factors.
B76.
Several other reports of the late effects after childhood radiotherapy revealed that thefrequency of thyroid cancer ranks second or third behind bone and soft tissue sarcomas. Mike et al.
[M37] found 17 thyroid cancers in 15,000 children who had received radiotherapy for other cancers.
Increases were noted mostly for patients who had been treated for Hodgkin’s disease, neuroblastoma, orWilms’ tumour [K9, T48]. Hancock et al. [H18] reviewed 1,677 patients who had received radiotherapy
for Hodgkin’s disease. Forty-four patients developed thyroid nodules; six of these proved to bepapillary cancers. The risk of thyroid cancer was 1.7%, and the risk was 15.6 times higher than that
expected in a normal population. In the Late Effects Study Group [T49], the mean thyroid dose was
12.5 Gy and the mean age at exposure was seven years (range 0–18 years). There was a 53-foldincreased risk of thyroid cancer compared to the general population rate in the 9,170 children who had
survived more than two years (up to 48 years) after treatment for another cancer. Sixty-eight per cent of
the cancers arose within the radiation field. The risk increased with dose and did not decrease even atdoses as high as 60 Gy. The ERR was estimated to be 4.5 (95% CI: 3.1, 6.4) Gy-1, but a later analysis aspart of a systematic pooled study of thyroid cancer found an ERR of 1.1 (95% CI: 0.4, 29) Gy-1 [R43].

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

95

B77.
A Nordic study by Sankila et al. [S21] of over 1,600 patients treated for Hodgkin’s disease
estimated a similar ERR of 0.8 (95% CI: 0.4, 1.5) Gy-1.
B78.
A study reported by de Vathaire et al. [D28] of 4,096 children treated for cancer in France andthe United Kingdom with a mean follow-up of 15 years was also consistent with an ERR in the range
4–8 Gy-1. In a small study by Cohen et al. [C32], there was a high incidence of thyroid cancer (eightcases among 113 children), perhaps because of annual screenings with ultrasound and palpation. Six
were papillary and two were follicular, and they appeared 3.1–15.7 years post-treatment.
B79.
The long-term risk of thyroid cancer associated with radiation treatment was quantified among
12,500 five-year survivors of a childhood cancer (leukaemia, Hodgkin’s lymphoma and non-Hodgkin’s
lymphoma, CNS cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed
between 1970 and 1986 in the CCSS and followed up to 2005 [B26]. There were 119 subsequent
pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were
estimated for the entire cohort. Thyroid cancer risk increased linearly with radiation dose up to
approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI: 6.8, 31.5). Age at exposure
modified the ERR linear-dose term (higher radiation risk with younger age, p <0.001), while sex(higher radiation risk among females, p = 0.008) and time since exposure (higher radiation risk withlonger time, p <0.001) modified the EAR linear-dose term [B26]. A follow-up of 14,359 patients in the
CCSS by Friedman et al. [F17] found an observed/expected (O/E) ratio of 128/12 and an SIR of 10.9
(9.1, 12.9) for thyroid cancer with a median time to diagnosis of 18.9 years.
B80.
Veiga et al. [V15] pooled four studies that included 187 primary thyroid cancer cases among
16,757 childhood cancer survivors. Radiation dose-related thyroid cancer risk increased approximately
linearly up to about 10 Gy, plateaued at about 10–15-fold risk for thyroid doses of 10–30 Gy, thendeclined but was still elevated at doses >50 Gy (figure B-VI). The fitted RR was 13.7 (95% CI: 8, 24)
at 10 Gy. The radiation excess RR increased with decreasing age at exposure (p<0.01), but did not vary
by attained age, time since exposure, or sex.
Figure B-VI. Modelled relative risk for thyroid cancer incidence by radiation dose after radiotherapy
at various childhood ages, based on a pooled analysis of data from four cohorts
Adapted from [V15]96 UNSCEAR 2013 REPORT

B81.
In a study of over 19,200 patients who had received allogenic bone marrow transplants
reported by Curtis et al. [C55], the absorbed fractionated whole body dose was about 12 Gy and the
median age was 25 years. There was a statistically significant increase in thyroid cancer with anobserved over expected ratio of 6.6 mostly occurring more than ten years after treatment. An observed
over-expected ratio of ten was found by Bhatia et al. [B24] that, considering their absorbed doses werein the range 10–12 Gy, would yield an ERR of about 1.0 Gy-1. Socie et al. [S93] reported on over 3,100
children following bone marrow transplantation and reported five cases of papillary carcinoma, withfour of the five occurring more than five years post-radiation.

D. Internal exposure
B82.
The major sources of human data concerning internal thyroid irradiation are: (a) patients
receiving 131I (and occasionally 135I) for therapeutic purposes; (b) those receiving 131I for diagnostic
purposes; and (c) persons receiving mixtures of radioiodines in the environment.

1.

Nuclear medicine

B83.
Patients are sometimes administered radioiodine for diagnostic purposes. Hahn et al. [H4]followed up about 800 of 2,200 children who had received 131I for diagnostic purposes and had an
average thyroid dose of 1 Gy, and 1,100 evaluated for thyroid disease without exposure to radioiodine.
The median age at exposure was 14.9 years. There was no increase in thyroid cancer later in life and thereported relative risk was 0.86 (0.14, 5.13). Possible participation biases cannot be ruled out in that only
about 40% of eligible subjects participated.
B84.
For up to 40 years, Hall et al. [H7] followed up 34,000 patients who had been given 131I for
diagnostic purposes. These had previously been reported on by Holm et al. [H57]. The mean thyroid
dose was estimated as 1.1 Gy. They observed 67 thyroid cancer cases while the expected number from
population rates was 50, giving an SIR of 1.35 (95% CI: 1.05, 1.7). However, subsequent excess
cancers were seen only among those who had been referred for diagnostic examination for a suspected
thyroid tumour, and there was no dose response. Among those irradiated before age 20, three thyroid
cancers were observed whereas 1.8 would be expected. This provided a risk estimate several times
lower than that obtained from the study of the survivors of the atomic bombings.

2.

Radionuclides in the environment

B85.
Fallout from testing nuclear weapons. Rallison et al. examined 5,179 children who had been
exposed to fallout from the testing of nuclear weapons in the western United States during 1965–1970.
The mean thyroid dose was estimated at that time to be 0.46 Gy [R4]. No significant difference
between irradiated and non-irradiated subjects was identified. In 1985–1986, a re-examination of about
2,500 of the cohort was conducted [K27], and an improved dosimetry led to an estimated average
thyroid dose of 0.17 Gy. Altogether, there were eight cases of thyroid cancer. This leads to an ERR ofabout 7.9 Gy-1 (lower 95% bound of 0.0, p = 0.10) which is substantially higher than risks obtained
from the Swedish studies of patients exposed to 131I for diagnostic purposes where the average thyroid
dose was 0.56 Gy and the ERR was 0.4 Gy-1, but the risk is similar to that seen in Chernobyl studies.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

97

B86.
Lyon et al. [L44] conducted a dosimetric and diagnostic reassessment of the above Utah
thyroid data. After further cleaning of the dataset, correction of the dosimetry algorithm and a blinded
review of the diagnoses using current criteria, they re-analysed the data. For the eight thyroid cancers,
they reported an ERR of 0.8 Gy-1 (lower bound of 0.0, p = 0.10). For total nodules and neoplastic
nodules, they reported large, statistically significant risk estimates. However, the original data had
several limitations having to do with incomplete blinding and comparability of the examiners, and to
uncertainties and possible biases in the dietary recall which was central to the dose estimates.
B87.
Machado et al. [M2] compared thyroid cancer mortality in southwestern Utah with that in therest of Utah and the rest of the United States. The odds ratio in both cases was non-significantly
reduced at 0.4 (90% CI: 0.08, 2.00), suggesting less thyroid cancer mortality in the areas receiving
heavier fallout. Gilbert et al. [G11] examined mortality from thyroid cancer across the continental
United States compared to areas felt to have been exposed to fallout from the testing of nuclear
weapons in Nevada. The result was a negative ERR in the potentially-exposed group which was notstatistically significant and the risk did not increase with total cumulative dose or dose received at ages
1–15 years. A non-significant positive association was suggested for those exposed at less than one yearof age with a mortality ERR of 10.6 (95% CI: -1.1, 29) Gy-1 and an incidence ERR of 2.4 (95%
CI: -0.5, 5.6) Gy-1.
B88.
In 1954, the residents of the Marshall Islands were exposed to fallout that resulted in both
external irradiation and ingestion of radioiodine. Nine thyroid tumours have been identified in 243
exposed subjects. The estimated risk was 145 (70 to 270) cases per 10,000 persons per gray. An
increased risk in children could not be supported by the data, although the confidence limits of thestatistics were quite wide. All the cancers occurred in females, again suggesting a higher induction rate
in females than males. No thyroid tumours were observed in 504 unexposed subjects [C42]. The major
contributions to dose were from the short-lived radioisotopes of iodine (132I, 133I and 135I) with only
about 10–15% of the dose from 131I. Conard et al. suggested that the effects of the shorter-lived isotopesof iodine appear to be more like those predicted from external radiation exposure than from 131I,
although the exact types of exposures and amount of exposure in the Marshall Islands is somewhat
difficult to ascertain.
B89.
A Scandinavian study of thyroid cancer by Lund and Galanti [L38] appears on initialinspection to indicate an increase in thyroid cancer in Norway and Sweden due to fallout from thetesting of nuclear weapons. The authors compared the incidence of thyroid cancer in children born inthe period 1951–1962 (the exposed cohort) with that in cohorts born prior to or after that period. They
found a borderline but significant RR of 1.7 (95% CI: 1.0, 3.0) for ages 7–14 years, but no excess risk
at older ages. They acknowledged there may be other explanations for the results than exposure to
fallout. Furthermore, they did not have any data on the different levels of dose to which the cohorts had
been exposed.
B90.
Hanford and Mayak. An analysis of the effects of discharges of radioiodine from the Hanford
nuclear facility in the United States of America included 3,447 subjects who were born between 1940
and 1946 and resided in the region around the Hanford plant. Their mean dose was 174 mGy. This
carefully conducted study reported by Davis et al. [D17] found 19 thyroid cancers, but it did not find asignificant increase in thyroid cancer based on a standardized thyroid screening protocol. The estimated
ERR was 0.7 (95% CI: <0, >500) Gy-1, and the relative risk detectable with an 80% or better power at
170 mGy was 2.14, which means that the study had low statistical power. A study of residents near the
Mayak facility suggested an increase in thyroid cancer risk, potentially associated with radioiodine
releases, but no excess of childhood thyroid cancer was found [K46].

98 UNSCEAR 2013 REPORT

B91.
Chernobyl. After the Chernobyl accident, there was an examination of the incidence of thyroid
cancer in the areas affected by release of radioactive material. The four components of exposure of the
thyroid were: (a) internal irradiation from intakes of 131I ; (b) internal irradiation from intakes of shortlived radioiodine (132I, 133I and 135I) and of short-lived radiotellurium (131mTe and 132Te); (c) external
irradiation from radionuclides deposited on the ground (predominantly 137Cs and 134Cs); and (d) internal
irradiation from intakes of long-lived radionuclides (including radiocaesium). The first component gave
more than 80% of the total thyroid dose and was predominantly due to the ingestion of fresh milk. The
estimated release of 131I was about 1.8 1018 Bq (about 45 million curies). The median thyroid dose in themost contaminated regions of both Belarus and Ukraine was about 0.3 Gy with a substantial fraction ofdoses exceeding 1 Gy.
B92.
As of 1989, no definite increase in thyroid cancer rates had been seen, in part, perhaps, owing
to the lack of a reliable pre-accident tumour registry [I2]. In 1991 and 1992, several reports were
published of a markedly increased incidence of thyroid cancer in children in Belarus and to some extent
in Ukraine [B18, K21]. These reports were unusual because the latent period was shorter than thosereported in other studies of the incidence of thyroid cancer and because no increase had been found atthat time in contaminated areas of the Russian Federation. As of 2000, however, many additionaldescriptive studies [I44, P55, S58, T37, T40, T45], two ecological studies by Jacob et al. [J3, J4] andone case–control study by Astakhova et al. [A27] had indicated a clear increased incidence ofchildhood thyroid cancer. More than 2,000 cases were diagnosed in the three affected countries in thoseunder the age of 18 at the time of exposure. Many of the studies published after 2000 continue to reportan increased SIR and the number of thyroid cancer cases in 2008 was estimated to be ~6,000.
Evaluation of the dose–response relationship is complicated by the fact that in most studies, very few ofthe persons who had developed thyroid cancer had had measurements made of the activity in the
thyroid shortly after the accident. As a result, most estimates of dose need to be based on dosereconstruction using caesium deposition as a surrogate for radioiodine exposure. In some cases, anaverage of the thyroid measurements in a particular settlement can be used.
B93.
In a carefully conducted ecological study, Jacob et al. [J5] examined 131I -associated risks ofthyroid cancer in over 1,000 settlements in Ukraine and Belarus using the average of the thyroid
measurements made in those settlements. They considered only settlements in which ten or moremeasurements had been made. The analysis was based on nearly 1,100 thyroid cancers. They estimateda linear ERR coefficient at 1 Gy of 18.9 (95% CI: 11, 27), but with a concomitant quadratic coefficientof -1.03 (95% CI: -1.46, -0.60) Gy-2. The linear EAR coefficient was 2.7 (95% CI: 2.2, 3.1), combinedwith a quadratic coefficient of -0.145 (95% CI: -0.17, -0.12). The negative curvatures occurred
primarily because of a downturn in risk at doses above 1 Gy. They reported that both the ERR and EAR
varied inversely with age at exposure.
B94.
The risks from 131I exposure have been examined in detail in a case-control study by Cardis etal. [C3] of childhood thyroid cancer following the Chernobyl accident. The study included 276 thyroid
cancer patients and 1,300 controls. Individual thyroid dose estimates were reconstructed, based
primarily on reported location, milk intake, other lifestyle habits and whether they underwent stableiodine prophylaxis. Unfortunately, it was not possible to keep interviewers blinded as to case–control
status because of visible thyroid surgery scars. The participation rates were much better for cases thancontrols, which might be another source of bias. Excess risk was identified at all doses above 0.2 Gy.
At thyroid doses in excess of 2.0 Gy, the risk plateaued. The odds ratio at 1 Gy was between 5.5 (95%
CI: 3.1, 9.5) and 8.4 (95% CI: 4.1, 17.3), depending on the risk model used. The risk is similar to thatreported by Davis et al. [D18] in a smaller case–control study in the Bryansk oblast in the RussianFederation, and also was approximately the same as that seen with published studies of external
exposure [R43].

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

99

B95.
The prevalence of thyroid cancer at the first screening of a fixed cohort of 13,000 children
exposed to radioiodine in Ukraine at ages 0–18 years was examined [T39]. The estimates of dose to thethyroid were based on individual measurements of 131I in the thyroid made soon after the accident alongwith dosimetric data obtained by questionnaire. Thyroid cancers were detected by ultrasound or
palpation, with fine needle aspiration for suspected cancer. A total of 45 thyroid cancer cases weredetected—43 papillary and two follicular cancers. The dose response was approximately linear andshowed an ERR of 5.3 (95% CI: 1.7, 28) Gy-1 for prevalent thyroid cancers. Those exposed at older
ages had lower ERRs than those exposed at younger ages but the difference was not statisticallysignificant. The ERRs were 9.1, 7.0 and 3.4 Gy-1 for those exposed at ages 0–4, 5–9 and 10–18 years,
respectively. This prospective cohort study is subject to less bias than the prior case–control studies
because the estimates of individual dose were based on direct measurements of activity in the thyroid,
potential recall or interviewer bias was avoided, and uniform screening of all study subjects across thedose range was undertaken.
B96.
Screening for thyroid cancer in this cohort has continued. After four screenings at
approximately two–three year intervals, 65 additional incident thyroid cancers were detected—61
papillary, three follicular and one medullary [B60]. This gave an ERR of 1.9 (95% CI: 0.4, 6.3) Gy-1 forincident thyroid cancers with an approximately linear dose response, and an EAR of 2.2 (95% CI: 0.04,
5.8) (104 PY Gy)–1. The risk estimates are somewhat lower than, but statistically compatible with, thosefound for external radiation exposure of children. A non-significant age-at-exposure effect wasobserved, with ERRs of 7.4, 1.6 and 0.7 Gy-1 for exposures at ages of 0–4, 5–9, and 10–18 years,
respectively.
B97.
A fixed cohort of nearly 12,000 Belarusians who were exposed at ages 0–18 years toradioiodine from the Chernobyl accident has been followed up with systematic screening for thyroid
disease [Z1]. Measurements of 131I in the thyroid of members of the cohort had been made shortly after
the accident; a questionnaire was used to obtain additional dosimetric information. Estimated thyroid
doses ranged from nearly 0 to 33 Gy with a mean dose of 0.56 Gy; since the dose response seemed toflatten out at higher doses, the primary risk estimates were based on the dose range 0–5 Gy. The
estimated excess odds ratio was 3.2 (95% CI: 2.1, 73) Gy-1 based on the thyroid cancers previously
diagnosed (n = 48) and those found through screening (n = 85). No age-at-exposure differences were
found over the range 0–18 years.
B98.
The role of iodine deficiency, iodine prophylaxis (iodine prophylaxis was used following theaccident and also as a public health measure because goitre was endemic in the area) and screening bias
remain possible confounding issues in risk estimation [R41]. Shakhtarin et al. [S48] and Cardis et al.
[C3] have indicated that the ERR at 1 Gy was two- to threefold higher in areas of severe iodine
deficiency. Ultrasound and physical screening of the general population appear to have had minimal
impact on the studies of the general population. During the period 1996–2000, screening found only
15% of the thyroid cancer cases in the most contaminated regions of Ukraine. In Gomel, Belarus, thepercentage found by screening seems to be greater, at least early on. Specifically, Astakhova et al.
[A27] found appreciably higher odds ratios with general-population controls than with screeningmatched controls (OR of 10.4 versus 7.4, respectively, for rural study subjects, and 5.1 versus 1.5,
respectively, for urban subjects).
B99.
The risk in children under the age of 10 has been reported by Heidenreich et al. [H37] to beabout three times higher than in older children. A recent analysis of over 1,000 thyroid cancer cases in
the regions contaminated by 131I from the Chernobyl accident found that the risk was three to six times
higher for those exposed at age five than for those exposed at age 15, with the ratio depending on thestatistical model that was used [W12].

100

UNSCEAR 2013 REPORT

E. Summary
B100. Excess thyroid cancer risk has been seen following childhood exposures to the atomic
bombings, Chernobyl fallout, and radiotherapy. The excess risk in children compared to that in adults is
not possible to quantify since those exposed as adults appear to have little or no subsequent risk ofradiation-induced thyroid cancer. The ERR for those irradiated in childhood derived from the major
studies of external irradiation ranges from about 3 to 20 Gy-1. A pooled analysis indicates a risk ofabout 7.7 Gy-1; with a statistical adjustment to the one study that seemed to be an outlier, the pooledrisk was reduced to 3.8 Gy-1. There is no clear evidence from the studies of medical irradiation as towhether dose fractionation or a low dose rate is associated with a lower risk per unit dose than the same
dose given acutely. However, the data from the populations exposed as a consequence of the Chernobyl
accident generally show that exposure to radioiodine (mostly 131I ) carries risks similar to those fromexternal, acute exposures. The studies from which risk estimates for thyroid cancer following childhood
exposure can be derived have been summarized by the UNSCEAR 2006 Report [U12] and are updated
for this report (see table B7).
Table B7. Age differences and risk estimates for thyroid cancer incidence and mortality from studies
of childhood radiation exposure in the LSS for an exposed group including survivors with organ
doses of 0.005 Sv (weighted thyroid dose) or more for incidence or mortality
Extracted from UNSCEAR 2006 Report (annex A, table 40) [U12] with updated and added studies. Studies listed are those forwhich quantitative estimates of risk could be madeStudy

Average ERR a at 1 Sv

Average EAR a(104 PY Sv)-1

Incidence
LSS [P52]
Age at exposure<20 years

3.93 (2.57, 5.81)

3.07 (2.14, 4.14)

20–40 years

0.99 (0.34, 1.93)

1.46 (0.49, 2.69)>40 years

0.29 (<0, 0.95)

0.86 (<0, 2.84)

1.59 (1.10, 2.19)

2.30 (1.67, 3.02)<20 years

1.36 (0.59, 2.7)

3.0 (1.4, 5.0)

≥20 years

0.27 (<0, 1.07)

All
LSS [F29]

j

Age at exposure

TB, adenitis screening[H23, S65]
<20 years

36.5 (16, 72) b

7.7 (3.3, 15) b>20 years

1.2 (0.1, 3.7) b

0.7 (0.1, 2.4) b

20 (12, 32) b

9.9 (5.7, 15) b

New York tinea capitis [S65, S71]

−0.67 (-29.96, 86.41) b, j

1.5 (0, 9.4) b

Rochester thymic irradiation [A7] e

3.2 (1.5, 6.6) b

2.2 (1.4, 3.2) b

Childhood cancer [R43, T49] f

4.5 (3.1, 6.4) bk
1.1 (0.4, 29)

0.4 (0.2, 0.5) b

Stockholm skin haemangioma [L40]4.9 (1.3, 10) j

0.9 (0.2, 1.9) j

Gothenburg skin haemangioma [L26]

7.5 (0.4, 18.1) j

1.6 (0.09, 3.9) j

Age at exposure

Israeli tinea capitis [S7] c

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

Average ERR a at 1 Sv

Average EAR a(104 PY Sv)-1

Lymphoid hyperplasia screening[P40, S65] e, g

5.9 (1.8, 12) b

9.1 (2.7, 18) b

Thymus adenitis screening [M11, S65]

4.5 (2.7, 7.0) b

1.2 (0.7, 1.8) b

Study

Michael Reese, tonsils [S33] h<1 year

3.6

1–4 years

2.8

5–15 years

1.4

All

3.0 (2.6, 3.5) b

37.6 (32, 43) b

Tonsils/thymus/acne screening[D32, S65]

12.0 (6.6, 20) b

3.5 (2.0, 5.9) b

Pooled external-irradiation study

7.7 (2.1, 28.7) j(all studies)4.4 (1.9, 10.1) j

LSS
Israeli tinea capitis
Rochester thymic irradiation
Lymphoid hyperplasia screening
Michael Reese, tonsil [R43]

3.8 (1.4, 10.7) l(excluding Israeli study)

Pooled childhood-cancer radiotherapy
studies [V15]2.2 (1.2, 4.3) j

1.3 (0.9, 1.8)

Russian Federation–Belarus Chernobyl
case–control study [C3]4.9 (2.2, 7.5) nn.a.

Ukraine–Belarus Chernobyl cohort study [J5]18.9 (11.1, 26.7) i

2.66 (2.19, 3.13) i

Ukraine cohort study [B60, T39]
Age at exposure
0–4 years nn.a.
9.1 (1.3, 85)
7.4 (<1.7, n.a.)

5–9 years(5–11 years)

7.0 (1.8, 33)
1.6 (<0, 8.5)

n.a.

10–18 years(12–18 years)

3.4 (0.7, 20)
0.7 (<0, 6.3)

n.a.

5.3 (1.7, 28)
1.9 (0.4, 6.3)

n.a.
2.2 (0.04, 5.8)

Belarus cohort study [Z1] d
Age at exposure
0–4 years

4.0 (1.0, 15)

n.a.

5–11 years

2.0 (0.4, 6.2)

n.a.

12–18 years

1.4 (n.a., 5.0)

n.a.

2.2 (0.8, 5.5)

n.a.

Utah fallout study [K27, L44]m

0.8 (0, n.a.)n.a.

United States fallout study [G11]2.4 (−0.5, 5.6)

n.a.

Hanford fallout study [D17]0.7 (<0, >500)

n.a.

All

All

101

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UNSCEAR 2013 REPORT

Study

Average ERR a at 1 Sv

Average EAR a(104 PY Sv)-1

Mortality
LSS [P50]
Age at exposure<20 years

1.67 (<0, 7.67)<0 (<0, 12.88)

20–40 years<0 (<0, 0.87)<0 (<0, 0.23)>40 years<0 (<0, <0)<0 (<0, 0.01)<0 (<0, 0.42)<0 (<0, 43.97)

Alla

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies
unless otherwise stated.

b

Estimates based on UNSCEAR 2000 Report (annex I) [U10].

c

Doses to the thyroid in this study may be much more uncertain than doses to organs directly in the X-ray beam.

dThyroid cancers detected at screening.

e

Known dose. Person-years and expected number of cases estimated from data given in reference [S65].

f

Based on cohort members with 15 or more years of follow-up and population-expected rates.

gThis was a study of nodular disease, and cancer cases were not confirmed.

hStudy includes no unexposed controls; estimates of the number of expected cases were computed using the fitted ERR reported
by Schneider et al. [S33]. The large EAR in this study illustrates the impact of screening on thyroid cancer risk estimates. A
special thyroid screening programme in this cohort was initiated in 1974 which led to a large increase in the number of cancer
cases detected among both cases and controls.

iLinear coefficient of linear-quadratic model fit, 95% CI.

j

95% CI in parentheses.

k

The publication gave an ERR estimate of 4.5, while the pooled analysis by Ron et al. [R43] produced an estimate of 1.1.

l

The value of 3.8 is based on a model that allowed for a non-zero intercept in the Israeli tinea capitis exposed group, i.e. an
overall difference between the exposed and non-exposed groups, perhaps because of a surveillance effect.

m

Based on only 8 thyroid cancer cases.

nFitted using linear-quadratic model for odds ratio over full dose range, 95% CI.

V. BREAST CANCER
B101. Breast cancer accounts for 32% of all malignancies in women but less than 0.2% in men. It is
the third most common cancer in the world and represents 9% of the global cancer burden. It is themost common cancer in females. Data concerning risk factors for breast cancer following radiation
exposure come primarily from three major population groups. These groups have been extensively
studied and include the survivors of the atomic bombings, patients who have had exposure to diagnostic
radiology, and persons who have had radiotherapy to the breast. Epidemiological studies of radiationinduced breast cancer are of special interest with regard to the effects of dose rate upon the process ofradiation carcinogenesis and age-at-exposure differences. The majority of studies indicate that breast
cancer may be induced with a reasonably high frequency after radiation exposure of women who areunder the age of 40 at exposure. Preston et al. [P48] have analysed the pooled dose–response data onradiation and breast cancer risk from eight studies, taking into account the age at exposure. The authors
indicated that they thought the best statistical fit to the available data was a dose–response curve of
approximate linearity. Although there may be a small element of curvilinearity, with the available data,
it appears that risk estimates based on linearity of the dose–response curve are not likely to be far
wrong.

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103

A. Modifying factors
B102. In general, the results of population studies have provided only suggestions about a number offactors that modify radiation risk. Those that might increase radiation risk are irradiation at the time of
menarche [B36] or the time of the first pregnancy [B36, S61]; nulliparity [B36, B65], obesity [V10];
family history of breast cancer [B36, R50]; and history of benign breast disease [S61]. Those that might
result in decreased radiation risk are early age at first full-term pregnancy; several childbirths; andbreast feeding [L3]. However, the results should be interpreted cautiously since most of the findings
regarding factors that modify radiation risk are marginal and the results of attempts to replicate themodifying effects in multiple studies have been inconsistent [H49]. Low statistical power of the studies
may have contributed to the inconsistency. Genetic factors may modify radiation risk. There is asuggestion that carriers of ATM gene mutations may be at heightened radiation risk for breast cancer[B16] while the data regarding BRCA1/BRCA2 mutations and radiation exposure are mixed [B17, B64].
B103. Time after exposure may have a weak effect on the expression of risk. Earlier data suggested
that the relative risk may increase for 15 years after exposure and then decrease [S56], but more recent
incidence data from the study of the survivors of the atomic bombings indicated no significant
modification of the relative risk with time since exposure (p = 0.13) [T23]. The effect of time since
exposure was not examined in the most recent update on breast cancer incidence [P52]. Two strong
modifying factors observed repeatedly are age at exposure and age at risk (attained age). A pooled
analysis of eight studies found that a model using both age at exposure and age at risk fit the data better
than one using age at exposure and time since exposure [P48].

B. External exposure
B104. In many studies of breast cancer, risk decreases markedly with increasing age at exposure. In
fact, the studies of patients receiving multiple fluoroscopies in Massachusetts and Canada showed little
if any detectable risk in women exposed over the age of 40 [B38, H67]. Studies of the survivors of theatomic bombings showed only a low risk after exposure above this age [L5, P52].
B105. In a pooled analysis of the data from eight studies using a smoothed model, the estimated
ERRs at 1 Gy for those exposed at ages 5, 25 and 45 years were 1.10, 0.86 and 0.65, respectively [P48](table B8). The corresponding EARs were 19.0, 13.4 and 8.8 per 10,000 person-years per gray,respectively. However, those analyses were based on a compilation of studies of subjects with disparate
limited ages at exposure and with special medical conditions that might modify the risk, so the results
may not be comparable across the age range.

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Table B8. Radiation risk for breast cancer incidence and mortality by age at exposureStudies listed are those for which quantitative estimates of risk could be madeAge-at-exposure group a (years)
Study and type of risk metric
Youngest

Intermediate

Older/Oldest

Oldest8-study pooled data [P48] —incidence, ERR b,c

Age 5
1.10

Age 25
0.86

Age 450.65

8-study pooled data [P48] —incidence, EAR b,e

Age 5
19.0

Age 25
13.4

Age 45
8.8

A-bomb incidence, ERR [P48] b,c

Age 5
2.6

Age 25
1.8

Age 45
1.1

A-bomb incidence, EAR [P48] b,e

Age 5
21.1

Age 25
11.6

Age 45
4.9

A-bomb mortality, ERR [P50] b

Age 5
2.1

Age 15
1.4

Age 300.79 (90% CI: 0.29, 1.5)

Age 450.4

A-bomb mortality, EAR [P50] b

Age 5
4.7

Age 15
3.1

Age 301.6 (90% CI: 1.2, 2.2)

Age 450.7

A-bomb mortality, ERR [O25] b

Age 5
2.3

Age 15
1.6

Age 300.9 (95% CI: 0.3,1.8)

Age 450.4

A-bomb mortality, EAR [O25] b

Age 5
6.4

Age 15
4.3

Age 302.3 (95% CI: 1.0,3.8)

Age 450.8

A-bomb incidence, ERR(as reported in) [U12]Age <20
1.89 (0.38, 2.50)

20–40
1.31 (0.86, 1.87)>40
0.62 (0.04, 1.51)

A-bomb mortality, ERR(as reported in) [U12]Age <20
2.94 (1.63, 4.86)

20–40
1.01 (0.31, 2.06)>40<0 (<0, 0.99)

A-bomb incidence, EAR(as reported in) [U12]Age <20
8.78 (6.54, 11.28)

Age 20–40
6.97 (4.71, 9.54)

Age >40
2.49 (0.02, 5.82)

BEIR VII — incidence, EAR [N43] b,c

Age 5
32.8

Age 15
19.9

Age 309.4

Age 45
4.4

Canada multiple fluoroscopy andA-bomb — mortality, ERR [H67] b

Age 5
1.5

Age 15
0.5

Age 300.11

Age 450.02

Canada multiple fluoroscopy andA-bomb — mortality, EAR [H67] b,d

Age 5
4.7

Age 15
2.6

Age 30
1.0

Age 450.3

Massachusetts multiple
fluoroscopy—incidence, ERR [B38]

Age 0–14
1.76

Age 15–19
0.90

Age 30–39
0.16

Age ≥40
0.06

Rochester thymus irradiation —incidence, ERR [A6]

Infancy
1.10 (0.61, 1.86)

Skin haemangioma irradiation —incidence, ERR [E10]

Early childhood
0.25 (0.14, 0.37)

Hodgkin’s disease — incidence,
relative risk, RT (not per Gy) [H20]

Ages <20
33 (12, 73)

Ages 20–29
11 (6.4, 18)

Ages ≥30
0.7 (0.1, 1.9)

Hodgkin’s disease — incidence,
SIR (not per Gy or limited to RT)[V10, V9]

Ages ≤20
17 (8, 32)

Ages 21–30
5.6 (2.9, 9.8)

Ages 31–39
2.4 (0.9, 5.2)

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105

Age-at-exposure group a (years)
Study and type of risk metric
Youngest

Intermediate

Older/Oldest

OldestAges >40
1.2 (1.0, 1.5)

Hodgkin’s disease —incidence,
SIR (not per Gy) [B25]

Ages 0–15
56 (40, 76)

Hodgkin’s disease—incidence, SIR(not per Gy or limited to RT) [M32]

Ages ≤16
22 (13, 34)

Ages 17–20
12 (8, 17)

Hodgkin’s disease—incidence, SIR(not per Gy or limited to RT) [D43]

Ages ≤20
14.2 (11, 19)

Ages 21–30
3.7 (2.9, 4.7)

Ages 31–40
1.2 (0.8, 1.7)

Hodgkin’s disease — incidence,
SIR, RT (not per Gy) [S118]

Age <25
14 (6, 29)

Age 25–44
1.6 (0.5, 3.7)

Age ≥45
1.5 (0.4, 3.8)

Hodgkin’s disease — incidence,
odds ratio, RT (not per Gy) [T35]Age 13–17
4.2 (1.1, 22)

Age 18–21
2.1 (0.7, 8.3)

Age 22–25
2.0 (0.3, 17)

Age 26–30
2.9 (1.0, 11)aNumbers in parentheses represent 95% confidence intervals, unless designated otherwise.

b

Estimates derived from the smoothed statistical model for age at exposure given in the publication, not estimates calculated foreach individual age-specific data point.

c

ERR at 1 Gy.

d

EAR per 10,000 person-years per gray.

e

Estimated as of attained age 60.

1.

Atomic bombing survivors

B106. Wanebo et al. [W13] identified a statistically significant excess of breast carcinoma amongfemales in Hiroshima and Nagasaki in 1968. A number of updates permitting a better assessment of themagnitude and time course of risk have been published since then [J1, L5, T30, T28, T29, W5]. In an
analysis of the survivors, who had a large range of ages and were unselected for medical conditions, theERRs were 2.6, 1.8 and 1.1 after exposure at ages 5, 25 and 45 years, respectively, and thecorresponding EARs were 21.1, 11.6 and 4.9 (104 PY Gy)-1 at 1 Gy [P48]. In summary, the risks in thesurvivors of the atomic bombings obtained from these data were 2.5–4 times greater after exposure atfive years of age 5 than after exposure at over 45.
B107. Land et al. [L5] performed a careful analysis of age-at-exposure effects on female breast
cancer risk. They found that the ERR at 1 Sv was greater for exposures before age 20 than that afterage 20. They did not find a significant variation in risk within the age-at-exposure range 0–19 years,
although there was some indication that risk might be higher after exposure in early childhood (seefigure B-VII). McDougall et al. [M17] also found similar risk estimates for those irradiated in earlychildhood and around the time of puberty.
B108. In the most recent examination of updated breast cancer incidence data, Preston et al. [P52]found that the ERR was comparable for all ages at exposure once attained age (age at risk) was
included in the model (figure B-VIII). But without an adjustment for attained age, the ERR was -19%
(90% CI: -33, -4) per decade of age at exposure. The EAR was appreciably higher for those exposed inchildhood than for those exposed later in life at any given attained age (figure B-VIII).
B109. A number of reports have indicated that radiation exposure during early childhood may resultin breast cancer in very young women [I32]. Land et al. [L2] evaluated this possibility in some detail.
Among the survivors of the atomic bombings who were exposed at ages 0–19 years, they found that the
ERR at 1 Gy was very high before the age of 35, being 13.5 (95% CI: 4.4, 64), compared to a twofold
ERR at 1 Gy for cancers occurring after age 35 [L2] (figure B-IX). A more recent analysis of updated

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data on the survivors of the atomic bombings showed that, even after allowing for an overall age-atexposure effect, the ERR at 1 Gy was still 4.5 times greater before the exposed persons attained age 35
than that after that age. The EAR was 3.5 times greater than expected before age 35 [P52]. That excess
is largely attributable to those exposed before age 20.
Figure B-VII. Estimated excess relative risk at 1 Sv for breast cancer incidence, by 5-year intervals ofages at exposure
Adapted from [L5]. The panel shows a non-parametric isotonic regression model with 90% confidence limits

Figure B-VIII. Variation in radiation-associated excess breast cancer risk by age at exposure andattained age for an effect-modification model
Adapted from [P52]. In this model the excess risks are proportional to a log linear function of age-at-exposure and a power ofattained age

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

107

Figure B-IX. Heightened breast cancer risk at young ages
Adapted from [T30]. Modelled ERR per sievert by intervals of attained age. Estimates and 90% confidence limits were
adjusted for city, age at exposure and time period. The corresponding total number of cases appears above the upper
confidence limit for each interval of attained age

B110. A high risk of radiation-induced breast cancer from exposure at an early age was also found by
van Leeuwen et al. [V9] in a study of survivors of Hodgkin’s disease. For those exposed before age 20,
they reported a relative risk of 61 (95% CI: 25, 127) for breast cancer occurring before age 40, but only
5.4 (95% CI: 0.7, 20) for breast cancer at ages 40–49. For those exposed after age 20, no differential
was seen for the attained ages of less than 40 compared to those of more than 40.
B111. The Committee independently analysed breast cancer incidence and mortality by age at
exposure [U12]. For breast cancer incidence, they derived an ERR at 1 Sv for exposure at ages <20,
20-40 and >40 years of 1.89 (95% CI: 1.4, 2.5), 1.31 (0.9, 1.9) and 0.62 (0.04, 1.5), respectively, while
for breast cancer mortality, the respective risk estimates were 2.94 (1.6, 4.9), 1.01 (0.3, 2.1) and <0 (<0,1.0). The EARs for the incidence of breast cancer were 8.78 (6.5, 11.3), 6.97 (4.7, 9.5) and 2.49 (0.02,
5.8) (104 PY Gy)-1. Thus a higher risk of breast cancer was evident from exposure at young ages.
B112. The BEIR VII committee adapted the risk estimates from the pooled analysis of [P48] using an
EAR model because that was considered to be better than the ERR model for the transfer of risk fromthe Japanese to the United States population [N43]. Their best-fitting model took into account both age
at exposure and attained age (age at risk). For an attained age of 60 years, the EAR per 10,000 personyears per gray ranged from 32 to 4 for exposures at ages 5 to 45, respectively (table B8) [N43].

2.

Background radiation, fallout and populations living near nuclear plants

B113. There are conflicting reports regarding breast cancer risk after the Chernobyl accident. One
study reported excess risks among females in the exposed areas of Belarus (RR = 2.2; 95% CI: 1.5,3.3), and Ukraine (RR = 1.8; 95% CI: 1.1, 2.9) with some indication that the risk may have been higher
among those exposed when young (but this was not formally tested) [P62]. Another study reported an
excess incidence of breast cancer among female Chernobyl clean-up workers, but not among Chernobyl
evacuees or residents of contaminated areas [P60]. A third study reported no radiation-associated108

UNSCEAR 2013 REPORT

excess of breast cancer in a highly exposed oblast in Belarus compared to a minimally exposed oblast[D10].
B114. Bauer et al. [B7] reported a significant dose–response trend (p = 0.004) for breast cancer
mortality in the female population downwind of the Semipalatinsk atomic bomb testing site in
Kazakhstan, with a relative risk in the exposed group, compared to the unexposed, of 1.85 (95% CI:
1.1, 3.2). However, effect modification by age at exposure was not examined. A study of residents near
the Techa River in the Russian Federation showed a dose-dependent elevated risk for breast cancer[O18]. Because of a relatively small number of breast cancers (n = 109) and the relatively low
distribution of breast doses, radiation modifying effects of various other factors were not statisticallysignificant, but they noted that women who were under age 10 at first exposure appeared to have thehighest excess breast cancer risk. Other studies of background radiation [N4, Z5] or radioactive fallout[H28, H29] have not studied breast cancer incidence or mortality.

3.

Diagnostic radiology

B115. In 1965, MacKenzie [M3] reported the occurrence of excess breast cancer incidence amongfemale patients exposed to multiple fluoroscopic examinations for treatment of pulmonary tuberculosis
by artificial pneumothorax. The patients studied were treated in a Nova Scotia sanatorium. The dose to
the breast was generally higher than that to the rest of the body because the patients receiving
fluoroscopy were turned to face the radiation source. When the pneumothorax treatment was unilateral,the cancer usually developed on the side that received the majority of the radiation exposure from thetreatment [M62]. An additional follow-up of this group was reported somewhat later by Myrden and
Quinlan [M61]. There were 256 patients exposed during pneumothorax treatment, 32 of whomdeveloped breast cancer. The control group comprised 535 patients with pulmonary tuberculosis who
had not been treated with pneumothorax. Seven members of the control group developed breast cancer.
The doses were estimated to be between 0.04 and 0.20 Gy for each examination, and the numbers offluoroscopic examinations often exceeded 100. The average dose to the breast was estimated to be
between 6 and 12 Gy. The Committee has previously estimated the excess cancer incidence rate to be
between 20 and 200 cases per million persons per 10 mGy [U6].
B116. In a large study of about 30,000 Canadian patients, Miller et al. [M39] reported similarfindings, but they indicated that when the females were between 10 and 14 years of age at exposure, theERR was 3.5 Sv-1 and the absolute risk was 6.1 (104 PY Sv)–1. The radiation effect appeared to peak
between 25 and 34 years after exposure. Of interest was that patients treated in Nova Scotia (where thewomen faced the radiation beam) had a three times higher relative risk per unit dose than women
treated in other provinces. One of the major problems associated with these studies is the exact
determination of the fluoroscopic dose, and also the effect of disease and nutritional status on thepatients.
B117. The most recent report on the Canadian multiple fluoroscopic examination study, based on themortality experience from 1950 to 1987, included 103 breast cancer deaths in the Nova Scotia series
and 578 in other provinces [H67]. The doses to the breast ranged from less than 0.01 Gy to greater than
10 Gy. The dose–response analyses were conducted in parallel with the data from the survivors of theatomic bombings for the purpose of comparison. The authors reported a statistically significantly higher
radiation risk for those exposed before the age of 10 than after that age in the fluoroscopy study. Their
model, treating age at exposure as a continuous variable (using the year of age (e.g. 5, 6, 7, 8) rather
than age bands) showed estimates of excess relative risk at 1 Gy of 1.5, 0.5, 0.11 and 0.02 after
exposure at ages 5, 15, 30 and 45, respectively, based on the combined data for the Canadian multiple-

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

109

fluoroscopy and atomic-bombing survivor cohorts. The excess relative risk estimates for the
fluoroscopy series (with combined fluoroscopy and atomic-bombing survivor cohort estimates inparentheses) were 1.25 (1.41), 0.17 (1.44), 0.37 (0.44), 0.22 (0.24), 0.04 (0.05) and <0.0 (<0.0) for
specific age bands of exposure of 0–9, 10–14, 15–19, 20–29, 30–39 and >=40, respectively.
B118. Boice et al. developed a cohort of former female patients at Massachusetts tuberculosis
sanatoria where some had been treated with pneumothorax that entailed multiple fluoroscopic
examinations to monitor the condition of the lung. Over successive reports, the irradiated cohort wasincreased from about 1,047 to 2,573 patients in the most recent report [B38, D14, H68]; the control
group comprised 2,367 patients without any fluoroscopic examinations. The patients withpneumothorax had an average of 88 fluoroscopic examinations with an estimated mean cumulative
dose to the breast of 790 mGy [B38]. The groups were followed up for an average of 30 years after
their exposure had ended. There were 147 breast cancers cases in the irradiated group, an excess of 33,
a small deficit was seen in the unexposed group. The overall ERR at 1 Gy was 0.61 (95% CI: 0.30,
1.01) and the EAR was 10.7 (95% CI: 6.0, 15.8) (104 PY Gy)-1. The values of ERR at 1 Gy ranged from1.76 and 0.90 when first treated at ages 0–14 or 15–19 years, respectively, to 0.16 and 0.06 whentreated at ages 30–39 or >39 years, respectively. The inverse age-at-exposure trend was statisticallysignificant (p = 0.03).
B119. Ronckers et al. examined breast cancer incidence among 3,010 women who received multiple
radiological examinations at young ages between 1912 and 1965 in the course of treatment for scoliosis[R50]. The dose to the breast per examination was estimated to be 11 mGy on average, and theestimated mean cumulative dose to the breast among those with exposure was 132 mGy (range of
estimated doses of 0 to 1,110 mGy). They received an average of 26.8 radiographs over the mean spanof 6.1 years. Exposures were received mainly between the ages of menarche and first childbirth (orsimilar ages for nulliparous women). A total of 78 women developed invasive breast cancer. The
estimated ERR at 1 Gy was 2.86 (95% CI: -0.07, 8.6; p = 0.06) based on a dose–response analysis. The
authors suggested that this risk, which was nominally higher than that found among the survivors of theatomic bombings, may have occurred because the doses to the breast had been underestimated,
although the relatively young age at exposure may have contributed as well, and the confidence interval
includes a wide range of risk estimates.
B120. A notable feature of both the fluoroscopic-examination studies and the scoliosis study was thelack of diminished risk after highly fractionated exposure compared to that seen after acute, single
exposures (such as those received by the survivors of the atomic bombings), although the confidencebounds on the risk estimates were fairly wide. Parallel analyses of the survivors of the atomic bombings
with both the Canadian [H67] and Massachusetts [L30] fluoroscopy cohorts confirm the comparabilityof the risk associated with highly fractionated and single-acute exposures.

4.

Radiotherapy for benign disease

B121. An increased risk of breast cancer in girls treated for presumed thymic enlargement in infancy
has been reported by Hildreth et al. [H48, H46]. The 1,201 girls treated were compared to their 2,469
non-irradiated siblings. An increased risk was identified even in the group that had received doses of
0.01 to 0.49 Gy. The strengths of this study are that individual dosimetry was available, there was along follow-up, and there was a sibling control group. The study also was able to evaluate the effects ofdose fractionation to a limited degree, and a dose–response analysis could be performed. The
weaknesses are that the size of the treatment fields varied, so the dosimetry for some sites is uncertain
and the questionnaire follow-up may have caused some under-ascertainment of cases. In the most

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recent update of this series, among the 1,120 women irradiated in infancy, there were 96 cases of breast
cancer, while among the 2,382 unexposed women there were 57 cases of breast cancer after a meanfollow-up of 57 years [A6]. The mean dose to the breast was 0.71 Gy (range from 0.02 to 14.4 Gy);
89% received only one or two treatments and 11%, three or more. A variety of risk factors were
examined but none proved to confound the radiation-breast cancer association. The dose–response ERR
for breast cancer was 1.10 (95% CI: 0.61, 1.86) Gy-1, indicating a high breast cancer risk among thosereceiving radiation exposure in early childhood.
B122. Furst et al. [F25] followed up a cohort of children who had been treated for skinhaemangiomas between 1920 and 1959 and reported an excess incidence of breast cancer related
radiation exposure. Holmberg [H60] updated and combined two cohorts that included 17,202 women
who had been irradiated for skin haemangiomas between 1920 and 1965 at a mean age of six months.
The doses to the breast ranged from 0 to 35.8 Gy; 89% of the children had been treated with 226Ra
applicators and 11% with X-rays. There were 307 cases of breast cancers. A linear dose–responsemodel, with adjustment for fertility pattern and menopausal status, showed an ERR at 1 Gy of 0.33
(95% CI: 0.17, 0.53). In the most recent report of this combined cohort, 678 cases of breast cancer wereobserved through 2004 [E10]. They reported mean and median absorbed doses to the breast of 0.29 and0.04 Gy, respectively. At age 50, the ERR was 0.25 Gy-1 (95% CI: 0.14, 0.37) and the EAR was 3.1(95% CI: 1.7, 4.3) (104 BreastY Gy)-1.
B123. In the Rochester study of radiation treatment for acute postpartum mastitis, the treatment
occurred over an age range of approximately 15–40 years [S64]. Within this age range, there was noevident differential in risk by age at exposure, but there were relatively few with exposure before age
18, and the data were complicated by the fact that the breasts were highly stimulated by hormones at
the time of the radiation treatment.

5.

Radiotherapy for malignant disease

B124. A number of studies examining the risk of breast cancer after the treatment of various
childhood malignancies have been performed. The common theme in these reports is the radiation
exposure to developing breast tissues, as can occur after radiation therapy for Hodgkin’s lymphoma,
Wilms’ tumour (when breast tissue is in the abdominal field or the chest is irradiated for pulmonary
metastases), sarcomas, etc. Relevant variables include the radiation dose both to breast tissues and tothe ovaries (the latter relating to oestrogen secretion), pregnancy history, patient age, and genetic
variations relating to the primary (initial) malignancy [H39].
B125. A breast cancer excess has been reported in the British CCSS [R19]. An SIR of 2.2 (95% CI:
1.8, 2.7) was found, but a breakdown was not given specifically for those who received radiotherapy.
The American CCSS also found an excess of breast cancer (SIR of 9.8; 95% CI: 8.4, 11.5) but did notprovide a breakdown by radiotherapy status [F17].
B126. Follow-up studies after treatment for Hodgkin’s lymphoma with mantle radiotherapy haveindicated at least a fourfold increase of breast cancer risk, with doses to the breast varying from 4 to40 Gy, depending upon the technical factors and positioning. Janjan and Zellmer [J12] have indicated adose response that is between a linear and cell killing model. Some authors [D35] believe that theincreased risk in young females receiving treatment justifies routine mammographic screening before
the age of 35. In general, the EAR increases dramatically more than 15 years after therapy. In a study of
885 women treated for Hodgkin’s disease, Hancock et al. [H20] found 25 patients who had developed
breast cancer. The estimated relative risk was 4.1 (95% CI: 2.5, 5.7). The relative risk in women treatedANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

111

under 15 years of age was extremely high, being 33 (95% CI: 12, 73). For women who were over
30 years of age at exposure, there was no elevation of risk, the relative risk was 0.7 (95% CI: 0.1, 1.9).
A United States study by Bhatia et al. [B25] of survivors of Hodgkin’s disease in childhood found an
SIR for breast cancer of 52 (95% CI: 40, 76). A Dutch cohort study by van Leeuwen et al. [V9];reported an SIR of 17 (95% CI: 8, 32) for paediatric cases but this was reduced to 2.4 (95% CI: 0.9, 5.2)
for women treated after the age of 30. This study is also of interest because it suggests that known
protective factors for breast cancer (e.g. multiple births) also reduce the risk of radiation-induced breast
cancer to the same degree as those that are not treated with radiation.
B127. A pooled study of European and United States survivors of Hodgkin’s disease in childhood by
Metayer et al. [M32] found SIRs of 22 for women treated prior to age 17, and 12 for those treated atages 17–20. An enlarged pooled study over a broad range of ages by Dores et al. [D43] included 13,877
female patients who had had Hodgkin’s disease with about 35% having ≥10 years of follow-up and 234
subsequent breast cancers. Those treated before age 21 had a large relative risk (SIR = 14.2; 95% CI:
10.7, 18.5) of subsequent breast cancer, while there was little risk for those treated at ages 31–50 (SIR =1.4; CI: 1.1, 1.8) and none when treated after age 50 (SIR = 1.05; CI: 0.8, 1.4).
B128. The volume of tissue irradiated and dose are primary determinants in the occurrence of breast
cancer. Mantle (chest) radiotherapy for Hodgkin’s lymphoma is associated with an odds radio of 2.7(CI: 1.1, 6.9) compared with similarly dosed mediastinal irradiation since the former includes the axilla
wherein lies additional breast tissues. However, emerging data indicate that females treated with lowdose, involved-field radiation (i.e. lower radiation doses and fields that do not necessarily include
axillary tissues) still exhibit excess breast cancer risk [O1]. As previously stated, for female patientstreated with radiation exposure to the chest for Hodgkin’s lymphoma before age 16 years, thecumulative incidence of breast cancer approached 20% by age 45 years [B25]. In a case–control study
conducted as part of the CCSS that included 6,647 women who were five-year survivors of childhood
cancer (all initial cancer types included), 120 patients (65% of whom were initially diagnosed with
Hodgkin’s lymphoma) were identified with breast cancer. The patients were matched with 464 sibling
control patients. The odds ratio for breast cancer increased linearly with radiation dose, reaching astatistically significant value of 7.1 for doses of 11.4–29.9 Gy and 10.8 for doses of 30–60 Gy relative
to no radiation exposure. The risk associated with breast irradiation was sharply reduced among women
who received a dose of 5 Gy or more to the ovaries, with an excess odds ratio of 0.36 Gy-1 for those
who received ovarian doses of less than 5 Gy and 0.06 for those who received higher doses. In this andother studies, the latency period after chest radiation ranged from 8 to 10 years, and the risk ofsubsequent breast cancer increases in a linear fashion with radiation dose (p for trend <0.001) [I40].
B129. Radiation-induced breast cancer has been reported to have more adverse clinicopathologicalfeatures compared with breast cancer in age-matched population controls [D44]. The incidence ofbilateral breast cancer seems to be increased in women treated with radiation exposure of the chest for
paediatric or young adult cancer. From the large CCSS cohort, Kenney et al. [K25] reported bilateraldisease in 17% of breast cancer cases: 5% were synchronous and 12% were metachronous. Other
studies specific to Hodgkin’s lymphoma also provide information about bilateral cancer [C59]. Of 219
women with breast cancer, 12.8% had bilateral disease (5.5% were synchronous and 7.3% weremetachronous). In contrast, in population-based studies of the general population, 3–5% of women had
bilateral disease; 1–3% were synchronous and 1–4% were metachronous. However, the population atrisk for breast cancer after radiation exposure of the chest is still relatively young, so the percentage ofcases with metachronous disease will probably increase over time.

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6.

Radiation and male breast cancer

B130. Male breast cancer following radiotherapy for benign conditions has occasionally beenreported as individual cases [L33, O15], but most cohorts that have been exposed to radiation have had
too few cases for analytical studies to be conducted. In the study of the Japanese survivors of the atomic
bombings, nine male breast cancer cases were observed among the exposed persons and three among
the unexposed, making a relative rate of 3.6 [R46]. A dose–response analysis showed an ERR of eight(95% CI: 0.8, 48) Gy-1. The risk was about twice as high among those exposed before age 15 comparedto those exposed after that age, but the small numbers precluded a formal statistical analysis. Thomas etal. [T18] suggested that male breast cancer could be increased by radiation exposure of the chest.
However, this study had significant limitations since “exposure” was determined by personal interview
after the breast cancer had occurred, and such studies may be subject to significant recall bias. In
addition, given the very low dose distribution from X-ray exposure of the chest, a detectable radiation
risk is not plausible with a sample size of less than 300 cases.

C. Internal exposure
B131. In a study of mortality among about 28,000 female patients treated for hyperthyroidism,
mainly in the United States of America, only 3% were under age 20 at the time of treatment [R44].
Among those treated with 131I, 248 breast cancer deaths were observed; the SMR was 1.10 (95% CI:
0.97, 1.2). There was a slight (non-significant) suggestion of a dose response in relation to the activityof the administered 131I. In a similar study in Sweden [H6], 94 breast cancers deaths were observed—
the SMR was 0.9 (95% CI: 0.7, 1.1)—among about 8,700 women treated with 131I for hyperthyroidism.
However, relatively few were under age 40 at treatment.
B132. A study of 5,260 Swedish, French and Italian female thyroid cancer patients, nearly half ofwhom had been treated with 131I, some with additional external beam radiotherapy, found a suggestionof an increase in breast cancer incidence in the group exposed to 131I ; the SIR was 1.2 (95% CI: 0.9,
1.6; 54 cases) [R62]. However, there was no trend of increasing breast cancer risk with theadministered quantity of 131I, either for those who also received external radiotherapy or for those who
did not. There was a suggestion of an increase in breast cancer risk among those exposed before age 20(five cases of breast cancer in 344 patients), but the fraction of those with 131I treatment was notreported and the number was too small for analysis. Other studies [D27, E8, G13, H5] of patientstreated with 131I for thyroid cancer had only small numbers of breast cancer cases.

D. Summary
B133. Female breast cancer can be induced by radiation. The difference in risk from exposure inchildhood compared to that in adulthood depends upon the model used to analyse the data. Much of the
published data indicate that age at exposure is an important factor in determining the risk of radiationinduced breast cancer. A number of studies attest that the highest risk occurs when age at exposure isless than about 18 years. The increased risk in those exposed as children compared to adults appears to
be a factor of about three to five. At ages over 40 at exposure, the risk appears to be minimal or too
small to be detectable in most low-dose studies. The minimum latent period may depend upon the age
at exposure, with longer latent periods in the groups exposed at younger ages, although the findings of

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the studies of the survivors of the atomic bombings in Japan [L2] and Hodgkin’s disease in the
Netherlands [V9] of a high risk at young ages (before age 35 or 40) suggests that there might be asusceptible subpopulation prone to early breast cancer risk. However, consistent findings from anumber of studies suggest that after the minimum latent period, the risk of radiation-induced breast
cancer persists for the remaining lifetime, much as it appears for other solid cancers [P52].
B134. Most data support a linear dose–incidence model for doses to the breast of up to about 3 Gy.
At higher doses, the risk may reach a plateau and then decrease. Many studies of groups exposed todoses less than 0.2 Gy do not show an increased risk, which may reflect inadequate statistical power.
There are a number of potential confounding variables that should be considered in an analysis of data,
especially length of follow-up and ages at follow-up, and sometimes potential for cell killing. There issome evidence that radiation may act additively with regard to the different baseline incidence rates for
the Japanese and western population. The limited data regarding modification of the radiation effect byreproductive and other breast cancer risk factors have tended to be inconsistent and do not suggest any
major radiation-risk modification. The literature on genetic radiation-risk modifiers has mixed results
and often methodological limitations.
B135. Risk estimates for population exposure have been summarized in detail by the Committee inthe UNSCEAR 2008 Report [U12]. Although it is generally felt that the risks at low doses and dose
rates are a factor of 1.5 to 2 lower than those observed at high acute doses, two sets of directcomparisons of single and highly-fractionated exposures have suggested there is little, if any,justification for such a reduction regarding breast cancer. Radiation risk factors for breast cancer havebeen summarized in the UNSCEAR 2006 Report [U12]. Variations in radiation-associated risk withregard to age at exposure are summarized in table B8.

VI. STOMACH CANCER
B136. In 1980, stomach cancer was considered to be the single most common form of cancer in theworld, accounting for about 10–11% of all new cases [I5]. The highest incidence areas are Japan,
Korea, and parts of China. Diet probably has an impact on the incidence of stomach cancer, with higher
nitrate, nitrosamines, and salt intake associated with higher risk. Persons with blood type A and those
who have had gastric surgery have also been shown to be at increased risk in some studies [H45].
Ninety-five per cent of malignant stomach tumours are adenocarcinomas. The most common sites are
the lesser curvature and antral portions of the stomach. A report on the atomic bombing survivors by Ito
et al. [I41] has suggested that the frequency of poorly differentiated adenocarcinoma was somewhat
higher in the group exposed to more than 0.01 Gy than in a no-exposure group.

A. External exposure
1.

Atomic bombing survivors

B137. The 1994 LSS incidence study of the atomic bombing survivors, which included 40,759
persons with >=10 mGy and 39,213 controls with <10 mGy, found a statistically significant increase

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for cancer of the stomach [T24]. During 1958–1987, 1,307 cancers were observed versus 1,222
expected (an excess of 85 cases) in 792,500 person years of observation for those who received 0.01 Sv
or more. A linear dose response fitted the data. The ERR at 1 Sv was estimated to be 0.32 (95% CI:
0.16, 0.50), and the EAR was 4.8 (104 PY Sv)–1. They reported that the ERR estimate decreased withincreasing age at exposure (p = 0.03), with ERR Sv-1 estimates of 0.65, 0.69, 0.43 and 0.12 for those
exposed at ages 0–9, 10–19, 20–39 and >=40, respectively. The ERR at 1 Sv was 0.18 for males of allages and 0.51 for females [T24].
B138. The LSS mortality study data for the period from 1958 to 1987 [P33] also demonstrated astatistically significant increase in cancer of the stomach. Compared with the 1,107 expected (an excess
of 56), 1,163 stomach cancer deaths were observed in 1,203,100 person years of observation for the
41,000 persons who received 0.01 Sv or more. In this study the ERR at 1 Sv was estimated to be 0.2,
and the EAR was 1.9 (104 PY Sv)–1. In the 2003 update studies of the mortality of atomic bombing
survivors during the period 1950−1997, Preston et al. [P50] had a cohort of 86,572 persons with anaverage external dose of 0.23 Sv. In males, there was a statistically marginally significant excess of
stomach cancer at dose levels of 1 Sv with an ERR of 0.20 (90% CI: 0.04, 0.39). In females, there wasa statistically significant excess at dose levels of 1 Sv with an ERR of 0.65 (90% CI: 0.40, 0.95).
B139. In the latest report on cancer incidence among the LSS survivors [P52] for the period 1958–
1998, an approximately linear dose response was seen. When both age at exposure and attained age(age at risk) were modelled, the ERR model gave no clear indication of more risk after exposure atyounger ages (change of -13% per decade of age, 90% CI: -35, 15; p = 0.4). For the EAR model there
was no indication of an age-at-exposure trend (EAR = -2%; 90% CI: -26, 29). The updated cancer
mortality data [O25] likewise showed no significant effect variation by age at exposure: an ERR modelchange of -18% per decade of age (95% CI: -47, 20), and an EAR model change of 18% per decade(95% CI: -18, 62).

2.

Medical radiation uses

B140. The studies of radiotherapy for benign conditions that have evaluated stomach cancer—
treatment for ankylosing spondylitis, benign gynaecological disorders, or peptic ulcer—have mainly
described effects associated with adult exposures and so are not informative regarding risks fromchildhood radiation exposure.
B141. A study of patients given multiple fluoroscopic examinations of the lung in conjunction withpneumothorax treatment for tuberculosis contained a large number examined before age 20 but did notreport an excess of stomach cancer mortality (sex-averaged SMR = 0.8) [D15]. However, the estimatedmean stomach dose was only about 60 mGy, so the lack of an excess was not surprising. Similarly, a
study of girls who received multiple radiographs for scoliosis showed no excess of stomach cancer[B26]. Again, the mean stomach doses were probably low, though the stomach doses per se were notestimated (mean lung dose of 41 mGy).
B142. Dores et al. [D43] reported on the follow-up of 32,000 patients treated for Hodgkin’s
lymphoma. They found an increasing risk of subsequent stomach cancers for younger ages at exposure(observed/expected ratio O/E = 13.8, 7.1, 3.1 and 1.1 for those diagnosed at ages <=20, 21–30, 31–50
and >50 years). However, the results were not broken out by radiotherapy alone versus multiple
therapies.
B143. Van Leeuwen et al. [V7] reported on second cancer risk in 1,909 testicular cancer patients andfound a significantly increased relative risk for stomach cancer of 3.7 (95% CI: 1.8, 6.8). Similar

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115

findings were reported by Travis et al. [T36], who examined long-term survival and second cancers inover 40,000 testicular cancer patients almost all of whom received infradiaphragmatic radiotherapy andin whom the relative risk for stomach cancer was significantly increased.

B. Internal exposure
B144. Hall et al. [H5] found a suggestion of excess stomach cancer (O/E = 7/4.0) among patients
given 131I therapy for thyroid cancer, with a mean stomach dose of 2.1 Gy but no information isavailable specifically related to childhood exposure.

C. Summary
B145. Risk estimates for stomach cancer can be derived from certain epidemiological studies. From
the atomic bombing survivor data, there appears to be a higher ERR in females than in males, but this is
not seen in all studies. There also appears to be a decrease in relative risk with age at exposure of over
30 years [U12].
B146. The UNSCEAR 2006 Report [U12] summarized radiation risk factors for stomach cancer that
could be derived from epidemiological studies (table B9). The updated information from the Japanese
LSS and the peptic ulcer radiotherapy study continue to show a positive dose-response relationship.
The LSS data provide weak evidence that the ERR may decrease with increasing age at exposure but
the EAR does not. Likewise, the very limited evidence from other studies does not support an increased
sensitivity among those exposed at young ages.
Table B9. Risk estimates for stomach cancer incidence and mortality from studies of childhoodradiation exposure
Updated and adapted from UNSCEAR 2006 Report (annex A, table 22) [U12]. Studies listed are those for which quantitative
estimates of risk could be madeStudy

Average ERR a at 1 Sv

Average EAR a(104 PY Sv)-1

Incidence
LSS (1958-1988) [U12], based on [P52]Sex

Age at exposure

All

Males

0.26 (0.14, 0.42)

2.45 (0.92, 4.49)

Females0.51 (0.33, 0.72)

4.36 (2.78, 6.15)<20 years

0.56 (0.32, 0.85)

2.74 (1.52, 4.19)

20–40 years

0.39 (0.22, 0.59)

6.18 (3.42, 9.32)>40 years

0.23 (0.07, 0.41)

7.99 (2.25, 14.59)

0.37 (0.26, 0.49)

3.61 (2.42, 4.96)

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Study

Average ERR a at 1 Sv

Average EAR a(104 PY Sv)-1

10 c years

0.44 (0.20, 0.83)

9.9 (4.5, 18)

30 years

0.34 (0.22, 0.47)

9.5 (6.1, 14)50 years

0.25 (0.12, 0.44)

9.2 (4.2, 16)d

0–9 years

0.63 (0.23, 1.4)

10–19 years

0.38 (0.19, 0.68)

20–39 years

0.38 (0.22, 0.56)≥40 years

0.23 (0.06, 0.42) b

LSS (1958-1998) [P52]
Age at exposure

Mortality
LSS [P50]
Sex

Age at exposure

Males

0.11 (<0, 0.30)

0.32 (<0, 1.33)

Females0.50 (0.27, 0.75)

1.46 (0.55, 2.56)<20 years

0.72 (0.29, 1.27)

0.51 (<0, 1.27)

20–40 years

0.42 (0.18, 0.71)

2.78 (1.06, 4.82)>40 years

0.12 (<0, 0.31)

3.46 (<0, 8.03)

0.28 (0.14, 0.42)

0.94 (0.31, 1.71)

10 years c

0.46

2.8

30 years

0.33(95% CI: 0.17, 0.52)

4.1(95% CI: 2.1, 6.7)

50 years

0.22

5.7

All
LSS [O25]
Age at exposurea

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

Estimates based on UNSCEAR 2000 Report (annex I) [U10].

c

Sex-averaged risk at attained age 70, smoothed assuming the ERR Gy-1 varies as a log-linear function of age at exposure.

d

Sex-averaged risk at attained age 70, assuming that within each age-at-exposure group the ERR Gy-1 varies as a power ofattained age, but with no smoothing across age-at-exposure groups.

VII. SKIN CANCER
B147. An excellent review of radiation effects on the skin has been produced by the ICRP [I12] andthe reader is referred to this for a more detailed discussion. Although skin cancers were the firstmalignant tumours reported to be induced by radiation (in 1902), and 50 cases were described by 1911,
to date still few data are available on the frequency and the risks of these tumours.
B148. The most common cell type is basal cell carcinoma. Squamous cell carcinomas are about 1/3 to1/6 as common. Skin cancer is not usually included in radiation mortality risk estimates because of thevery low mortality associated with basal cell and squamous cell skin cancers. The statistics of theincidence of skin carcinomas are somewhat difficult to evaluate because often melanomas are included

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117

with basal cell carcinoma and squamous cell carcinoma. However, it should be noted that there is noclear evidence of excess cutaneous malignant melanomas following ionizing radiation exposure.

A. Modifying factors
B149. Epidemiological studies suggest that the effects of ultraviolet irradiation and ionizing radiation
are probably additive. One study suggested that ultraviolet and ionizing radiation exposure effects may
be multiplicative [S62, S70], but a study on the atomic bombings did not confirm that finding [K35].
The latent period for induction of skin tumours is extremely wide, with the risk continuing for over four
decades to the maximum lengths of follow-up thus far. Patients with ataxia telangiectasia have cells thatare sensitive to ionizing radiation cell-killing effects, but there is no evidence of increased skin cancer
after ionizing radiation exposure. The frequency of A-T in Jewish children of Morroccan ancestry is
about five times higher than in most populations, and how much of a role this may play in the findings
reported in Israeli children (discussed below) is unknown. A study has examined genetic susceptibility
factors for radiation-associated non-melanoma skin cancer risk. Among atomic bombing survivors,certain alterations in the p53 and PTCH genes were found in a greater proportion of the exposed groupcancers than in low/unexposed group cancers [M43].

B. External exposure
1.

Fallout and atomic bombing survivors

B150. Originally, there was no excess of skin cancer identified in the atomic bombing survivors. Thismay be because the studies were primarily mortality studies, and mortality from skin cancer is so low.
At the end of the last decade, reports began to appear of an increased incidence of skin cancer at
Nagasaki [S3, S1, S2, S4]. The incidence study from Hiroshima and Nagasaki [T24] of the 41,000
persons who received 0.01 Sv or more and an average dose of 0.23 Sv showed that there were 98 nonmelanoma skin cancers observed versus 76 expected (excess of 22) in the 863,000 person years ofobservation. The data can fit a linear dose-response model, but there was no effect of sex, age at
exposure, time since exposure, or attained age.
B151. A more detailed analysis of skin cancer data among atomic bombing survivors for the years
1958–1987 was based on 80 basal cell and 69 squamous cell skin cancers [R45]. They found thatneither a linear-quadratic, nor a spline model with a change-point at 1 Gy improved the fit significantly,
although the latter was marginal (p = 0.09). The ERR was strongly modified by age at exposure,decreasing by 11% (90% CI: 6, 16) per year of age at exposure.
B152. The published data for 1958–1998 [P52] were based on 330 non-melanoma skin cancers,
including 166 basal cell and 131 squamous cell cancers. Because of possible Adult Health Study
clinical surveillance effects, all analyses were adjusted for membership in the study. Radiation risk was
confined to basal cell cancers (ERR Gy-1 of 0.57; 90% CI: 0.18, 1.38; squamous cell ERR Gy-1 of 0.17,
not significant). For all non-melanoma skin cancer a linear model gave a ERR estimate of 0.58 Gy-1.
However, a spline model with a change-point at 1 Gy provided a significantly (p = 0.005) better fit andyielded an ERR estimate of 0.17 below 1 Gy and 1.2 above 1 Gy. The sex-averaged EAR was 0.35

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UNSCEAR 2013 REPORT(104 PY Sv)-1. There was a strong age-at-exposure effect (p < 0.001), such that radiation risk decreased
with increasing age at exposure. The age-at-exposure effect for the ERR was −73% (90% CI: −85, −55)
per decade age at exposure, and for the EAR was −61% (−75, −42).

2.

Radiation therapy

B153. Two studies have been conducted on children given radiotherapy to the scalp to treat tinea
capitis (ringworm of the scalp). The study results are of special interest because they represent ethnic
groups with different susceptibilities to ultraviolet-induced skin cancers. A study was conducted in
Israel on 10,834 children (ages <1 to 15 years) given scalp irradiation plus 16,226 non-irradiatedcontrols, including 5,392 non-irradiated sibling controls. The patients were followed up for up to
30 years [G19, M44, R40]. They estimated the mean scalp dose as 6.8 Gy (range 5.5 to 24.4 Gy). They
identified medical records for 42 non-melanoma skin cancers (41 were basal cell) in the irradiatedgroup and 15 in the larger group of controls. They found a significant dose response (p < 0.001) and an
ERR Gy-1 of 0.7. The EAR (104 PY Sv)-1 was 0.31. The relative risks for those given radiation
treatment at ages 1–4, 5–9 and 10–15 were 19.0 (95% CI: 14, 28), 5.9 (CI: 3.3, 11) and 2.0 (CI: 1.3,4.0), respectively. They reported that the patients who developed cancers reported more radiodermatitis
and epilation, suggesting that they may have received higher doses than originally recorded [M46,
R40]. There was also some indication that they were more frequent sunbathers, suggesting that there isa potentiating effect of ultraviolet light. The relative risk decreased significantly with increasing age at
exposure. Specifically, a five-year increase in age at exposure led to an 80% decrease in the relativerisk.
B154. The New York study was based on tinea capitis patients—2,224 children with and 1,380
without X-ray treatment. In both groups 24–25% were blacks and the remainder whites, and the groups
were followed up for up to 50 years [S70]. The mean dose to the scalp and 2 cm around the scalp(where a number of basal cell carcinomas occurred) was estimated as 4.3 Gy. They identified 128 casesof non-melanoma skin cancer of the head and neck in the irradiated group and 21 in the non-irradiatedcontrols. Seven irradiated cases had a squamous cell carcinoma, of which six also had one or morebasal cell cancers. In the black subgroup, only three cases occurred among the irradiated and none
among controls; the EAR was 10.0 (95% CI: 3.2, 31) times as great among whites as blacks. Amongwhites, the ERR Gy-1 was 0.6 (95% CI: 0.3, 1.1) and the EAR (104 PY Sv)-1 was 1.9 (CI: 0.5, 3.3). An
analysis of susceptibility factors showed that northern European ancestry, sunburn susceptibility andlight skin colour were statistically significant joint predictors along with radiation of basal cell cancer
risk, but no factors showed interaction (effect modification) with radiation. Age at irradiation was asignificant co-factor (p = 0.002). Ionizing radiation exposure at a younger age conferred more skincancer risk than exposure at an older age. The risk declined by 12% per year of age at irradiation.
B155. Four other groups were treated with radiation therapy for other reasons and, again, the results
are diverse. Hempelmann et al. [H38] found nine of 2,872 persons irradiated for thymic enlargement tohave skin cancer versus three among a group of 5,055 controls. Skin doses ranged from about 0.4 to
15 Gy, with a mean of 3.3 Gy. The absolute risk was not substantially different between those who
received less than 4 Gy and those who received more than 4 Gy. The risk estimates did differ,depending on the number of fractions given in the dose regimen. There may be a slightly increased
subsequent risk of skin cancer in children who have been treated with radiotherapy for retinoblastoma[M23]. Whether this is the result of radiation exposure or of a genetic susceptibility is not clear.
B156. A case-control study of non-melanoma skin cancer and history of radiotherapy found that only
radiotherapy before age 20 conferred a significant risk for basal cell skin cancer (OR = 3.4; 95% CI:

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119

1.5, 7.5) and squamous cell skin cancer (OR = 2.8, 95% CI: 1.1, 7.3) [L24]. The study was
subsequently enlarged to include 1,121 basal cell carcinomas and 854 squamous cell carcinomas [K10].
For basal cell carcinomas within the radiotherapy field, the odds ratios before and after age 20 were 4.1(95% CI: 1.8, 9.4) and 1.8 (0.9, 3.5), respectively. For squamous cell carcinomas, the corresponding
odds ratios were 1.7 (0.6, 4.7) and 1.9 (1.0, 3.8), respectively.
B157. The CCSS reported 213 non-melanoma skin cancers as second cancers [P25]. They found that
90% of the skin cancers were among those who had received radiotherapy and that 90% of those were
within the radiation field. Radiotherapy was associated with a RR of 6.3 (95% CI: 3.5, 11.3).

C. Summary
B158. A number of studies indicate an association between non-melanoma skin cancer and radiation.
The positive studies include both Asians and Caucasians while the limited data available suggest there
may be relatively little risk for blacks. The issue of interaction between exposure to solar UV radiationand ionizing radiation remains unclear though there are several suggestions that it may be the case. A
few genetic conditions confer particular susceptibility. The induced tumours are predominantly basal
cell and, to a much lesser extent, squamous cell carcinomas. The UNSCEAR 2006 Report [U12] hassummarized radiation risk estimates for non-melanoma skin cancer that can be derived from theepidemiological literature (table B10) and concluded that there is strong evidence that non-melanoma
skin cancer and, specifically, basal cell carcinoma is inducible by ionizing radiation with relative risk
strongly decreasing with increasing age at exposure. Recent data have also supported that conclusion.
Table B10. Age differences in risk estimates for non-melanoma skin cancer incidence in the LSS andrisks from studies of childhood radiation exposure
Based on the UNSCEAR 2006 Report (annex A, table 32) [U12].Studies listed are those for which quantitative estimates of risk
could be madeAverage ERRa at 1 Sv

Average EAR a(104 PY Sv)-1

2.3

2.3

0.63

0.90

0.17

0.35

Israel tinea capitis [L27, R40] c

0.70 (0.35, 1.32)

1.31 (0.94, 1.77) d

New York tinea capitis (whites) [S70] c

0.6 (0.3, 1.1) e

1.9 (0.5, 3.3) e

Rochester thymic irradiation [H47, L27]

1.05 (0.50, 1.84)

15.9 (7.5, 27.9) d

Tonsil irradiation [L27, S32]

0.11 (0.04, 0.19)

10.2 (3.3, 18.3) d

Study
LSS [P52]
Age at exposure

10 years
20 years
30 yearsba

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

Sex-averaged risk at attained age 70, smoothed assuming the ERR Gy-1 varies as a log-linear function of age at exposure.

c

All estimates are for basal cell carcinoma.

d

Risks normalized to 3,000 cm2 of UVR-exposed skin as presented by Little et al. [L27].

e

95% CI in parentheses.

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VIII.COLON CANCER
B159. Colon cancer is most common in industrialized countries. Although non-hereditary factors
appear to play a major role in the aetiology, because migrants to an area soon have rates approachingthat of the local population, a genetic factor also exists, at least for some cancer-prone families. There
are a large number of studies relating colorectal cancer to diet. Positive associations have been reported
for intake of red meat and diets low in fibre and high in dietary fat. Tumours of the rectum and colon
appear to be aetiologically different because colon cancer is more frequent in females, and rectal
tumours are more common in males [H45, I5, P39].

A. External exposure
1.

Atomic bombing survivors

B160. In an early study of the incidence of colorectal cancer in the LSS sample of survivors of theatomic bombings reported by Nakatsuka et al. [N7], during 1950–1980 there was an excess risk ofcolon cancer, the ERR at 1 Sv being 0.8 (90% CI: 0.37, 1.36) but no excess rectal cancer risk. There
was no difference in colon cancer risk by sex, but the ERR decreased with age at exposure (ERR Sv-1 of
3.7, 0.96 and 0.31 for ages <20, 20–39 and >=40, respectively). Later follow-up by Thompson et al.
[T23] also indicated a statistically significant increase in cancer of the colon. In the period 1958–1987,
223 cases were observed compared to 194 expected (an excess of 29 cases) in the 788,600 person-yearsof observation for the 41,000 persons who received a dose of 0.01 Sv or more and a mean dose of
0.23 Sv. They estimated an ERR at 1 Sv of 0.72 (95% CI: 0.29, 1.28) and an EAR of 1.8 (104 PY Sv)-1.
There was no significant male–female difference in risk, nor was there an effect of age at exposure.
B161. In the latest cancer incidence report, there were 1,516 colon cancer cases based on follow-up
through 1998 [P52], reporting no ERR change (+1% per decade), but a -56% per decade change in the
EAR. However, the model they used (standardized for exposure at age 30 and risk assessed at age 70)
may not fully account for the data. In particular, from the left-hand side of figure B-X, it can be see that
the ERR is much higher at early ages for those exposed at age 10.
B162. Preston et al. [P50] reported on mortality among the survivors of the atomic bombings during
the period 1950–1997. There was a statistically significant excess of colon cancer at dose levels of 1 Sv
with an ERR of 0.54 (90% CI: 0.13, 1.2) in males and an ERR of 0.49 (90% CI: 0.11, 1.1) in females.
There was an ERR change of -25% per decade of age at exposure, and an EAR change of -50% (but thestatistical significance of those changes was not reported). The latest mortality report, through 2003,
identified 621 deaths due to colon cancer [O25]. An analysis of the change in the ERR by age at
exposure did not show a significant effect (a −3% change per 10 years of age, 95% CI: −51, 63);
however, the change in the EAR (104 PY Sv)-1 by age at exposure was nearly statistically significant:−30% per decade (95% CI: −58, 2).

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Figure B-X. ERR and EAR models of colon cancer risk by age at exposure and attained age, averaged
across sex
Adapted from [P52]2.

Background radiation

B163. Zou et al. [Z5] reported that the RR was less than 1.0 for colon cancer in the study of those in a
relatively high-background area of China, where annual whole-body exposures were 2.1 to 4.7 mSv. No
specific information was available regarding ages at exposure since all are exposed at this level ofradiation throughout their lifetimes. No other data are available regarding colon cancer risk in relatively
high-background areas.

3.

Fallout and populations near nuclear plants

B164. A study of the cancer risk in the vicinity of the Three Mile Island nuclear power plant before
and after the accident in March 1979 showed a nominal gradient of elevated risk close to the plant
during the period from April 1979 to 1985 compared to the period from 1975 to March 1979 [H29].
However, evidence that there might have been an effect due to increased surveillance and theimplausible time period for an excess suggest the pattern was likely an artefact according to the authors.
Age at exposure was not examined in the study.

4.

Medical irradiation for benign conditions

B165. Lundell and Holm [L41] studied 14,351 subjects who had received radiotherapy for skinhaemangiomas at 0–17 months of age. The mean dose to the intestine was estimated to be about
0.09 Sv, with a range from <0.05 to 5.9 Sv [L39]. They were followed up until age 39 on average. The

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authors observed 12 cases of colon cancer but found no significant dose-related increase in risk, with areported ERR of 0.37 Sv-1 and an EAR of 0.11 (104 PY Sv)-1.
B166. Several studies have been conducted of women who received X-ray treatment or radium
implants for benign gynaecological disorders, often with colon doses of a sievert or more [I38], butessentially all were adults when exposed, so childhood risk cannot be documented from those studies[D8, I38, R66, W4]. Although studies of patients given radiotherapy for ankylosing spondylitis [W17]or for peptic ulcer [C6] had colon doses of one to several sieverts, essentially all the patients were
adults when treated so no data on childhood exposure are available from the studies.

5.

Radiotherapy for malignant disease

B167. There are several reports of children treated with radiotherapy for cancer. Hawkins et al. [H31]reported that the survivors of childhood cancer had an increased risk of second primary tumours in thedigestive tract, with a relative risk of 10 (95% CI: 5, 20). Most of this risk was from five cases of coloncancer observed in over 10,000 patients studied. Tukenova et al. [T51] reported on cancers of the colonor rectum occurring after childhood cancer radiotherapy in the British and French parts of the European
Childhood Cancer Survivor Study consortium. They found an SIR of 7.2 (95% CI: 4.4, 10.9; O/E
19/2.62), but did not present a further breakdown into colon and rectum.
B168. Travis et al. [T36] reported on the long-term survival and incidence of second cancers in over
40,000 testicular cancer patients almost all of whom received a dose from infradiaphragmaticradiotherapy of about 30 Gy. The relative risk for colon cancer was significantly increased among thosegiven radiotherapy alone, with a relative risk of 1.9 (95% CI: 1.5, 2.5). They reported a strong age-atexposure trend (p <0.001) for all solid cancers such that those youngest at the time of treatment had thehighest subsequent cancer risk, and indicated that the trend was consistent across tumour sites.
B169. In a follow-up study of 1,507 Hodgkin’s lymphoma patients, Tucker et al. [T48] observed fourcases of colon cancer compared to 1.2 expected, giving an observed over expected ratio of 3.5 (95% CI:
0.9, 8.8). Castellino et al. [C8] found an elevated risk of colorectal/small intestine cancer among 2,633
five-year survivors of Hodgkin’s lymphoma in the CCSS. About 94% of the study members hadreceived radiotherapy and about 60% had received chemotherapy as well. The SIR was 6.6 (95% CI:
3.7, 12; n = 11 cancers). Another study reported 13 cases of gastrointestinal cancers among a cohort of930 patients who had been treated for Hodgkin’s lymphoma in childhood followed up for an average of
16.8 years (range of <1 to 39 years) [C48]. A total of 91% had received radiotherapy, including 48%
with additional chemotherapy. The SIR for gastrointestinal cancer was 27.2 (95% CI: 15.1, 45.3).
B170. A large pooled study of 32,591 patients who had been treated for Hodgkin’s lymphoma
examined second-cancer risks by age at exposure and time since exposure [D43]. In the subgroup of
5,925 diagnosed with Hodgkin’s lymphoma at ages 0–20 years, they found four cases of colon cancers.
The SIR of 4.7 (95% CI: 1.3, 12) was higher than for older age groups. The SIR was 3.5 for thosetreated at ages 21–30 years, and was about 1.4 (95% CI: 1.2, 1.7) for those treated at ages >30 years.
Another pooled study of 18,862 five-year survivors of Hodgkin’s lymphoma reported that modelledrisk estimates for those treated at age 20 with Hodgkin’s lymphoma were higher than for those treatedat ages 30 or 40 [H52].
B171. Among 14,358 five-year survivors of all children cancers in the CCSS, the risk ofgastrointestinal malignancies as a subsequent malignant neoplasm (GI SMN) was almost fivefold
higher than the risk of such malignancies in the general population, with an SIR of 4.6 (95% CI: 3.5,
6.1). The SIR for colorectal cancer was 4.2 (95% CI: 2.8, 6.3). The highest risk for GI SMN was

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associated with abdominal radiation exposure, with an SIR of 11.2 (95% CI: 7.6, 16.4). However,survivors who had not been exposed to radiation had a modest but significantly increased risk, with an
SIR of 2.4 (95% CI: -1.4, 3.9). The 30-year post-cancer cumulative incidence of GI SMN was 0.64%(95% CI: 0.43, 0.86) for all patients, and almost 2% in those treated with abdominal radiation(cumulative incidence of 1.97% (95% CI: 1.15, 2.80) (figure B-XI). The most frequent GI SMN sites
were the colon (38%) and rectum/anus (18%). In addition to abdominal radiation, with a relative risk of
5.4 (95% CI: 2.6, 11.2), high dose procarbazine and platinum drugs independently increased the
GI SMN risk [H40].
Figure B-XI. Cumulative incidence of subsequent gastrointestinal malignancies in survivors ofchildhood malignancy treated with or without abdominal radiotherapy
Adapted from [H40]

B. Internal exposure
B172. The literature generally does not reveal a significant increase in the frequency of colon cancer
after internal administration of radioiodine. However, the populations studied were essentially all adults
when exposed [H5, H53, H59, H58, R45, R63].
B173. Thorotrast studies are a potential source of information on high-LET radiation exposure andcolon cancer. The mortality experience of over 2,300 German thorotrast-exposed patients has been
documented for up to 70 years since exposure [B11]. Only about 280 were under age 20 at the time ofthorotrast administration. No excess of colon cancer mortality was seen in the cohort as a whole(SMR <1).
B174. A pooled analysis of cohorts given cerebral angiography with thorotrast was based on 1,650
exposed patients, of whom 220 were under age 20 at the time of thorotrast administration [T34]. The
study showed a non-significant risk for colon cancer, with a relative risk of 1.5 (95% CI: 0.7, 3.0; n =16) compared to patients diagnosed using a non-radioactive contrast agent; no analysis by age at
exposure was conducted.

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C. Summary
B175. The lifetime fatal risk estimate for a population of all ages exposed to low doses of radiation
given by the ICRP in 1990 [I11] was 8.5 × 10-4 Sv-1, and for workers 6.8 × 10-4 Sv-1. In 2007, the ICRP
[I25] gave an ERR for colon cancer mortality of 0.25 Gy-1 (for age 70 after exposure at age 30) with achange in the risk coefficient of -31% per decade of age at exposure.
B176. The BEIR V Committee [N38] pointed out that the data from the survivors of the atomic
bombings did not show an increase in risk for at least 15 years after exposure, following which the ERR
for fatal colon cancer was then 0.85 Gy-1 or 0.8 (104 PY Gy)-1. The BEIR VII Committee [N43]estimated the ERR to be 0.65 for males and 0.79 for females, with a 19% decrease in risk per decade ofage at exposure, up to age 30.
B177. The UNSCEAR 1988 Report [U7] risk estimate for radiogenic cancer of the colon, using a
multiplicative risk model, was 7.9 (90% CI: 3.6, 13.4) excess lifetime fatal cancers for 1,000 persons
exposed to a dose of 1 Gy of low-LET radiation at a high dose rate.
B178. The UNSCEAR 2000 Report [U9] indicates that the data on the Japanese survivors of theatomic bombings are consistent with a linear dose response. The report indicated that effects of sex, age
at exposure and time since exposure on the ERR per sievert are not clear, although the EAR does
increase with increasing time since exposure in the LSS. Changes over time in baseline rates in Japan
make it difficult to decide how to transfer risks across populations. Also the lack of precision in low
dose studies of external low-LET radiation exposure and of internal low-LET and high-LET radiation
exposure do not allow conclusions to be drawn.
B179. Additional studies on radiation and colon cancer have been summarized by the UNSCEAR
2006 Report [U12] (table B11), and it was concluded that there is evidence that colon cancer can be
induced by ionizing radiation, compatible with a linear dose-response pattern. The evidence forapproximate linearity comes almost entirely from the Japanese LSS mortality data. The Committee
cited ERR estimates from LSS for the period 1958–1997 of 0.54 (90% CI: 0.13, 1.2) for males and 0.49
(0.11, 1.1) for females, with a 25% decrease per decade of age at exposure.
B180. To summarize the present review of colon cancer risk in relation to childhood radiation
exposure:−

Among the survivors of atomic bombings in the LSS, both the cancer mortality and cancer
incidence data indicate that the EARs are greater after childhood radiation exposure than after
adult exposure, with estimated declines of 30% and 56% per decade of age at exposure,respectively. No differences were reported in the ERRs by age at exposure in the most recent
data, although that may be partly a function of the choice of model used to assess the ERR.
Both mortality and incidence data agree that there is an age-at-exposure effect for the EAR
model (i.e. a greater risk from exposure at younger ages), but it is inconclusive for the ERR
model.

−No data are available regarding colon cancer risk after childhood exposures to fallout from thetesting of nuclear weapons, from discharges or accidental releases from nuclear installations orin high-background areas. Occupational radiation studies also do not contain any informationon colon cancer after childhood exposures.

−

Several studies of irradiation for benign medical conditions had too few patients exposed
before age 20 to provide useful information on childhood exposures. A study of infant

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125

treatments for skin haemangiomas did not show a significant colon cancer risk, but the meandose to the intestine was low (<0.1 Sv).
−

An excess of colon cancer was reported among those given radiotherapy for childhood cancer.
Studies of patients treated for Hodgkin’s lymphoma before adulthood also reported coloncancer excesses. However, information on excesses per unit radiation dose was not available.

−

Studies of internal exposures, either to low-LET radiation from 131I or high-LET radiationfrom thorotrast, have not reported excesses of colon cancer, but nearly all the patients were
adults at the time of exposure.

Table B11. Risk estimates for colon cancer incidence and mortality from studies of childhoodradiation exposure
Updated and adapted from UNSCEAR 2006 Report (annex A, table 23) [U12, U13]. Studies listed are those for whichquantitative estimates of risk could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]
Sex

Age at exposure

Males

0.85 (0.52, 1.26)

1.41 (0.10, 3.07)

Females0.42 (0.14, 0.76)

1.46 (0.69, 2.45)<20 years

0.81 (0.46, 1.24)

0.99 (0.31, 1.92)

20–40 years

0.44 (0.14, 0.82)

1.78 (0.56, 3.46)>40 years

0.45 (<0, 1.13)

3.11 (0.22, 6.54)

Mortality
LSS [P50]
Sex

Age at exposure

Males

0.53 (0.04, 1.20)<0 (<0, 707.28)

Females0.50 (0.06, 1.09)<0 (<0, 623.23)<20 years

1.13 (0.32, 2.34)<0 (<0, 210.88)

20–40 years

0.23 (<0, 0.84)<0 (<0, 966.47)>40 years

0.38 (<0, 1.12)<0 (<0, 1 440.1)

10 years b

0.36

2.7

30 years

0.34(95% CI: 0.05, 0.74)

1.6(95% CI: 0.5, 3.0)

50 years

0.32

0.8

LSS [O25]
Age at exposurea

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

Sex-averaged risk at attained age 70, smoothed assuming the ERR Gy-1 varies as a log-linear function of age at exposure.

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IX. LIVER CANCER
B181. The LSS of atomic bombing survivors has reported an excess risk for liver cancer incidence,with an ERR Gy-1 of 0.30 (90% CI: 0.11, 0.55, n = 1,494) and an EAR (104 PY Sv)-1 of 4.3 (0.2, 7.2)
[P52]. The analysis did not show any statistically significant changes in risk by age at exposure—an
ERR estimate of 3% (CI: −37, 69) and EAR of −21% (−57, 378) change per decade of age at exposure.
The most recent mortality data also show a significant dose-response relationship for liver cancer, with
an ERR Gy-1 of 0.38 (95% CI: 0.11, 0.62) but a non-significant age-at-exposure effect for the ERR
model: −8% (−62, 42) per decade [O25]. However, the LSS data on liver cancer risk by age at exposure
are especially difficult to interpret because Japanese birth cohorts differed markedly in the frequency of
infection by hepatitis C virus which is a major risk factor for hepatocellular carcinoma and may be aneffect modifier of the radiation risk [S53].
B182. It should be noted that a number of other studies of liver cancer risk in relation to external lowLET exposures do not show statistically significant risks for liver cancer incidence or mortality [U12].
Most of the studies have shown a high risk for liver cancer after thorotrast injection: German study, RR= 152 (95% CI: 48, 594; n = 454) [V5]; Danish-Swedish study, RR = 109 (95% CI: 91, 129; n = 136)
[T34]; Portuguese study, RR = 42 (95% CI: 14, 210, n = 67) [D45]; Japanese study, RR = 31 (95% CI:
19, 50; n = 143) [M49]. However, none of the studies had an analysis by age at exposure.

X. LUNG CANCER
B183. Lung cancer was one of the earliest cancers identified as possibly being related to radiation
exposure. The relationship was initially suggested in a study of Bohemian miners. To date, several
other major population groups have been studied, including those exposed to natural background,fallout, and occupational radiation, atomic bombing survivors, patients exposed to radiation therapy,
and those exposed to radon daughter products in homes and underground mines. These sources of
information used for risk estimates are rather discordant for several reasons: uncertainties in dosimetry
in most of the studies, problems of comparison of external radiation exposure with internal exposure
from radon daughter products, and confounding of the data by other associated carcinogenic agents(such as cigarette smoking).
B184. Estimates of the risk of radiation induction of lung cancer depend upon the age of the subjects
at the time of exposure. Relative risk appears to differ in expression between the atomic bombing
survivors and the uranium miners. In the uranium miners, the ERR declines over time—following
cessation of exposure—while among the atomic bombing survivors, if this trend exists at all, it is muchless marked [L1]. The risk from radiation-induced lung cancer at later ages rises steeply, as it does fromnormally occurring lung cancers.
B185. The interaction between smoking and radiation continues to be a subject of intense interest
with reports based on miner radon studies [N41, S36, U14] residential radon studies [D5, K53] and theatomic bombing survivors [F28, U14]. However, it is notable that in all the studies, a radiation risk isseen for non-smokers as well as for smokers.

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127

A. External exposure
1.

Atomic bombing survivors

B186. The 1958 to 1987 incidence study of atomic bombing survivors [T24] yielded incidence risk
estimates of an ERR of 1.0 at 1 Sv and an EAR of 4.4 (104 PY Sv)-1. The mortality data from the same
period yielded comparative risk estimates of 0.6 and 1.9, respectively. The mortality data up to 1985
published by Shimizu et al. [S55] found 638 lung cancer deaths and indicated a relative risk at 1 Gy of
1.46 (90% CI: 1.25, 1.72) and an EAR per 10,000 PYGy of 1.25 (90% CI: 0.70, 1.89). The attributablerisk was estimated to be 11.4% (90% CI: 6.4, 17.1), given the dose distribution of the atomic bombing
survivors. The paper also has data on ERR by dose level and age at exposure for lung cancer andindicates a significant ERR for lung cancer at <0.5 Gy. A later mortality study up to 1990 published by
Pierce et al. [P33] in 1996 indicated an ERR/Sv in males of 0.33 (95% CI: 0.03, 0.69), an ERR in
females of 0.75 (95% CI: 0.30, 1.33) and for both sexes an ERR of 0.42 Gy (95% CI: 0.24, 0.63).
B187. In an update through 1998 of tumour incidence in the LSS, there were 1,759 lung cancer cases[P52]. The analysis showed no variation by age at exposure. Using their analysis, which wasstandardized to exposure at age 30 and risk at age 70 years, the effect for the ERR model was a positive
20% (90% CI: −7, 54) per decade of age at exposure and that for the EAR model was 2% (90% CI:−20, 28). Estimated risks for representative age at exposure are shown in table B12.
B188. A recent update of lung cancer mortality through 2003 reported a sex-averaged ERR Gy-1 of
0.74 (95% CI: 0.51, 1.03) with a significant sex effect: female/male ratio of 2.7 (1.3, 6.8) [O25]. The
age-at-exposure effect of −7% (95% CI: −35, 29) per decade of age at exposure was not significant.
Table B12. Risk estimates for lung cancer incidence and mortality from studies of childhoodradiation exposure
Updated and adapted from UNSCEAR 2006 Report (annex A, table 27) [U12]. Studies listed are those for which quantitative
estimates of risk could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52] b
Both sexes
Age at exposure

LSS [P52]

0.81 (0.56, 1.1)

7.5 (5.1, 10)10years0.56 (0.26, 1.1)

7.3 (3.4, 14)30 years

0.81 (0.56, 1.1)

7.5 (5.1, 10)50 years

1.15 (0.69, 1.8)

7.8 (4.6, 12)

0-9 years

0.66 (-0.02, 2.0)

n.a.

10–19 years

0.57 (0.23, 1.1)

n.a.

20–39 years

0.79 (0.48, 1.2)

n.a.

≥40 years

1.2 (0.71, 1.7)

n.a.

c

Age at exposure

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UNSCEAR 2013 REPORT

Study

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Males

0.32 (0.13, 0.55)

0.57 (0.04, 1.54)

Females

1.48 (1.04, 1.99)

2.38 (1.37, 3.53)<20 years

0.68 (0.28, 1.20)

0.64 (0.10, 1.38)

20–40 years

0.65 (0.35, 1.00)

2.65 (1.04, 4.60)>40 years

0.71 (0.40, 1.09)

9.47 (5.75, 13.78)

All

0.69 (0.49, 0.92)

1.55 (0.84, 2.37)

Hodgkin’s disease - international [G12, T33, V8](5-year lagged dose >0)0.15 (0.06, 0.39)n.a.

LSS [P52]
Sex

Age at exposure

Mortality
LSS [P50]
Sex

Age at exposure

Males

0.57 (0.30, 0.89)

0.19 (<0, 0.85)

Females

1.28 (0.84, 1.80)<0 (<0, 1269.1)<20 years

0.94 (0.42, 1.63)

0.11 (<0, 0.56)

20–40 years

0.78 (0.43, 1.19)

0.51 (<0, 1.83)>40 years

0.76 (0.38, 1.23)<0 (<0, 4062.9)

0.84 (0.59, 1.11)

0.37 (0.02, 0.87)

10 years b

0.86

8.7

30 years

0.75 (95% CI: 0.51, 1.03)

6.5 (95% CI: 4.3, 9.0)

50 years

0.65

4.6

All
LSS [O25]
Age at exposurea

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

Sex-averaged risk at attained age 70, smoothed using the assumption that the ERR Gy-1 varies as a log-linear function of age at
exposure.

c

Sex-averaged risk at attained age 70, assuming that within each age-at-exposure group the ERR Gy-1 varies as a power ofattained age, but with no smoothing across age-at-exposure groups.

2.

Radiation therapy

B189. A number of studies have examined the risk of second tumours after treatment for childhood
cancers. In a study by van Leeuwen et al. [V6], 14 lung cancers were identified in 744 patients treatedfor Hodgkin’s disease. Nine cases were seen in the patients treated with radiotherapy alone (RR = 5.4),
and none were found in patients treated by chemotherapy alone. Kaldor et al. [K6] examined cases oflung cancer occurring in Hodgkin’s disease survivors and found that lung cancer was twice as common
in those treated with chemotherapy as compared to those treated with radiotherapy. They concluded
that Hodgkin’s disease itself may be associated with an increase in lung cancer. This was supported by
the fact that 3/4th of the cases occurred within 10 years of the treatment.
B190. In an international study of second malignant neoplasms among 32,000 Hodgkin’s lymphoma
patients, Dores et al. [D43] observed 377 lung cancers and found a statistically significant trend for a

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129

higher risk after treatment at young ages than at older ages. However, specific results were not provided
by age at exposure for those who received radiotherapy.
B191. In a 2003 report by Gilbert et al. [G12] on 227 patients who developed lung cancer among
19,000 who had been treated for Hodgkin’s disease, the ERR for lung cancer was elevated at 0.15 (95%
CI: 0.06, 0.39). There was no evidence of a departure from linearity even though lung doses exceeded
30 Gy. Also the relationship of radiation to smoking was more consistent with a multiplicative than an
additive relationship. Curtis et al. [C55] reported on solid cancer incidence in 19,229 patients followingbone marrow transplantation. Treatment regimens often included total-body (usually about 10–12 Gy)or nodal irradiation and cyclophosphamide. Lung cancer was not found to be increased and the O/E
ratio was 0.7. The study is limited by the small number of lung cancer cases.
B192. As reviewed by Goodman et al. [G20], a number of cohort studies of patients who received
radiotherapy for Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, breast cancer and a variety of othercancers have shown excess risks for pleural and other mesotheliomas, though the risks per sievert or
breakdowns by age at exposure were generally not available.
B193. In summary, several studies have shown an increase in the risk of lung cancer following lowLET external radiation exposure. However, there are also a number of studies involving nuclear
workers, populations exposed to fallout, and populations living in areas of high natural backgroundradiation or around nuclear plants that do not show an increase in lung cancer. Many of the positive andnegative studies are complicated by the lack of adjustment for factors such as cigarette smoking, otherpollutants and the “healthy worker” effect.
B194. The data from the positive studies are compatible with a linear dose-response relationship. The
minimum latent period for lung cancers appears to be at least 10 years. The atomic bombing survivor
mortality study indicates that age at exposure has no consistent effect and there does not appear to besignificantly decreasing relative risk with increasing time since exposure. The effect of fractionation is
not clear, but the data suggest that the risk decreases with fractionation of low-LET radiation but notwith high-LET radiation. The interactive effect of smoking is probably between additive andmultiplicative. At low doses, the interaction of smoking and radiation has not been confirmed becauseof the overwhelming carcinogenicity of smoking which obscures any possible radiation effect.
B195. Risk estimates summarized by UNSCEAR 2006 Report [U12] from the various low-LET
radiation epidemiological studies are shown in table B12.

B. Internal exposure
B196. The main body of scientific literature on the relationship between lung cancer and internal
irradiation concerns radon exposure. The literature has been summarized by a number of scientificgroups including the ICRP 1990 Recommendations [I11], NCRP reports [N16], the UNSCEAR 2006
Report [U12], and the BEIR Report on radon [N37].

1.

Underground miner studies

B197. Although most miner studies have dealt exclusively with adult exposures to radon, in a
Chinese tin miner cohort, 37% were first exposed before age 13 [L34, X1]. Of 2,585 lung cancer deaths

130

UNSCEAR 2013 REPORTin a pooled analysis of 11 miner studies, only the Chinese tin miner study had miners first exposed
under age 15 (522 cases, 20%) and various studies had 629 lung cancer deaths among miners first
exposed at ages 15–24 years [L35]. The study found non-significant modification of the ERR per
working level month by age at first exposure. There was a slight indication that those exposed at earlier
ages had a higher lung cancer risk, but this needs to be tempered by the possibility that exposure toarsenic and other contaminants may have confounded the risk estimates.

XI. BRAIN AND CENTRAL NERVOUS SYSTEM TUMOURS
B198. The reported radiation-induced tumour types are often mesenchymal (sarcomas, meningiomas)
but have also included malignant glioma, astrocytoma, haemangioblastoma, and acoustic neuroma[P41]. It is often difficult to separate brain tumours into either strictly malignant or non-malignant
categories because many (particularly astrocytomas) may be very slow growing. Additionally, very few
brain tumours metastasize in the way that other malignancies do and, for this reason, many of the
published reports give a total brain tumour induction rate rather than indicating a separate malignant
brain tumour rate.

A. Modifying factors
B199. Little et al. [L28] examined the interaction of radiation and various genetic syndromes withbrain tumour risk among 4,000 brain tumour cases. They found a weak effect modification byneurofibromatosis (44 cases), but none by various other familial syndromes of which only two
syndromes had appreciable cases (31 with Li-Fraumeni syndrome, 80 with bilateral retinoblastoma).
B200. Sadetzki et al. [F10, S6] examined candidate polymorphisms in 12 genes in the DNA-repair,cell-cycle control, or meningioma pathogenesis pathways in relation to radiation risk of meningioma.
They found suggestive effect modification of radiation risk by polymorphisms in the Cyclin D1 gene(p = 0.005) and the p16 gene (p = 0.06). Another study of a variety of DNA repair genes foundradiation risk for gliomas to be modified by variations in the MGMT and PARP1 genes [L32].
However, these studies require confirmation by studies in other irradiated groups.

B. External exposure
1.

Atomic bombing survivors

B201. Data from the survivors of the atomic bombings for 1958–1995 revealed an excess of brain
tumours; however, the confidence intervals of relative risk usually encompassed unity for individual
tumour types owing to the relatively small numbers. Preston et al. [P49] reported a dose-dependent
ERR for nervous system tumours, with an ERR of 1.2 Gy-1 (95% CI: 0.6, 2.1) in the LSS. The EAR
was 0.51 (95% CI: 0.17, 0.95) (104 PY Gy)-1. For schwannomas, the ERR was 4.5 (95% CI: 1.9, 9.2,

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n = 55), and for all other types, the ERR was 0.6 (95% CI: 0.1, 1.3, n = 173). For other specific types ofinterest, owing in part to the small numbers, the ERRs were positive but not statistically significant: formeningioma, the ERR was 0.6 (n = 88); for glioma, the ERR was 0.6 (n = 43); and for pituitary tumour,the ERR was 1.0 (n = 35) [P49]. Further details on subtypes are given in [Y6]. For those exposed before
age 20, the ERR per unit dose for all nervous system tumours except schwannomas was 1.2 (95% CI:
0.3, 2.9) Sv-1; that for those exposed at ages 20 or more was 0.2 (95% CI: <−0.2, 1.0) Sv-1. A model ofage at exposure for nervous system tumours other than schwannoma showed a relative change in ERR
of −62% (95% CI: −95, 4) per decade of exposure age, which was nearly statistically significant(p = 0.06) [P49].

2.

Fallout from nuclear weapon testing

B202. Darby et al. [D7] reported on 22,000 men who had participated in the United Kingdom’s
atmospheric nuclear weapon tests or related programmes compared to 22,000 others who had notparticipated. A non-significant SMR of 1.3 (95% CI: 0.8, 2.2) was found for tumours of the CNS
among participants. The radiation doses were uncertain. Another study among United States military
nuclear weapon test participants likewise reported no significant elevation in brain tumour risk, with an
SIR of 1.4 (95% CI: 0.5, 3.2; n = 5) [C1]. However, in neither study would any subjects have been
below the age of 16.

3.

Diagnostic radiology

B203. Several population-based case–control studies of brain tumours and medical diagnostic
radiation exposures have been conducted. Howe et al. [H66] found an odds ratio of 6.7 (95% CI: 1.7,27) for the association of childhood brain tumours with a history of medical X-irradiation of the skull.
Preston-Martin et al. [P43, P42] reported, in a study of meningiomas, an odds ratio of 4.0 (95% CI: 2.1,
−7.5) for those receiving full-mouth dental radiological examinations before age 20. They also
indicated an odds ratio of 2.1 (95% CI: 1.2, 3.6) for those receiving such examinations before 1945,
when dental X-ray doses were sometimes as high as 100–150 mGy (10–15 R) per film and the beam
diameters were excessive [J15, P46]. The association was evident for tentorial/subtentorial
meningiomas, but not for supratentorial tumours, which accords with the likely topographicaldistribution of the dental X-ray dose to the brain [P42].
B204. However, other case–control studies have produced negative findings. A more recent study ofgliomas and meningiomas by Preston-Martin et al. did not show a significant association with dental
radiological examinations before age 25 [P45]. Ryan et al. [R65] reported no association between
frequency of dental radiological examinations and either gliomas or meningiomas. Nor was there an
association when dental X-rays before age 25 were examined, or when panoramic or full-mouth X-rays
were specifically examined. The study by Burch et al. [B70] also produced negative findings withregard to dental radiological examinations and brain tumours. As part of the large European Interphonestudy of brain tumours, medical radiation exposure and brain tumours were examined in Germany[B29]. For 366 glioma and 381 meningioma cases, no positive associations were found with reported
medical radiation exposure. The results of retrospective case–control studies should be treatedcautiously because of the potential for differential recall between diseased cases and controls, which
can produce biases of unknown direction and magnitude.
B205. Brain tumour incidence was recently reported for 176,000 patients who received one or more
CT scans before the age of 22, including 135 who developed brain tumours five or more years after the132

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initial CT [P22]. Compared to children who received <5 mGy to the brain, those who received
50-74 mGy (mean of 60.4 mGy) had a RR of 2.82 (95% CI: 1.33, 6.03), and all those with >=50 mGy(mean of 104.2 mGy) had a RR of 3.32 (95% CI: 1.84, 6.42). They further reported a significant
increase in the RR with increasing age at exposure. However, there are concerns about the risk
estimates because of lack of information about indications for the CT scans and the consequentpotential for “reverse causation” (i.e. cancers may have been caused by the medical conditions
prompting the CT scans rather than by the CT dose) and lack of individual dosimetry.
B206. Brain tumour incidence among 860,000 persons following paediatric CT examinations wasrecently reported in comparison with 10 million persons without a report of a CT examination [M9].
For brain cancers diagnosed one or more years after the initial CT examination, they reported a relativerisk of 2.44 (95% CI: 2.12, 2.81; n = 210) for those who received CT examinations of the brain, and abrain cancer relative risk of 1.51 (95% CI: 1.19, 1.91; n = 73) after CT scans of other body locations.
The 50% elevated risk for brain cancer after receiving CT examinations at non-brain sites suggests thepotential for bias in the study. When they further examined the radiation dose response for brain cancer
risk with different lag periods after brain CT examinations, they found ERR Gy-1 estimates of 29 (95%
CI: 23, 37), 21 (14, 29) and 15 (7, 26) for lag times of 1, 5 and 10 years, respectively. The implausibly
early risk that declined with time suggests the possibility of “reverse causation”.

4.

Radiotherapy for benign conditions

B207. The effects of radiation therapy for childhood tinea capitis in New York patients has beenreported by Shore et al. [S60] and in Israeli patients by Ron et al. [R37]. The mean dose to the brain in
both studies was between 1.4 and 1.5 Gy. The Israeli tinea capitis studies by Ron et al. [M44, R38]
include 10,834 exposed persons and 16,226 controls. The children were seven years old on average(range of 0 to 15 years) at the time of treatment. In the most recent report of the Israeli series, with a
median follow-up of 40 years since exposure, an excess incidence of brain cancers was found, based on
67 meningiomas and 44 malignant brain tumours in the irradiated group [S5]. Seventy-five per cent of
the malignant tumours were of neuroepithelial tissue origin. There was some statistical evidence for alinear-quadratic model for meningiomas, but a linear fit was adequate for malignant brain tumours.
Since the linear models provided a good fit up to a dose of 2.7 Gy (the range that contained 95% of thedata points) for both tumour types, the risks were estimated using a linear model. For benign
meningiomas, the ERR was 4.63 (95% CI: 2.43, 9.12) Gy-1 and the EAR was 0.48 (95% CI: 0.28, 0.73)(104 PY Sv)-1. For malignant brain tumours, the ERR was 1.98 (0.73., 4.69) Gy-1 and the EAR was 0.31
(95% CI: 0.12, 0.53) (104 PY Sv)-1. For malignant brain tumours, but not benign meningiomas, the risk
was higher during the first 20 years after irradiation than subsequently.
B208. Sadetzki et al. [S5] did not see any age-at-irradiation effect for benign meningiomas, but there
was a significant (p = 0.03) decrease in the ERR with irradiation age for malignant brain tumours; theERRs were 3.6 (95% CI: 1.0, 9.9), 2.2 (0.8, 5.5) and 0.5 (<0, n.a.) Gy-1 for ages 0–4, 5–9 and 10–15
years, respectively. In the New York study [S60, S71] of 2,224 irradiated and 1,380 non-irradiated tinea
capitis patients, seven malignant brain tumours (six gliomas/astrocytomas, one haemangioblastoma)and nine benign intracranial tumours (four meningiomas, five acoustic neuromas) were found in theirradiated group versus only one benign tumour in the controls. By comparison with the general
population, the SIR for malignant brain tumours was 3.0 (95% CI: 1.3, 5.9) which, with a mean brain
dose of about 1.4 Gy, gives an ERR of 1.4 (95% CI: 0.2, 3.5) Gy-1.
B209. Colman et al. [C38] reported on nervous system tumours found in about 3,100 children who
had received X-ray treatment for tonsillar enlargement or other head/neck/chest disorders in Chicago at

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133

a mean age of 3.5 years and were followed up for 30 years, on average. The mean dose was about
0.8 Gy at the midbrain [N38] and 4.6 Gy at the cerebellopontine angle. They found 14 intracranialtumours when about 1.6 would have been expected; the SIR was 8.8 (95% CI: 4.4, 12.7) [N37]. Six ofthe tumours were malignant. A more recent report showed 15 meningiomas of the brain and 27 cranial
nerve schwannomas, but no expected numbers were provided [S119].
B210. Another series of 2,580 patients received radiotherapy for various head-and-neck benign
conditions at young ages were followed up for subsequent tumours. A total of 66 neural tumours wasreported [S32, S59], of which about half were intracranial tumours. No analysis by age at exposure wasreported.
B211. Furst et al. [F25] followed up a cohort of 14,647 children who were treated with 226Ra for skinhaemangiomas in Sweden between 1920 and 1959, as compared to 2,694 patients not treated withradiotherapy. In this study, there was no elevation in the relative risk of brain cancer in the irradiatedgroup. However, the estimated mean brain dose was only 0.1 Gy, so a null result is not surprising[F27].
B212. Karlsson et al. [K11] reported on a cohort of 11,805 infants treated with 224Ra for skinhaemangioma in Sweden and followed up for about 34 years. They reported an SIR compared togeneral population rates of 1.8 (95% CI: 1.3, 2.4; n = 46) for all intracranial tumours; an SIR of 1.9(95% CI: 1.2, 2.8; n = 23) for gliomas; and an SIR of 2.4 (95% CI: 1.1, 4.8; n = 8) for meningiomas.
The mean dose to the brain was only about 70 mGy, so the excesses are unexpected; furthermore, there
was no significant dose response.
B213. Karlsson et al. [K12] then pooled the two Swedish cohorts of infants treated with radiation forskin haemangiomas, making a total of 26,949 irradiated infants and 1,859 who did not receive
radiotherapy. For almost all irradiated infants the treatment consisted of 226Ra applicators on the skin.
Again the mean brain dose was low, about 70 mGy, but the range was substantial (from 0 to 11.5 Gy).
They found intracranial tumours (including 35 gliomas and 20 meningiomas) in 83 irradiated and three
non-irradiated infants, giving an SIR of 1.4 (95% CI: 1.1, 1.8). They found a statistically significant
dose response (p = 0.02). The ERR Gy-1 was 2.7 (95% CI: 1.0, 5.6) and the EAR was 2.1 (95% CI: 0.3,
4.4) (104 PY Sv)-1. The slope of the dose response was significantly modified by age at first irradiation,such that it was higher at younger ages (p = 0.02). Specifically, the ERR was 4.5 Gy-1, if treatment
occurred before five months of age; 1.5 Gy-1, if given at five–seven months; and 0.4 Gy-1, if given atover seven months.
B214. An excess of brain neoplasms has been reported in subjects who had received radiation
exposure in childhood for the prevention of deafness. In those circumstances, a radium applicator wasapplied to the nasopharynx to reduce the size of the adenoid tissue. The dose at a distance of 1 cm fromthe applicator was estimated to be 7.2 Gy, dropping to 0.78 Gy at 3 cm. The series included 904
irradiated subjects and 2,021 controls, who were treated surgically. Three brain tumours were identified
in the irradiated population compared to none in the controls in the earliest report [S20]. Continued
follow-up of the study subjects found three malignant and four benign brain tumours in the irradiatedgroup and none in the unexposed comparison group [Y5]. A Dutch study of over 4,000 patients withnasopharyngeal irradiation found five malignant brain tumours, which was not statistically significant;the SIR was 1.3 (95% CI: 0.4, 3.1) [R48].
B215. An excess of benign nervous system tumours (mostly non-intracranial) was found in a thymus
infant irradiation study; the odds ratio was 6.0 (95% CI: 2.0, 19; n = 13), but there was no excess ofmalignant tumours [H47].

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5.

Radiotherapy for cancer

B216. A number or studies [E9, F11, S11] link gliomas to previous cranial radiation for childhood
leukaemia (usually acute lymphocytic leukaemia). A number of authors [H31, K33] have indicated thepossibility of genetic predisposition, IT methotrexate, and radiation as possible causes. In one study of981 children in Nordic countries [N45], the incidence of brain tumours was 27 times greater than
expected. No increase was seen after chemotherapy alone. There are several isolated case reports ofmeningioma occurring after cranial radiotherapy [D41, S107].
B217. Neglia et al. [N21] followed up 9,720 children who had been treated for ALL at the averageage of 4.7 years and who were enrolled in one of 23 clinical (mostly randomized) trials conducted by
the United States Children’s Cancer Study Group. The doses of cranial radiation were 18–24 Gy.
Seventy-two per cent were followed up for five or more years and 10% for over ten years. A total of 24
neoplasms of the CNS were diagnosed as second primaries compared to 1.06 expected, which
represents an SIR of 23 (95% CI: 15, 33). All of the CNS tumours occurred among those who hadreceived cranial irradiation. However, the numbers with and without irradiation were not reported, andno indication was given as to what percentage of the study population and cases also had had
chemotherapy.
B218. In a 2006 report on 14,000 persons in the CCSS who were treated for childhood cancers,
Neglia et al. [N22] reported that radiation was associated with an increased risk of subsequent glioma;
the odds ratio was 6.78 (95% CI: 1.54, 29.7), and meningioma; the odds ratio was 9.94 (95% CI: 2.17,45.6). The dose response for ERR was approximately linear—for glioma, the slope was 0.33 (95% CI:
0.07, 1.71) Gy-1 and for meningioma, the slope was 1.06 (95% CI: 0.21, 8.15) Gy-1. For glioma, theERR per unit dose was highest among children exposed at less than five years of age. After adjustment
for radiation dose, neither the original cancer nor chemotherapy was associated with the increased risk.
The distribution of subsequent gliomas and meningiomas differed strikingly over time. The radiationrelated increase in glioma became apparent five–ten years after exposure but largely disappeared after
15–20 years. By the time the survivors of childhood cancer had reached their mid-20s, the risk ofglioma had dropped to nearly background levels. The ERR per unit dose for subsequent glioma wassignificantly greater than zero only for ages at irradiation of less than five years, which suggests thatsusceptibility to radiation-related brain cancer decreases as brain development nears completion. In
contrast to gliomas, meningiomas took longer to appear and showed no signs of subsiding in the latest
follow-up intervals.
B219. Subsequent brain and CNS tumours have been ascertained among 18,000 children treated forcancers in the British Childhood Cancer Survivor Study [T11]. They observed 247 second primary
tumours of the CNS, including 73 gliomas and 137 meningiomas. For gliomas, there was not a linear
radiation dose response although the risk was statistically significantly elevated at the highest doselevels (40 Gy or greater). However, for mengiomas there was a strong, approximately linear dose
response, with relative risks ranging from 1.8 at <10 Gy up to 479 at >=40 Gy (analyses adjusted forconcomitant intrathecal methotrexate exposure).
B220. Albo et al. [A14] reported on brain tumours that developed among 8% of the children involvedin a clinical trial for the treatment of ALL. The protocol involved radiation exposures of 24 Gy(2,400 R) and several types of chemotherapy. Nine brain tumours occurred when 0.04 were expected.
The brain tumours developed 16–54 months after the irradiation. This study is difficult to interpretbecause of the concomitant chemotherapy. In a study of second malignancies after treatment forchildhood cancer, Smith et al. [S90] observed 12 CNS second malignancies, but none was associatedwith radiotherapy alone and only four with radiation plus an alkylating agent. Among 4,400 persons
treated for childhood cancer, subsequent brain tumour incidence was determined [L28]. A statistically

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135

significant (p = 0.003, n = 10) radiation dose response was reported for benign brain tumours, but not
for malignant ones (n = 12).
B221. Curtis et al. [C55] studied 19,229 bone marrow transplant patients who averaged 25 years ofage at transplant. A conditioning regimen of total-body irradiation was given to 73% and another 3%
received limited-field irradiation; 65% also received cyclophosphamide and 8% other drugs. Doses tothe brain were not reported. An excess of brain/CNS cancers was observed; the SIR was 7.6 (95% CI:
3.8, 13.5; n = 11). Of particular interest was the fact that 9 of the 11 cases occurred among the 18%
who were under age 10 at the time of transplantation, for whom the SIR was 41 (95% CI: 20, 75), butthere was no excess at older ages, for whom the SIR was l.6 (95% CI: 0.3, 5.4).
B222. There is a substantial mortality among childhood cancer survivors with secondary neoplasmsof the CNS. A study by Vasudevan et al. [V13] based on the Surveillance, Epidemiology, and End
Results (SEER) database, reported a 10-year survival rate of 13.6% among those with secondary CNS
tumours after a primary diagnosis of paediatric solid tumour. A report from the British CCSS [T10]reported 62 patient deaths among 73 survivors with secondary gliomas, but only 42 patient deaths
among 137 survivors with secondary meningiomas.

C. Internal exposure
B223. In a study by Hall et al. [H5] of patients treated with 131I for thyroid cancer, the irradiatedgroup showed a suggestive, but not statistically significant, excess of nervous system malignancies
when compared to the general population (the SIR was 2.4) or to an non-irradiated thyroid cancer group(the relative risk was 1.5). Other studies of patients treated for thyroid cancer have similarly shown noexcess of brain/CNS cancers. However, the numbers of patients in the series were relatively small [B62,
D27, D46, G13]. Holm et al. [H59] reported a modest excess of brain cancer in patients who had beentreated with 131I for hyperthyroidism; the SIR was 1.3 (95% CI: 1.0, 1.7; n = 48). None of the studies
showed brain tumour results for those young at exposure.
B224. Andersson and Storm [A18] found a large excess of malignant brain/CNS tumours (the SIR
was 28, n = 71) among 999 Danish patients who had received thorotrast for cerebral arteriography.
However, many of those tumours were diagnosed by or shortly after the cerebral arteriography andshould be discounted. For the period of 10 or more years after the thorotrast injection, the SlR was 5.6(95% CI: 3.0, 9.8; n = 11). For the period of more than 20 years after thorotrast injection, the relativerisk was found to be approaching unity and increased risk was no longer statistically significant [A19].
Doses to the brain were not reported. Van Kaick et al. [V4] also reported a small excess of brain
tumours in patients with administered thorotrast—the SMR was 1.32 (95% CI: 0.8, 2.1; n = 18)—but
again, doses to the brain were not reported and there may have been subjects with pre-existing brain
tumours.

D. Summary
B225. Ionizing radiation can induce tumours of the CNS, with a moderate degree of association(relative risk) in the LSS, although it does not account for a large number of excess cancers because
CNS tumours are relatively rare. There appear to be strong age-at-exposure effects. The risk for glioma

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UNSCEAR 2013 REPORT

is greatest at ages of irradiation of five years or less and there is little risk for irradiation after age 20,
suggesting that susceptibility decreases as brain development nears completion. The UNSCEAR 2006
Report [U12] points out that malignant tumours of the CNS are seen mostly after high doses fromradiotherapy and the risk is predominantly after exposure in childhood (table B13).
Table B13. Age differences in risk estimates for brain and CNS cancer incidence and mortality fromstudies of radiation exposure
Updated and adapted from UNSCEAR 2006 Report (annex A, table 39) [U12]. Studies listed are those for which quantitative
estimates of risk could be madeAverage ERR a at 1 Sv

Study

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]c

Age at exposure<20 years

0.88 (0.28, 1.78)

0.68 (0.24, 1.28)

20–40 years

0.64 (<0, 1.82)

0.48 (<0, 1.43)>40 years<0 (<0, 0.51)<0 (<0, 0.28)

0.55 (0.16, 1.07)

0.57 (0.23, 1.01)

All
LSS–incidence (excluding schwannomas) [P49]
Age at exposureb<20 years

1.2 (0.3, 2.9)

≥20 years

0.2 (<-0.2, 1.0)All

0.6 (0.1, 1.3)

Israeli tinea capitis [S5] – Malignant brain
tumours
Age at exposure

0–4 years

3.6 (1.0, 9.9)

5–9 years

2.2 (0.8, 5.5)

10–15 years

0.5 (<0, n.a.)All

1.98 (0.73, 4.69)

0.31 (0.12, 0.53)

All benign meningiomas

4.63 (2.43, 9.12)

0.48 (0.28, 0.73)

1.4 (0.2, 3.5)

n.a.

New York tinea capitis [S71]Brain cancer
Swedish pooled skin haemangioma [K12] b
Age at exposure

0–4 months

4.5

5–7 months

1.5>7 months

0.4

All

2.7 (1.0, 5.6)

2.1 (0.3, 4.4)

All brain tumours

0.19 (0.03, 0.85)

n.a.

Malignant tumours

0.07 (<0, 0.62)

n.a.

Benign tumours

n.a.

n.a.

Childhood cancer survivors [L28]bANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

Study

Average ERR a at 1 Sv

137

Average EAR a (104 PY Sv)-1

Incidence
Childhood cancer survivors [N22]
GliomasAge at exposure<5 years

0.64 (0.12, 5.66)

5–9 years

0.10 (-0.20, 0.39)

10–20 years

0.15 (-0.23, 0.52)<5 years

0.75 (00.11, 6.59)

5–9 years

1.99 (0.28, 21.1)

10–20 years

1.36 (0.10, 30.7)

Meningioma
Age at exposure

Mortality
LSS [P50] c
Age at exposure<20 years

5.72 (1.56, 17.04)<0 (<0, <0)>20 years

0.77 (<0, 4.88)<0 (<0, 35.70)

2.86 (0.83, 6.76)<0 (<0, 35.75)

Alla

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

95% CI in parentheses.

c

Data are for all brain and nervous system tumours combined.

XII. KIDNEY CANCER
B226. The incidence of primary renal-cell carcinoma has increased slowly over the last decade.
Primary renal-cell carcinoma accounts for about 85% of primary malignant tumours of the kidney.
Other malignant tumours include Wilms' tumour, transitional cell carcinoma and lymphoma.

A. External exposure
B227. There are no data available regarding age-at-exposure effects for induction of radiation-related
kidney cancer from epidemiological studies of populations exposed to relatively high levels of natural
background radiation, populations living near nuclear facilities or patients who have undergone medical
diagnostic exposure.
B228. The incidence study of the survivors of the atomic bombings through 1987 [T24] yielded an
ERR for kidney cancer of 0.71 (90% CI: -0.11, 2.2) Sv-1 and an EAR of 0.29 (90% CI: −0.50, 0.79)(104 PY Sv)-1. The attributable risk was 15.2% (90% CI: -2.6, 41.3). In a report on mortality through2000 [P50] for kidney cancer in males, there was a non-significantly reduced relationship with radiation
dose. The male ERR at 1 Sv was −0.2 (90% CI: <−0.3, 1.1) and the EAR was −0.01 (90% CI: −0.1,0.28) (104 PY Sv)-1 and the attributable risk was –0.4% based on 36 deaths. For kidney cancer infemales, there was a non-significantly reduced relationship with radiation dose. The ERR at 1 Sv was

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UNSCEAR 2013 REPORT

0.97 (90% CI: <−0.3, 3.8), the EAR was 0.14 (90% CI: <−0.1, 0.42) (104 PY Sv)-1 and the attributablerisk was 14% based on 31 deaths. No age-at-exposure effect was identified (see table B14).
Table B14. Risk estimates for kidney cancer incidence and mortality from studies of childhoodradiation exposure
Adapted from UNSCEAR 2006 Report (annex A, table 38) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]
Sex

Age at exposureMales<0 (<0, 0.42)

0.18 (0.02, 0.61)

Females

1.04 (0.02, 2.83)<0 (<0, 244.95)<20 years

0.75 (<0, 2.19)

0.31 (0.08, 0.74)

20–40 years

0.23 (<0, 1.94)<0 (<0, 304.44)>40 years<0 (<0, <0)<0 (<0, <0)0.16 (<0, 0.78)

0.28 (0.09, 0.58)

All

Mortality
LSS [P50]
Sex

Age at exposure

All
a

Males

<0 (<0, >10 000)<0 (<0, 114.09)

Females

1.17 (<0, 4.28)<0 (<0, 71.62)<20 years<0 (<0, >10 000)<0 (<0, 39.84)

20–40 years

0.86 (<0, 4.13)<0 (<0, 106.20)>40 years<0 (<0, <0)<0 (<0, 198.97)

0.35 (<0, 1.51)<0 (<0, 88.31)

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

B229. In the LSS incidence study for 1958–1998 of renal cell cancer [P52] the estimated ERR at 1 Sv
was 0.13 (90% CI: −0.25, 0.75). An analysis of effect modification suggested that the ERR decreased
with either age at exposure (p = 0.005) or attained age (p < 0.001), but both could not be modelledsimultaneously because the excess number of cancers was too small. The EAR at 1 Sv was statisticallysignificant (EAR = 0.25; 90% CI: 0.07, 0.53 (104 PY Sv)-1).
B230. Radiotherapy can give quite high doses to specific organs. Radiotherapy patients have been
followed up after treatment for benign as well as those treated for malignant conditions. Hawkins et al.
[H31] reported a slight increase in genitourinary second primary tumours in survivors of childhood
cancer. The ratios of observed over expected numbers of tumours was 1.9 (95% CI: 0.5, 4.8). Friedman
et al. have followed up 14,359 five-year survivors in the CCSS [F17] and reported an increase in kidneycancer (ratio of observed over expected numbers was 20/3) with an SIR of 7.4 (95% CI: 4.6, 11.6) witha median time to occurrence of 19.6 years (range of 6.3 to 28.4 years). These results should be treatedwith caution as they include patients treated with chemotherapy, radiotherapy or a combination of both.
Wilson et al. [W26] updated the kidney cancer data in the CCSS study and observed 26 kidney cancers.
For renal-directed radiotherapy of 5 Gy or greater, they observed a relative risk of 3.8 (95% CI: 1.6,

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

1399.3). Dores et al. [D43] reported in a pooled follow-up study of 32,000 patients an SIR of 1.5 (95% CI:
1.1, 2.1, n = 42) for subsequent kidney cancer, but did not report results by age at treatment.

B. Summary
B231. The BEIR VII report [N43] does not provide any risk factor for kidney cancer. The
UNSCEAR 2006 Report [U12] has summarized those epidemiological studies that can be used toderive risk estimates for kidney cancer following childhood exposure. These are shown in table B14.
The UNSCEAR 2006 Report also indicates that there is only weak evidence linking kidney cancer withradiation exposure and it comes primarily from those studies where the dose to the kidney is high (inthe radiotherapy range). There does not appear to be any significant age-at-exposure effect.

XIII.BLADDER CANCER
B232. Bladder cancer represents about 3 to 4% of all cancers in the world. Rates are high inindustrialized countries, particularly in Europe and North America. Low rates occur in India and Japan.
A wide variety of causes of bladder cancer have been identified. The most common causes in adults aretobacco smoking, occupational exposure to aromatic amines and parasitic infection.

A. External exposure
1.

Atomic bombing survivors

B233. The incidence study of atomic bombing survivors through 1987 and published by Thompson
et al. [T24] yielded an ERR for bladder cancer of 1.0 (95% CI: 0.27, 2.1) Sv-1 and an EAR of 1.2(104 PY Sv)-1. The ERR risk was 0.35 for males and 1.80 at 1 Sv for females. The absolute risk formales was 0.84 (104 PY Sv)-1. The attributable risk was 16.3%. In the report on mortality through 2000
by Preston et al. [P50], there was a statistically significant relationship between radiation dose andcancer of the bladder. For males, the ERR at 1 Sv was 1.1 (90% CI: 0.2, 2.5) and the EAR was 0.7(90% CI: 0.1, 1.4) (104 PY Sv)-1 and the attributable risk (17%) was based on 83 deaths. For females,
the ERR at 1 Sv was 1.2 (90% CI: 0.1, 3.1) and the EAR was 0.33 (90% CI: 0.02, 0.74) (104 PY Sv)-1
and the attributable risk (16%) was based on 67 deaths.
B234. The incidence data were updated through 1998 by Preston et al. [P52]. The ERR for bladdercancer was among the highest of the tumour sites, with a sex-averaged ERR Gy-1 of 1.23 (90% CI:
0.59, 2.1). However, since bladder cancer is relatively uncommon, the EAR (104 PY Sv)-1 wasmoderate: 3.2 (90% CI: 1.1, 5.4). The ERR was much higher for females than males: 1.9 (0.8, 3.4)
versus 0.6 (0.1, 1.2), respectively, though the EAR estimate was nominally lower for females 2.6 (90%
CI: 1.1, 4.4) than for males 3.8 (90% CI: 0.2, 8.0). There was no age-at-exposure trend per decade of

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UNSCEAR 2013 REPORTage at exposure for either the ERR model −3% (90% CI: −42, 56), or the EAR model −19% (90% CI:−54, 41).
B235. The updated mortality data likewise indicate no age-at-exposure effect; the effect on the ERR
model was −2% (95% CI: −62, 92) per decade of age at exposure [O25]. A detailed study of urothelial
cancer incidence by Grant et al. [G26] (of which >90% were bladder cancers) found very similar results
to the Preston et al. study [P52] regarding risk estimates, and additionally found that smoking and otherlifestyle or occupational factors had almost no impact on the radiation risk estimates, indicating thatsecular or birth cohort trends in smoking did not appear to confound the age-at-exposure risk estimatesfor bladder/urothelial cancer.

2.

Radiation therapy

B236. Radiation therapy can give quite high doses to specific organs, and patients have been
followed up after therapy for benign, as well as for malignant, conditions. Travis et al. [T36] havereported on long-term survival and second cancers in over 40,000 testicular cancer patients almost all ofwhom received infradiaphragmatic radiotherapy. The relative risk for bladder cancer was significantly
increased (RR = 2.7; 95% CI: 2.2, 3.1). Hawkins [H31] reported a slight increase in genitourinary
second primary tumour GU SPT as a group (ICD-8: 180–189) (O/E = 1.9; 95% CI: 0.5, 4.8).

B. Summary
B237. The bladder appears to be sensitive to radiogenic tumour induction. In spite of this, the mostcommon cause of bladder cancer is cigarette smoking, and a number of other causative factors are
known as well. All of these need to be considered in evaluation of any specific case, as was recently
done in the LSS study of atomic bombing survivors. Most occupational radiation studies are negative,
and the positive correlations come primarily from the atomic bombing survivors and patients who
received very high bladder doses from radiotherapy.
B238. The 1990 ICRP report [I11] estimates the probability of fatal bladder cancer after exposure of
the general population to be 0.30 × 10-2 Sv-1. The 1990 BEIR V report [N38] concluded that radiation
can cause cancer of the bladder and, to a lesser extent, cancer of the kidney and suggested use of theatomic bombing survivor risk estimates. The BEIR VII report [N43] provides a lifetime risk estimate
for bladder cancer of 25 excess deaths for a population of 100,000 persons exposed to 0.1 Gy and a
lifetime bladder cancer estimate of 0.90 Sv-1 (95% CI: 0.30, 2.90).
B239. The UNSCEAR 2006 Report [U12] has summarized those epidemiological studies that can beused to derive risk estimates for bladder cancer. These are shown in table B15. It is clear that there is apositive association between radiation and bladder cancer in the atomic bombing survivors and after
high dose radiotherapy. However, most low dose studies of nuclear workers and medical applications
do not show increased risk of bladder cancer (perhaps due to limited statistical power). The atomic
bombing data do not show any special radiation sensitivity among those irradiated in childhood.

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Table B15. Risk estimates for urinary bladder cancer incidence and mortality from studies ofchildhood radiation exposure
Updated and adapted from UNSCEAR 2006 Report (annex A, table 37) [U12]. Studies listed are those for which quantitative
estimates of risk could be madeStudy

Average ERR a at 1 Sv

Average EAR a(104 PY Sv)–1

Incidence
LSS [P52]
Sex

Age at exposure

Males

0.63 (0.17, 1.25)

0.47 (<0, 1.60)

Females

1.74 (0.71, 3.22)

0.52 (0.12, 1.13)<20 years

1.00 (0.16, 2.32)<0 (<0, 0.46)

20–40 years

0.95 (0.23, 2.01)

0.69 (<0, 1.89)>40 years

0.78 (0.14, 1.70)

2.28 (0.21, 5.01)

0.92 (0.46, 1.50)

0.51 (0.14, 1.02)

All
LSS [P52]c

Age at exposure

0–9 b years−0.09 (<−0.1, 5.1)

10–19 years

1.3 (0.16, 3.9)

20–39 years

1.1 (0.33, 2.2)

≥40 years

1.4 (0.47, 2.8)

Mortality
LSS [P50]
Sex

Age at exposureMales

1.03 (0.07, 2.53)<0 (<0, 313.73)

Females

1.37 (0.15, 3.40)<0 (<0, 170.04)<20 years<0 (<0, 2.28)<0 (<0, 43.45)

20–40 years

1.52 (<0, 4.72)<0 (<0, 176.04)>40 years

1.36 (0.34, 2.89)<0 (<0, 848.46)

1.17 (0.36, 2.30)<0 (<0, 226.53)

10 years b

1.24

1.22

30 years

1.19(95% CI: 0.27, 2.7)

1.2(95% CI: 0.3, 2.4)

50 years

1.15

1.18

All
LSS [O25]
Age at exposurea

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

Sex-averaged risk at attained age 70, smoothed using the assumption that the ERR Gy-1 varies as a log-linear function of age at
exposure.

c

Sex-averaged risk at attained age 70, assuming that within each age-at-exposure group the ERR Gy-1 varies as a power ofattained age, but with no smoothing across age-at-exposure groups.

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XIV. OVARIAN CANCER
B240. Cancer of the ovary is more common in industrialized countries. Most tumours are serous or
pseudomucinous cystadenocarcinomas, and most have a relatively poor prognosis. Studies of changes
in incidence among migrant populations suggest environmental influences may be present [H45]. Earlyand frequent parity may be associated with an over 50% reduction in risk. Breast cancer is also
associated with ovarian cancer. Oral contraceptives may reduce the risk of ovarian cancer. There aresome unusual genetic associations, including the Peutz-Jeghers syndrome, basal cell nevus syndrome,and gonadal dysgenesis.

A. External exposure
1.

Atomic bombing survivors

B241. Incidence and mortality studies [R42, S55, T24] of the atomic bombing survivors report risksof ovarian cancer. The 1958–1987 incidence study yielded an ERR estimate for ovarian cancer of 1.0(95% CI: 0.12, 2.34) Sv-1 and an EAR of 1.1 (104 PY Sv)–1. There was a statistically significant linear
relationship between dose and risk. No effect of age at exposure, time since exposure, or of attained age
was found. In the update of mortality of atomic bombing survivors during the period 1950–1997,
Preston et al. [P50] found a statistically significant excess of ovarian cancer with an ERR of 0.94 (90%
CI: 0.07, 2.0) Sv-1. There was no significant difference in risk between those <20 years at exposurecompared with those >40 years of age at exposure.
B242. In the latest incidence report for 1958–1998 [P52], the ovarian cancer ERR Gy-1 was 0.61
(90% CI: 0.00, 1.5) and the EAR was 0.56 (90% CI: 0.02, 1.3) (104 PY Gy)–1. There were too few
excess cases, however, to examine age at exposure meaningfully. The mortality report for 1950–2003[O25] indicated an ERR Gy-1 of 0.79 (95% CI: 0.07, 1.86). Age at exposure was examined, but the CIs
were very wide, and the modelled age-at-exposure effect was −22% per 10 years of age (95% CI: −96,
218).

2.

Radiation therapy

B243. Few studies have examined radiation therapy for benign diseases and the subsequent risk ofovarian cancer. Many patients were treated with radiotherapy for ankylosing spondylitis. Darby et al.
[D6] have extended the follow-up of this group, and cancer of the ovary was not elevated, with areported O/E ratio of 0.93. Most studies of radiotherapy for benign gynaecological disease have notreported on ovarian cancer risk [D8, I38], although one study reported no excess based on small
numbers [S91].

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B. Internal exposure
B244. The studies examining ovarian cancer after administration of radioiodine have yielded
negative results although essentially all the patients were exposed as adults [E8, H5, H53, H59, H58,
R45].

C. Summary
B245. With the exception of the atomic bombing survivor data, not much epidemiological evidenceof radiation induction of ovarian cancer exists either in those exposed as adults or children. The
UNSCEAR 2006 Report [U12] has summarized risk factors that can be obtained from epidemiologicalstudies (table B16) and concluded that although the body of evidence is not strong, the Japanese LSS
provides evidence that ovarian cancer is inducible by ionizing radiation.
Table B16. Risk estimates for ovarian cancer incidence and mortality from studies of childhoodradiation exposure
Adapted from UNSCEAR 2006 Report (annex A, table 35) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

EXTERNAL LOW-LET EXPOSURES
Incidence
LSS [P52]
Age at exposure<20 years

1.16 (0.15, 2.86)

0.71 (0.09, 1.72)

20–40 years<0 (<0, 0.71)<0 (<0, 0.71)>40 years

1.73 (0.20, 4.45)

3.24 (0.45, 7.21)

0.61 (0.08, 1.35)

0.59 (0.07, 1.34)

0.62

0.33

All
Stockholm skin haemangioma [L41]

Mortality
LSS [P50]
Age at exposureAlla<20 years

1.53 (0.19, 4.06)<0 (<0, 185.15)

20–40 years

0.92 (<0, 2.65)<0 (<0, 386.99)>40 years

1.33 (<0, 4.25)<0 (<0, 717.59)

1.18 (0.39, 2.31)<0 (<0, 348.40)

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

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UNSCEAR 2013 REPORTXV. UTERINE CERVIX AND CORPUS CANCER
B246. Worldwide, cervical cancer is the second most common cancer in women but, in developing
countries, it is the most frequent cancer [I5]. Endometrial cancer is 1/3 as frequent as cervical cancer.
Cancer of the endometrium is more common in nulliparous women. Obese women have a two- to
fivefold increase in risk. Menopause may have a protective influence. Exogenous oestrogens are amajor risk factor, with increases in cancer associated with use of oral conjugated oestrogens
administered for replacement therapy and use of sequential oral unopposed oestrogen contraceptives.
The risk of cervical cancer is higher with earlier age at first intercourse and rises with the number ofsexual partners throughout life. Thus, there is very likely a sexually transmitted factor (humanpapilloma virus). In most studies there is also an increased risk of cervical cancer with smoking, andsmokers have a relative risk of about two compared with non-smokers.

A. External exposure
1.

Atomic bombing survivors

B247. Neither the 1958–1987 incidence [T24] nor the 1958–1987 mortality study [R42] of the atomic
bombing survivors showed any increase in cancer of the uterus. The ERR at 1 Sv derived from theincidence study was negative, at –0.2, and the EAR was –1.1 (104 PY Sv)–1. In the mortality study
through 1987, the corresponding values were 0.1 and 0.3 (104 PY Sv)–1. In the 2003 mortality updatefor 1950–1997 [P50], the survivors had a non-significant excess of uterine cancer with a corresponding
ERR Gy-1 of 0.17 (90% CI: −0.10, 0.52). No age-at-exposure effect was identified.
B248. The most recent study of uterine cancer incidence for 1958–1998 [P52] reported no associationof radiation with cervical cancer (ERR at 1 Sv, 0.06; 90% CI: −0.14, 0.41) and no overall association
with uterine corpus cancer (ERR, 0.3; CI: −0.14, 0.95). However, among those exposed before age 20,
the ERR at 1 Gy was 1.00 (CI: 0.14, 2.4) for uterine corpus cancer and the risk was significantly greater(p = 0.04) among those exposed before age 20 compared with after age 20.

2.

Radiation therapy

B249. No specific data relevant to childhood exposure is available. Although various studies ofradiotherapy for benign [I38, S91] or malignant [B37] gynaecological disease have reported on
subsequent uterine cancer, they have had few or no patients irradiated before age 20. A study of second
cancers among Hodgkin’s disease patients treated in childhood or adolescence reported a statisticallysignificant excess of cervical cancer but no excess for uterine corpus cancer [M32]. Another larger
pooled study that included those and other subjects found, however, that cervical cancer risk waselevated with or without radiotherapy [D43].

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145

B. Summary
B250. The epidemiological literature in general does not support radiation induction of uterine
neoplasms. While there are a few anecdotal case reports in the literature, these should not be taken to
prove a causal relationship, and the recent suggestive finding of an excess of uterine corpus cancers
among those exposed to the atomic bombings when young requires confirmation with longer follow-up
and other studies. The UNSCEAR 2006 Report [U12] has summarized those epidemiological studies
that provide risk factors for uterine cancer following radiation exposure (table B17). The UNSCEAR
2006 Report [U12], concluding that there is no strong radiation dose response for uterine cancer andthat the absence of an association between cervical cancer and radiation is a consistent finding evenafter very high radiation doses. It also concludes that for cancer of the uterine corpus (endometrial
cancer), the evidence is largely negative and that if there is an association with radiation it is confinedto very high doses.
Table B17. Risk estimates for uterine cancer incidence and mortality from studies of radiation
exposure
Adapted from UNSCEAR 2006 Report (annex A, table 34) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]
Age at exposure<20 years

0.38 (<0, 0.90)

0.75 (<0, 2.59)

20–40 years<0 (<0, 0.33)

0.20 (<0, 2.85)>40 years<0 (<0, 0.41)

0.09 (<0, 4.88)

0.10 (<0, 0.32)

0.09 (<0, 1.48)

All

Mortality
LSS [P50]
Age at exposureAlla<20 years

0.42 (<0, 1.68)<0 (<0, 333.82)

20–40 years

0.17 (<0, 0.77)<0 (<0, 1.61)>40 years<0 (<0, 0.51)<0 (<0, 3.53)

0.09 (<0, 0.44)<0 (<0, 0.33)

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

XVI. BONE AND CONNECTIVE TISSUE TUMOURS
B251. Tumours of bone and cartilage account for about 0.5% of all malignant neoplasms. Malignant
bone tumours are divided into several types, with osteosarcoma accounting for 38%; chondroblastic
sarcoma, 17%; Ewing’s sarcoma, 15%; and all other histological forms, 30%. There is a male–female
sex ratio of 1:3; five-year survival is approximately 30% for radiation-induced tumours of bone. An
overall fatality rate of 75–80% is usually seen. The various types of tumours are quite age dependent.
Osteosarcomas tend to occur in teenagers and in adults who have predisposing Paget’s disease. Ewing’s

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sarcoma occurs in childhood and early adult life. Fibrosarcomas mostly occur in middle-aged adults
and chondrosarcomas in older adults. There is a relative lack of variation in incidence rates, whichargues against a common environmental aetiology. There may be some evidence of a familial tendency
for osteogenic sarcoma in families with multiple tumours. An increase in bone tumours occurs after useof alkylating agents in treatment of childhood cancer. The attributable risk due to radiation is estimatedto be less than 10% [H45, I5]. The frequency of soft tissue sarcomas is greater than for bone sarcomas,
but the former has been studied less in relation to radiation.

A. Modifying factors
B252. The absolute radiation risk estimates are somewhat clouded by the fact that many of the
population groups exposed to external irradiation received irradiation in body areas where thespontaneous incidence of osteosarcomas is low. For example, the most common site of osteosarcoma is
the distal femur (i.e. peripheral skeleton). The patients exposed either for treatment of tinea capitis orfor ankylosing spondylitis received the radiation predominantly to the axial skeleton. People who
received internal exposures from radium are somewhat difficult to evaluate because the different
radioisotopes of radium decay with substantially different rates; thus, the dose is delivered by alpharadiation to different portions of the bone on the basis of the position of the radionuclide in themetabolic cycle of bone. With a physical half-life of 3.62 days, 224Ra yields a relatively high endostealdose, whereas longer-lived 226Ra decays mainly within the bone volume. An additional problem inderiving risk estimates is the appropriate RBE to be used for alpha particles. In general, the ICRP
quality or radiation weighting factor of 20 has been used by most authors. Fractionation is a major
modifying factor that has been rather clearly demonstrated in the case of 224Ra. Contrary to most othertypes of irradiation, for radium the effectiveness of a given dose increases as the time of irradiation is
protracted. Thus, the absolute risk factors rise if 224Ra is administered over weeks and years rather thanin a single injection. The risk factors appear to be relatively similar for children and adults, and also formales and females [S101, S102].

B. External exposure
1.

Atomic bombing survivors

B253. The older incidence and mortality studies of the atomic bombing survivors do report casenumbers, but they did not show significantly increased risks for bone and connective tissue cancers.
The incidence study during the period 1958–1987 [T24] observed 16 cases of bone and connective
tissue cancer versus 12 expected in 41,000 persons who received 0.01 Sv or more. In the comparable
mortality study [S55], there were 24 deaths versus 19 expected. A recent report suggested a dosethreshold up to a dose of about 0.85 Gy with an approximately linear, statistically significant slope
above that level. Those younger at exposure had a shorter interval between atomic bombing exposureand bone cancer diagnosis than did those who were older when exposed, but the groups did not differ inoverall risk [S12]. For connective tissue malignancies (104 soft-tissue sarcomas), a recent report
showed an approximately linear dose response and an ERR risk estimate of 1.0 (95% CI: 0.13, 2.5) Gy-1

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147

and an EAR of 0.4 (95% CI: 0.1, 0.9) (104 PY Sv)-1 [S13]. The effects did not vary by age at exposurefor either model.

2.

Radiation therapy

B254. In treatment of tinea capitis, bone tumours have been reported in at least two studies. The
UNSCEAR 1977 Report [U6] reviewed these latter studies and, assuming that the skull forms about
25% of total bone mass in children, derived an absolute lifetime risk factor of three–five cases/million
persons for each 10 mGy. Most studies involving external irradiation yield risk estimates that may varywith the skeletal site involved. The BEIR III report [N37] indicated that different portions of theskeleton may have different radiosensitivity.
B255. In a study by Evans et al. [E14] of about 700 patients treated for Wilms' tumours withradiotherapy, subsequent bone cancer was not observed, even though there were 19 patients withbenign exostoses or osteochondromas. Osteosarcomas have been reported after radiation therapy for
Ewing's tumour, although the series are too small to develop risk estimates [S89].
B256. In a study by Hawkins et al. [H31] of 10,106 childhood cancer survivors, there was asignificant increase (20-fold) in the number of sarcomas. Risk was particularly high (400-fold) inpatients with familial retinoblastomas. In fact, in patients with this entity, the risk was 200-fold times
the normal even without radiotherapy or chemotherapy. Sagerman et al. [S9] have reported thatapproximately 1.5% of children treated for retinoblastoma will develop radiation-induced malignancies
with about half of these being osteosarcomas. However, that children with heritable retinoblastomas areat increased risk for other tumour types even outside the radiation therapy field [S29]. The CCSS
reported an SIR for osteosarcoma of 30 (95% CI: 21, 42; n = 35) after treatment for childhood cancer[F17]. A more detailed study of sarcomas after childhood cancer in the CCSS reported that the riskfunction was essentially linear with an excess odds ratio (EOR) of 1.32 (95% CI: 0.44, 4.22) Gy-1 basedon 105 sarcomas and adjusted for chemotherapy [H41]. Within the childhood age range there was no
significant age-at-exposure effect, nor was there modification by sex or attained age.
B257. In a study of patients treated for Hodgkin’s disease, Tucker et al. [T48] reported an O/E ratioof 31 (95% CI: 3.5, 111.8) based upon two cases versus one expected. Most patients received both
radiotherapy and chemotherapy [T46]. Woodard et al. [W41] have reported on 16 cases of malignant
bone tumours that arose 4–31 years after irradiation for Hodgkin’s disease. The median absorbed dose
was 40 Gy, and it was estimated that up to 25% of the skeleton was exposed in the primary beam. The
same authors also reported on the survival of 59 patients with post-irradiation osteosarcomas and 20
with malignant fibrous histiocytomas. The five-year, disease-free survival rate for osteosarcomas was
17% compared with a three-year disease-free survival rate for malignant fibrous histiocytoma of 58%[H77]. A similar pattern of subsequent tumours was also reported by Laskin et al. [L8] and in children
by Newton et al. [N30]. A post-radiation case of multicentric osteosarcoma has been reported by
Tillotson et al. [T26] and there are case reports of chondrosarcomas [V12].
B258. Radiation-induced osteochondromas have been reported in 6% of long-term surviving children
who received radiation therapy. It has been postulated that this represents a growth disturbance in theepiphyseal plate rather than a true neoplasm [J8]. These benign “tumours” have been noted in the spine,
pelvis, scapula and ribs [N28].

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UNSCEAR 2013 REPORT

C. Summary
B259. The epidemiological data show convincing excesses of bone and connective tissue tumours
after childhood radiation therapy and a small risk among atomic bombing survivors. Most authoritative
reports give risk estimates for bone cancer although usually not at low doses. The UNSCEAR 2006
Report [U12] has summarized radiation risk factors regarding bone and connective tissue cancer fromepidemiological studies (table B18) and concluded that there is an increased risk of bone sarcomas
following low-LET radiation in the range of tens of grays and that risk factors cannot be derived atdoses below a few grays.
Table B18. Risk estimates for cancer incidence and mortality from studies of childhood radiation
exposure on malignancies in bone and connective tissue
Adapted from UNSCEAR 2006 Report (annex A, table 30) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]
Sex

Males

3.34 (0.90, 9.69)<0 (<0, <0)Females<0 (<0, <0)<0 (<0, 9.75)<20 years

4.33 (0.90, 16.11)<0 (<0, <0)

20–40 years

3.16 (<0, 24.05)<0 (<0, 12.66)>40 years<0 (<0, <0)<0 (<0, <0)

Retinoblastoma patients [W39] b(bone and soft-tissue sarcoma)

0.19 (0.14, 0.32)

n.a.

Childhood radiotherapy,
international [T46] c

0.06 (0.01–0.2)

n.a.

Childhood cancer, United Kingdom(bone) [H34] b

0.16 (0.07, 0.37)

n.a.

Age at exposure

Mortality
LSS [P50]
Sex

Age at exposureMales

1.24 (0.03, 4.47)<0 (<0, 24.40)

Females<0 (<0, 3.15)<0 (<0, 25.43)<20 years

2.11 (<0, 11.62)<0 (<0, 7.21)

20–40 years

8.26 (0.70, 50.09)<0 (<0, <0)>40 years<0 (<0, 0.01)<0 (<0, 35.48)

a

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

95% CI in parentheses.

cEstimates based on UNSCEAR 2000 Report (annex I) [U10].

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XVII. PROSTATE CANCER
B260. Prostate cancer is the most common cancer in elderly males, and the highest rates in the world
are observed in African Americans. The causes of the tumour remain generally obscure. At various
times, sexual activity, vasectomy, intake of dietary fat, hormonal factors and cirrhosis have been
implicated as causes but have yet to be confirmed. Radiation does not appear to be a cause of prostatecancer [H45, I5].

A. External exposure
B261. There are no data on radiation-induced prostate cancer by age at exposure in areas of relatively
high natural background radiation, populations living near nuclear facilities or patients following
medical exposure.
B262. The only age-at-exposure data are from the survivors of the atomic bombings. The incidence
data [T24] for prostate cancer in the survivors show that there was no excess except for one data point
at 2.5 Sv. The ERR at 1 Gy for cancer of the prostate was non-significantly elevated at 0.29 (95%
CI: -0.21, 1.16) and the EAR was 0.6 (104 PY Sv)–1. In the LSS mortality study of the survivors of theatomic bombings from 1958 to 1987, the calculated ERR at 1 Sv was 0.3 (95% CI: -0.3, 1.6), and theEAR was 0.2 (95% CI: –0.2, 0.9) (104 PY Sv)–1. In the update studies of mortality of the survivors of
the atomic bombings from 1950 to 1997, Preston et al. [P50] found that there was a non-significant
excess of prostate cancer at doses of 1 Sv amounting to a non-significant ERR of 0.21 (90% CI: <−0.3,0.96). In the most recent update of prostate cancer incidence (1958–1998), Preston et al. [P52] found noevidence (p > 0.5) of an association with radiation dose. The ERR at 1 Sv was 0.11 (90% CI: −0.10,0.54) and the EAR was 0.34 (CI: −0.64, 1.60). No childhood exposure data were reported.
B263. Most radiotherapy studies have likewise not seen elevations in prostate cancer rates. Aninternational study of Hodgkin’s lymphoma patients found an SIR of 1.0 (95% CI: 0.8, 1.2, n = 98) for
subsequent prostate cancer in about 19,000 male patients [D43].

B. Summary
B264. A number of epidemiological studies have looked for an increased risk of prostate cancer afterradiation exposure. At present, there is no clear evidence that prostate cancer is induced by radiation asa result of either childhood or adulthood exposure. In the UNSCEAR 2006 Report [U12], theCommittee summarized the risk estimates for prostate cancer from various epidemiological studies(table B19) and concluded that there was little indication of radiation effects on prostate cancer risks. A
committee of the National Research Council [N42] was more definite and concluded that there was noconvincing epidemiological evidence that prostate cancer was induced by radiation.

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Table B19. Risk estimates for prostate cancer incidence and mortality from studies of childhoodradiation exposure
Adapted from UNSCEAR 2006 Report (annex A, table 36) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeAverage ERR a at 1 Sv

Study

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]
Age at exposure<20 years

0.12 (<0, 1.38)<0 (<0, 0.42)

20–40 years

0.03 (<0, 0.70)<0 (<0, 1.84)>40 years

0.11 (<0, 0.70)<0 (<0, 2.96)

0.12 (<0, 0.51)<0 (<0, 0.38)

All

Mortality
LSS [P50]
Age at exposureAlla<20 years<0 (<0, >10 000)<0 (<0, 45.63)

20–40 years<0 (<0, 1.10)<0 (<0, 473.90)>40 years

1.01 (0.01, 2.78)<0 (<0, 910.84)

0.40 (<0, 1.31)<0 (<0, 298.22)

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

XVIII. PANCREATIC CANCER
B265. The most recent report on pancreatic cancer incidence in the LSS of atomic bombing survivors
did not find a statistically significant dose-related increase in pancreatic cancer [P52]. Neither the ERR,
which was estimated to be 0.26 Gy-1 (90% CI: −0.07, 0.68), nor the EAR was statistically significant.
There was no examination of age at exposure as a co-factor. Similarly, the pancreatic cancer mortality
data were not significant: ERR Gy-1 of 0.08 (95% CI: −0.18, 0.44) [O25].
B266. A study of 1,859 patients given X-ray treatment for peptic ulcer and 1,860 without irradiation
was conducted with an average follow-up of 22.5 years for the irradiated group [C6]. Those who
received <13 Gy to the stomach had an excess of pancreatic cancer, but cell-killing apparently reduced
the risk at higher doses. The study reported a marginal trend (p = 0.13) by age at radiation exposure.
The RRs, adjusted for sex and smoking, were 2.99 (95% CI: 1.15, 7.8), 1.69 (0.74, 3.9) and 1.19 (0.32,
4.4) for ages <35, 35–54 and ≥55, respectively. However, few if any study subjects would have been
exposed before age 20.
B267. A study of 40,000 men treated for testicular cancer showed an excess of pancreatic cancers(RR = 3.8; 95% CI: 2.7, 5.0) among those who received radiotherapy for testicular cancer with pancreas
doses in the range of about 13–28 Gy [T36]. No data were reported for age at exposure. A report on
pancreatic cancer after radiotherapy for ovarian cancer also showed a modest excess of pancreaticcancer (SIR = 2.1; 95% CI: 1.1, 3.6), but age at exposure was not considered [T32]. An international

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study of patients treated for Hodgkin’s lymphoma reported a small elevation in risk (SIR of 1.5, 95%
CI: 1.1, 2.0, n = 40), but no information on an age-at-exposure effect was available [D43].
B268. In a cohort of patients who received thorotrast for cerebral angiography in Denmark andSweden, an excess of pancreatic cancer was seen (RR = 3.8; 95% CI: 1.3, 12.3; n = 11), but nocomparison was made by age at exposure [T34]. A German thorotrast cohort study also found an excess
of pancreatic cancer (RR = 2.4; 95% CI: 1.0, 6.0; n = 18) but age at exposure was not examined [V5].

XIX. MULTIPLE MYELOMA
B269. Until about 1990, the risk of multiple myeloma was thought to be increased by radiation
exposure [N38]. However, as more evidence has accumulated, this seems unlikely to be the case. Thereis little or no evidence of the induction of myeloma by radiation as a result of childhood exposure in theareas of relatively high natural background radiation, among populations living near a nuclear facilityor among those having received medical radiation exposure [M35].
B270. The LSS mortality study data as of 1985 indicated statistically significant increases inmortality from multiple myeloma due to radiation exposure [S55]. However, a more recent LSS
incidence study by Preston et al. [P47] did not find an increase in the incidence of multiple myeloma
among the survivors of the atomic bombings in Japan. For the 41,000 persons who received a dose of
0.01 Sv or more and a mean dose of 0.23 Sv, there were 30 observed cases of the disease whereas 29
were expected in over one million person-years of study. This study has included a large number of
new cancer cases. Several of the incident cases used in the earlier reports were excluded from the new
analysis as a result of dose-range restrictions or as a consequence of a review of the clinical pathology
of presumed cases. In a recent analysis, the estimated risk using a linear dose-response model was notstatistically significant (ERR Gy-1 of 0.38, 95% CI: −0.23, 1.36, p = 0.21) [H70]. The addition of aquadratic term was not significant (p = 0.44). There was no indication of a trend by age at exposure(p > 0.5) for the ERR model. For the linear EAR model, the estimated risk was 0.07 (104 PY Sv)-1 (95%
CI: <−0.05, 0.29, p = 0.25) and there was no variation by age at exposure (p > 0.5).
B271. In summary, radiation risk estimates for multiple myeloma that can be derived from childhood
exposure epidemiological studies were summarized by the Committee in the UNSCEAR 2006 Report[U12] and are shown in table B20. The UNSCEAR 2006 Report concluded that there was only weakevidence linking myeloma to radiation exposure and that the better quality of diagnostic informationfrom incidence data would suggest that there was little evidence of an association with low-LET
radiation exposure. While there was some evidence of an association with high-LET radiation
exposure, it was based on only a few studies and very few cases. There was no evidence of an age-atexposure effect.

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Table B20. Risk estimates for cancer incidence and mortality from studies of childhood radiation
exposure on multiple myeloma
Adapted from UNSCEAR 2006 Report (annex A, table 43) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P47]

b

Sex

Males

0.17

0.26

Females

0.28

0.08

Age at exposure <20 years

1.07

0.07

0.09

0.04

0.20 (<0, 21.7)

0.05 (<−0.05, 0.4)

>20 years
AllMortality
LSS [P33]
Sex

All

b

Males

1.13 (<0, 6.41)

0.15 (<0, 0.51)

Females

1.16 (0.01, 3.9)

0.19 (0.001, 0.5)

1.15 (0.12, 3.27)

0.17 (0.02, 0.4)a

90% CI in parentheses derived from published data for the LSS and using exact Piosson methods for other studies.

b

Estimates based on UNSCEAR 2000 Report (annex I) [U10].

XX. HODGKIN’S LYMPHOMA
B272. Hodgkin’s disease typically afflicts teenagers and young adults and is thought to be associatedwith viral infections such as the Epstein-Barr virus and with immunosuppression in HIV, AIDS andbone marrow transplant patients. There also appears to be a significant genetic component with anelevated shared risk between identical compared to fraternal twins.
B273. A recent update of the atomic bombing data did not show a statistically significant association
between radiation and Hodgkin’s disease (ERR of 0.20 (95% CI: -1.0, 2.6) Gy-1), nor was there effectmodification by age [H70]. A review of the available epidemiological data indicates that there is nodemonstrable risk for Hodgkin’s disease from radiation exposure and no age-at-exposure effect.
Friedman et al. have followed up 14,359 five-year survivors in the CCSS [F17] and reported noincrease in Hodgkin’s disease (ratio of observed over expected of 9/9) with an SIR of 1.0 (95% CI: 0.5,
1.9). Evaluation for the induction of secondary Hodgkin’s disease post-therapy would be complicatedby the need to distinguish secondary from the more likely recurrent disease.
B274. In summary, with the exception of what are thought to be statistical chance associations [G10,M18], radiation has not been found to be associated with the development of Hodgkin’s disease
following either childhood or adult radiation exposure. The wide confidence limits on the risk estimates
are due to the very small number of cases in most studies. The UNSCEAR 2000 Report [U10]concluded that the available data did not indicate an association between Hodgkin’s disease andANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

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external or internal radiation exposure, but that the data were limited. The UNSCEAR 2006 Report[U12] summarized the radiation risk factors for Hodgkin’s disease and concluded that there was noclear indication of an excess of Hodgkin’s disease associated with radiation exposure but that the dataremained sparse and lacked a dose-response analysis. A committee of the National Research Council[N42] concluded that epidemiological studies failed to show any significant association between
Hodgkin’s disease and radiation exposure.

XXI. NON-HODGKIN’S LYMPHOMA
B275. An earlier analysis by Preston et al. of non-Hodgkin’s lymphoma incidence in the LSS foundno excess for females, but an estimated EAR for males of 0.56 (104 PY Sv)-1 (95% CI: 0.08, 1.39)[P47]. No age-at-exposure effect was found (p > 0.5). A recent analysis by Hsu et al. suggested thepossibility of risk among men, with an ERR Gy-1 of 0.46 (95% CI: -0.08, 1.3) and an EAR(104 PY Sv)-1 of 0.54 (95% CI: 0.09, 1.32), but both the ERR and EAR were essentially zero among
women [H70]. The male EAR did not vary with age at exposure (p = 0.15).
B276. A study of tuberculosis patients who received multiple fluoroscopic examinations inmonitoring pneumothorax treatments found a non-significant excess of non-Hodgkin’s lymphoma(RR = 1.3, 95% CI: 0.5, 3.5) and did not examine age at exposure [D15].
B277. A follow-up of Hodgkin’s disease patients in the CCSS found an excess of non-Hodgkin’s
lymphoma (SIR = 8.1; 95% CI: 4.6, 14.3), but the excess was not analysed specifically for radiotherapy[C8]. Similarly, an examination of secondary cancer incidence in the entire CCSS cohort found an
excess of non-Hodgkin’s lymphoma (SIR = 2.5; 95% CI: 1.6, 4.0) but it was not broken down bywhether the first primary cancer treatment had included radiotherapy [F17].

XXII. SALIVARY GLAND TUMOURS
B278. Salivary gland tumours are uncommon, with incidence rates below 0.1 per 100,000. Much
higher rates have been seen in Eskimos. About 80% of the malignant salivary tumours involve theparotid glands.

A. External exposure
1.

Atomic bombing survivors

B279. Benign and malignant tumours of the salivary, and particularly parotid, glands have beenreported to follow external exposure in the atomic bombing survivors and in children who havereceived radiation therapy. These are easily detected because spontaneous salivary gland tumours are
rare. The risk rates are usually reported in numbers of cases rather than mortality. Presently, data are

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insufficient for assessing the effect of age at irradiation or the possible difference in induction rates
between males and females.
B280. An analysis of radiation and salivary gland tumours among atomic bombing survivors [L4]reported a dose response based ERR of 3.5 (90% CI: 1.5, 7.5) at 1 Sv for malignant tumours and0.7 (90% CI: 0.1, 1.7; n = 41) for benign tumours. EARs were 3.73 (90% CI: 2.02, 6.04; n = 94)(104 PY Sv)-1 for malignant tumours and 1.89 (90% CI: 0.27, 4.21) for benign tumours. They reported
ERRs of 8.3 (90% CI: 2.5, 29.6) for mucoepidermoid cancers and 3.1 (90% CI: 0.6, 10.3) for benign
Warthins’ tumours. The risk estimates for malignant tumours were non-significantly higher for
exposures before age 20, compared to those older at exposure. In a pathological review of the atomic
bombing survivor data, Saku et al. [S10] reported on 120 histologically confirmed salivary gland
tumours. Mucoepidermoid tumours were more highly represented (p = 0.04) among the 41 malignant
tumours than were other types. Benign Warthins tumours were most strongly related to radiation
exposure (p = 0.06).

2.

Medical radiation uses

B281. Studies involving children who received radiotherapy for benign diseases have been performedby Saenger et al. [S8], Pifer et al. [P35], Janower and Miettinen [J13], Shore et al. [S60] and Modan etal. [M45]. The series yield absolute risk factors in the range of 5–16 excess salivary gland tumours in
one million exposed children for each 0.01 Gy over a follow-up of approximately 20 years. Annual risk
estimates are in the range of 0.06 to 0.25 cases of malignant and benign tumours in one million persons
annually for 0.01 Gy. If there were a longer follow-up period, the absolute risk factor might besomewhat greater. Although the data concerning adults and children are limited and from fairly
different exposure circumstances and populations, it appears that exposure may involve a higher risk inchildren than in adults.
B282. A paper by Schneider et al. [S32] reported an increase in salivary gland tumours after head andneck therapy following childhood irradiation. A more detailed analysis [S59] reported 40 benign and
14 malignant salivary gland tumours among 2,311 irradiated study subjects after childhoodradiotherapy (85% <10 years old) for enlarged tonsils and adenoids. Although a formal dose-response
analysis was not conducted, there appeared to be a radiation dose effect. Within the restricted age range
there was no age-at-exposure effect. Colman et al. [C38] reported a dose-related excess of salivary
gland tumours (10 malignant and 27 benign) following X-ray treatment for benign conditions inchildhood. The mean neck dose for tumour cases was 8.1 Gy.
B283. A study was conducted of about 11,000 patients given radiotherapy for Hodgkin’s disease, forwhich the salivary gland doses were thought to range from 20 to 35 Gy, depending on the treatment
regimen [B52]. It revealed 21 salivary gland cancers (SIR = 16.9; 95% CI: 10.4, 25.8). The risk was
higher among those under the age of 20 at the time of radiotherapy (SIR = 45.5; 95% CI: 12.4, 117). In
the CCSS, salivary gland cancer incidence was determined among 14,100 childhood cancer survivors[B53]. The SIR for second-primary salivary gland cancers was 39.4 (95% CI: 25, 58) based on
23 tumours. Individualized radiation doses to the salivary glands were estimated, and the ERR Gy-1 was
0.36 (95% CI: 0.06, 2.5).

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B. Internal exposure
B284. Holm et al. [H59] reported no excess of salivary gland cancer among 10,500 patients treatedwith 131I for hyperthyroidism. Similarly, a report of 1,771 patients treated with 131I for thyroid cancer
showed no excess of subsequent salivary gland cancers [D27]. Dottorini et al. [D46] found 3 salivary
cancers (SIR = 60; 95% CI: 12, 175) in a cohort of 627 patients treated for thyroid cancer with 131I, as
did Hall et al. [H5] among 834 thyroid cancer patients, SIR = 15.0 (95% CI: 3.1, 44). All of the studies
contained few or no exposed children.

C. Summary
B285. The UNSCEAR 2006 Report [U12] has summarized radiation risk factors for salivary glandcancer from the epidemiological studies where they could be derived (table B21) and concluded that thesalivary gland is susceptible to the induction of cancer by ionizing radiation. The evidence for thiscomes almost exclusively from studies of external low-LET exposure. There appears to be little
modifying effect of sex, age at exposure or time since exposure [U12].
Table B21. Age differences in risk estimates for salivary gland cancer incidence from studies ofchildhood radiation exposure
Adapted from UNSCEAR 2006 Report (annex A, table 20) [U12]. Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52]b

Age at exposure<20 years

11.12 (3.40, 43.32)<0 (<0, 64.40)

20–40 years<0 (<0, 0.46)<0 (<0, 0.05)>40 years

1.39 (<0, 8.30)<0 (<0, 63.69)

2.55 (0.87, 5.72)<0 (<0, 73.21)

Benign tumours

19.6 (0.16, ∞)n.a.

Malignant tumours−0.06 (−∞, 4.0)

n.a.

All tumours

0.82 (0.04, ∞)

n.a.

All
Childhood benign head and neck tumour
cohort [S34] c

a

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

b

Calculated using brain dose.

c

95% CI in parentheses.

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UNSCEAR 2013 REPORTXXIII. RECTAL CANCER
B286. The incidence of rectal cancer is lower than that of cancer of the colon. The geographicalincidence is broadly similar. In contrast, however, rates in immigrants to an area tend to remain similar
to those in the country of origin [I5]. While many reports group colon and rectal cancers together, thetwo organ sites seem to have different susceptibilities relative to radiation carcinogenesis. In theJapanese atomic bombing survivor incidence data, there is a fairly strong, approximately linear dose–
response relationship for colon cancer, but no relationship between radiation dose and rectal cancer.

A. External exposure
1.

Atomic bombing survivors

B287. In a study of colorectal cancer incidence in the atomic bombing survivor LSS sample reported
by Nakatsuka et al. [N7], there was no excess risk of rectal cancer. Later follow-up by Thompson et al.
[T24] did not indicate a significant ERR; at 1 Sv, the ERR was estimated to be 0.21 (95% CI: 0.17,0.75). The LSS mortality study data as of 1985 also demonstrated a statistically significant increase incolon cancer but, again, cancer of the rectum was not increased. In the 2003 update studies of mortalityof atomic bombing survivors during the period 1950–1997, Preston et al. [P50] analysed a cohort of86,572 persons with an average external dose of 0.23 Sv. In males there was a statistically nonsignificant decrease of rectal cancer at dose levels of 1 Sv with an ERR of −0.25 (90% CI: <−0.3, 0.15).
In females there was a statistically significant excess at dose levels of 1 Sv with an ERR of 0.75 (90%
CI: 0.16, 1.6). In the most recent cancer incidence report, the radiation risk for rectal cancer was notstatistically significant (ERR Gy-1 of 0.19; 90% CI: −0.04, 0.47), nor was there significant variation inrisk by sex (p = 0.3), age at exposure (p = 0.4) or attained age (p > 0.5) [P52].
B288. The most recent mortality study reported an ERR Gy-1 of 0.17 (95% CI: -0.17, 0.64) based on
427 rectal cancer deaths [O25]. The age-at-exposure effect was not reported. In neither the incidence
nor the mortality studies is there an effect of age at exposure.

2.

Radiation therapy

B289. Reulen et al. [R19] have reported an increase in digestive cancers in the British CCSS, with an
SIR of 4.6 (95% CI: 3.8, 5.6; n = 105). Friedman et al. [F17] reported an elevated risk for small
intestine and colorectal cancer in the CCSS cohort (SIR of 4.6 (95% CI: 3.2, 6.8; n = 27). Among 5,400
Hodgkin’s disease patients, the risk of rectal cancer was elevated for 10 or more years afterradiotherapy. Based on 15 cases, the SIR = 2.5 (95% CI: 1.4, 4.0) [D43]. Five of the rectal cancer cases
had been diagnosed with Hodgkin’s disease before age 21 (SIR = 12.4; 95% CI: 4.0, 29), but it was notreported whether they had received radiotherapy.

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B. Summary
B290. The epidemiological data indicate that, compared with the colon, the rectum has a low
sensitivity to radiation-induced cancer. A statistically significant risk is evident only after extremely
high radiation therapy doses. The UNSCEAR 2006 Committee [U12] reviewed risk estimates fromepidemiological studies. These are shown in table B22, where it can be seen that most studies did notshow a statistically significant relationship between rectal cancer and radiation exposure (especially atdoses less than 1 Gy) but there is an excess evident at high rectal doses (tens of Gy).
Table B22. Risk estimates for rectal cancer incidence and mortality from studies of childhoodradiation exposure
Adapted from UNSCEAR 2006 Report (annex A, table 24) [U12] Studies listed are those for which quantitative estimates of risk
could be madeStudy

Average ERR a at 1 Sv

Average EAR a (104 PY Sv)-1

Incidence
LSS [P52, U12]Sex

Age at exposureMales<0 (<0, 0.28)<0 (<0, 0.35)

Females0.46 (0.08, 0.97)

0.40 (0.03, 1.11)<20 years

0.16 (<0, 0.60)

0.10 (<0, 0.58)

20–40 years

0.12 (<0, 0.58)<0 (<0, 1.70)>40 years

0.24 (<0, 0.97)

0.64 (<0, 3.44)

0.18 (<0, 0.46)

0.19 (<0, 0.64)

All

Mortality
LSS [P50]
Sex

Age at exposure

All
a

Males

<0 (<0, 0.33)<0 (<0, 601.18)

Females0.95 (0.28, 1.86)<0 (<0, 488.26)<20 years

0.48 (<0, 1.82)<0 (<0, 167.70)

20–40 years

0.20 (<0, 1.08)<0 (<0, 590.50)>40 years

0.49 (<0, 1.37)

1.11 (<0, 3.23)

0.36 (<0, 0.88)<0 (<0, 532.76)

90% CI in parentheses derived from fitting models for the LSS detailed in [P52], and from published data for the other studies,
unless otherwise stated.

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APPENDIX C. DETERMINISTIC EFFECTSI.

INTRODUCTIONC1.
The ICRP—in its publication 118—groups adverse health effects from radiation exposure into:(a) stochastic or probabilistic (e.g. the mutagenic and carcinogenic effects), which are assumed toincrease in frequency as non-threshold functions of the dose; and (b) deterministic, which occur only
above certain dose thresholds, and are also sometimes referred to as “harmful tissue reactions”. Cell
death (including mitotic arrest and apoptosis) and cell malfunction are central to all deterministic
effects [I29]. The UNSCEAR 1993 Report (annex I) [U8] contained information on late deterministic
effects in children.
C2.
The depletion of renewing parenchymal cell populations, modified by interactions with othertissues, is the pathogenesis of early tissue reactions (or acute effects). After depletion of a certain
proportion of the cells, a level is reached (threshold) at which there is clinical manifestation of injury.
Above the threshold, deterministic effects increase in both frequency and severity with further increasein the dose.
C3.
The deterministic effects observed in a person depend on the dose received, volume of tissue
irradiated, quality or type of radiation, time over which the dose is received and age. The magnitude
and type of deterministic effects that may be evident also depend critically on the time of observation
after irradiation. Comprehensive reviews of deterministic effects in children may be found in the
publications of Rubin and Casarett [R57], Schwartz et al. [S44] and Friedman and Constine [F16].
Further publications dealing with both acute and late deterministic effects include textbooks onradiation pathology by Fajardo [F5], Scherer et al. [S28] and UNSCEAR Reports [U8, U10, U12].
Finally, this is an ongoing area of investigation with comprehensive studies continually appearing, suchas the one by Hudson et al. at St. Jude Children’s Research Hospital [H74].
C4.
Deterministic radiation effects were initially classified into a temporal scheme by Rubin andCasarett [R57]. In their scheme, acute effects were those occurring within the first six months of
exposure, subacute effects within the second six months, chronic effects in the second through fifth
years, and late effects after the fifth year. Fajardo [F5] divided pathological effects into immediate,
acute effects occurring within days to weeks, and delayed effects occurring within months to years. The
ICRP [I25] refers to early effects as those occurring in hours to a few weeks. Obviously, the effects
observed are a spectrum of cellular responses occurring over various times, and often these cannot bestrictly related to temporal categorizations.
C5.
Deterministic effects of radiation exposure can be augmented or suppressed by various
modifying agents and conditions that include chemical and physical factors, and genetic predisposition
causing increased radiation damage. Acute deterministic effects usually result from sterilization of therapidly proliferative-stem and progenitor-cell lines (particularly those of the intestine, bone marrow,germinal cells, and embryonal tissues) resulting in a transitory or permanent lack of mature cells

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depending on the level of the radiation dose. Early changes may be accompanied by transient vascular
dilatation, histamine release and permeability changes at the capillary level [M35].
C6.
Delayed lesions are usually progressive stromal lesions whose full clinical impact is manifest
long after progressive fibrosis can be demonstrated pathologically. Fibrosis is the result of oedema
followed by fibrinous exudate, fibrin deposition, and collagen formation. Late effects can also be theresult of dysfunction of intercellular signalling pathways. The most characteristic delayed radiation
lesion is eccentric myointimal proliferation of the small arteries and arterioles. The dose–survival
relationship for late effects differs from that of acute effects and injury to slowly responding tissues ismore dependent on fraction size. In radiotherapy, fewer fractions with larger doses lead to an increasein late complications. It was dogma for decades that the most critically radiation-sensitive cell typewithin a tissue was its parenchymal-cell population, and that dysfunction of this population and themicrocirculation was responsible for the manifestation of late effects. It is now recognized that theinteraction of multiple cell systems is affected by complex intra- and extra-cellular signalling, theimmune system and genetic factors [C44].
C7.
Paulino et al. [P19] have pointed out that there are significant differences in chronic adverse
tissue effects based upon the age of the individual. Sensitivity to radiation injury is a function of thedevelopmental dynamics and status of the organ, its regenerative potential, and ultimately the extent towhich it has begun to senesce. Pathogenetically, cell death, cell malfunction, perturbation of both
intracellular and intercellular signalling, and fibrosis are central to all deterministic effects. Increased
mitotic activity in developing tissues may relatively increase radiation sensitivity in these tissues during
periods of rapid growth. However, cellular damage from radiation can sometimes also occur during
intervals when the cellular activity is relatively quiescent, but the injury is not expressed until
development of that tissue accelerates. The role of stem cells in response to radiation exposure atvarious ages is unclear. Stem cells can be depleted by radiation, with injury expressed as the patientages. However, a greater abundance of stem cells in some tissues at a younger age may decrease
radiation sensitivity because of compensatory mechanisms. Conversely, limitations in cellular repair
capacities at an older age can sometimes actually increase the sensitivity of some normal tissues indeveloped or senescing tissues. Consequently, the ultimate expression of deterministic effects resultsfrom a complex array of issues related to cellular proliferation, developmental stage of the tissue,
regenerative potential and cell attrition. For instance, organizational maturational processes in children
can be impaired or even disabled by radiation therapy leading to a spectrum of effects that differ fromthose in adults in which the capacity and means for tissues to repair damage are the predominantpredictor for chronic injury. Radiation-induced impairment of growth and maturation is unique tochildren, whereas organ damage, with tissue-specific dysfunction in repair processes is common to bothchildren and adults. Susceptibility to late effects in the elderly seems to involve not only a decline intheir ability to repair damage but also cell attrition combined with co-morbid illness. These issues arecentral to contrasting deterministic effects in children with those of adults.
C8.
Few tissues show clinically significant deterministic effects at doses of less than a few grays.
The exceptions are gonads, lens of the eye and bone marrow. Deterministic effects in humans havesince been seen in radiation accidents and, clinically, in radiation therapy. Since it is rarely possible tosterilize a cancer without having an adverse effect on the normal surrounding tissue, radiotherapists
have developed the concept of a tolerance dose. The tolerance dose depends upon the level of risk ofdeterministic effects in normal tissue that the physician is willing to accept in order to sterilize atumour. The TD5/5 refers to a dose that is documented to cause a 5% incidence of serious
complications or side effects within five years. It is important to realize that the “tolerance dose” canhardly be termed a dose that is tolerable to healthy people but rather refers to the dose that is tolerable
or acceptable to patients in order to cure them of cancer. Moreover, it must be understood that this is a
probabilistic figure and not specific to an individual patient. The significance of the tolerance dose forANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

161

this text is that the practice of radiotherapy using the tolerance dose has provided a relatively large bodyof literature on the incidence and dose levels required to produce deterministic effects in normal tissue,
their time course, and their dependence upon quality and temporal distribution of the irradiation [N14].
C9.
Radiation oncologists have devised a scoring system for toxicity in an attempt to have uniform
reporting of deterministic effects [R61]. The late effects normal tissue (LENT) system considers
subjective, objective, management and analytical (SOMA) factors. Subjective refers to what is
generally reported as symptoms by the patient, objective to findings of a skilled clinician, management
to measures taken to alleviate or reduce toxicity and analytical to laboratory and procedural findings.
These measures can be combined into a summary score. The system uses grades 1–4 for the degree of
toxicity. Grade 0 is not used as it would indicate no toxicity, and Grade 5 is not used as it indicates afatal outcome.

II. BRAIN
C10.
The developing human brain is especially sensitive to ionizing radiation exposure. The
response of the normal brain to radiation exposure depends on the total dose, individual fraction size,
the time interval over which radiation is delivered, the volume of the exposed tissue and the age of the
exposed subject. The outcome of iatrogenic radiation damage to the normal brain depends on themagnitude of the damage and the brain’s limited capacity for cellular repopulation (neurogenesis).
Although partial recovery takes place between fractionated exposures, the brain has very little repair
capacity. After birth, the period of greatest radiosensitivity of the human brain is during the first two
years of life, because of the relative immaturity of myelination and synaptogenesis [P4]. Normal
maturation of the brain has been discussed earlier in this annex. High dose radiation involving thewhole brain is more likely to have an adverse effect compared with comparable doses of focal
irradiation [U8].
C11.
Radiation changes in the brain are of several general types: acute reactions; early delayed
reactions; and late delayed reactions. There are several target cell types and pathways by whichradiation injury of the CNS may occur. Historically, late changes were thought to be secondary tovascular changes, but it now appears that the two main target cells are both oligodendrocytes andendothelial cells: however, other glial cells, and also neuronal cells can be primary or secondary targets.
In addition, the vascular changes appear to be preferentially venous (rather than arterial) damage [S37].

A. Radiotherapy for malignant lesions
C12.
Primary brain damage is usually the result of an insult to the glial cells and vascular system
although occasionally an acute demyelinating process is observed [R22]. Subacute changes appear to be
the result of deterministic effects on proliferating oligodendrocytes and temporary changes in the
blood–brain barrier. Abrupt deterioration has been reported in radiotherapy when large fractional doses(i.e. 7.5–10 Gy) have been used. Excessive (by current therapeutic standards) doses or relatively few
fractions of large doses (i.e. greater than 10 Gy) have caused radiation-induced brain necrosis [K49].
C13.
The tolerance dose to the brain with fractionated radiotherapy over a period of five–six weeks
is thought to be 55 Gy, although small areas of the brain may tolerate doses up to 65–70 Gy. Post-

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irradiation necrosis has rarely been reported at fractionated doses of less than 60 Gy. Overall, the whitematter of the CNS is more susceptible to radionecrosis than the grey matter or the brain stem. The
paraventricular and supraoptic nuclei of the hypothalamus appear to be more radiosensitive than thewhite matter.
C14.
Early delayed reactions appear from a few weeks to a few months after radiotherapy. They areusually self-limiting and are easily mistaken for effects of the residual tumour or chemotherapy. In
children treated for leukaemia with methotrexate and radiation, about 60–80% will exhibit anorexia,
irritability, and a “somnolence syndrome” 2–6 months post-therapy, probably due to transient diffuse
demyelination. The late delayed reaction has a number of forms, ranging from asymptomatic
periventricular white matter changes to decreased mental status, endocrine changes, and even focal
necrosis. The maximum tolerable dose in children up to the age of three is 33% less than that for adults,
and Bloom [B34] has also estimated that for children 3–5 years of age, the adult dose has to be reduced
by 20%.
C15.
With the advent of magnetic resonance imaging (MRI), it has become clear that many patients
will develop areas of diffusely increased signal in the white matter seen on T2-weighted images.
Reports indicate that 50–100% of patients will show these findings after radiotherapy. The changes
occur preferentially in the periventricular white matter and may extend to the grey–white junction.
Patients with mild forms appear to have no clinical symptoms, while patients with extensive
abnormalities on MRI are more likely to have more mental impairment such as personality change,
confusion, seizure disorders, and learning difficulties [C54, T44]. Leukoencephalopathy refers to whitematter injury caused by demyelination following treatment with chemotherapeutic agents with orwithout associated radiotherapy. The most typical situation is after doses of 20 Gy, combined with theuse of methotrexate [K20, P29, R64], although it has also been reported after whole-body doses of
10 Gy given in total body irradiation (TBI) conditioning regimens for bone marrow transplantation. On
CT and MRI scans, this entity is indistinguishable from the white-matter radiation changes. Corticalgrey matter and basal ganglia are not affected. Clinical findings are lethargy, poor school performance,
ataxia, spasticity, progressive dementia, and even death.
C16.
Another change sometimes seen in children treated for leukaemia with cranial irradiation andmethotrexate is mineralizing microangiopathy [B30]. This is seen as calcification in the grey matter,basal ganglia, putamen, and sometimes in the cortex and even the brain stem [P53]. There iscalcification in small blood vessels that are surrounded by necrotic mineralized brain tissue. It is notfatal and it is unknown if this produces any specific neurological signs, although it is often associatedwith leukoencephalopathy. The entity is seen in about 25% of patients who have received intrathecal
methotrexate and cranial irradiation of 24 Gy and who survive for more than nine months. Another latechange that may be seen in about 50% of patients after cranial radiotherapy is cortical atrophy. This isseen either on CT or MRI scans as enlarged cortical sulci and enlarged ventricles, usually detectable
one to four years after radiotherapy. This is seen in about half of the patients who have received a doseof more than 30 Gy to the brain with fractionated radiotherapy, but can occur at lower doses [R14]. In
addition to parenchymal changes of the brain due to radiation exposure, there are vascular changes thatcan be imaged. Koike et al. [K40] have shown that MRI can visualize radiation-induced telangiectasia
in about 20% of children who have received cranial radiotherapy. All doses quoted in this report were
18–20 Gy and the abnormalities appeared as early as three years after exposure, although additional
lesions still developed 10 years post-therapy. They were seen as small foci of very low-signal intensity
on MRI images.
C17.
The increased sensitivity of the nervous system in children requires radiotherapy treatment
schedules to be adjusted according to the age of the patient. Arteriosclerosis may lower the tolerance ofthe brain since the occlusive changes due to radiation exposure may be additive with regard to pre-

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163

existing arteriosclerotic changes. Sheline et al. [S54] and others [R64] have suggested thatchemotherapy contributes (perhaps synergistically) to the occurrence of radionecrosis and possibly
enhances the level of injury. Both depression and somnolence, probably as a result of a transientdemyelination, have been reported six to eight weeks after cranial irradiation to dose levels of 24 Gy
given in 10 to 15 fractions, but can occur at lower doses. Such findings have been seen in children andadults treated for ALL [F14, P59]. The somnolence is distinct from the more severe neurologicalabnormalities produced by intrathecal methotrexate.

1.

Neurocognitive late effects

C18.
Neurocognitive late effects most commonly follow treatment of CNS malignancies using
cranial irradiation or intraventricular/intrathecal chemotherapy, and even high dose systemic
chemotherapy such as methotrexate or cytosine arabinoside [P4].
C19.
Children with CNS tumours, head and neck sarcomas, and ALL are most commonly affected.
Reductions have been observed in the following [N11, R31]:(a) General intelligence;(b) Age-appropriate developmental progress;(c) Academic achievement (especially in reading, language, and mathematics);(d) Visual and perceptual motor skills;(e) Non-verbal and verbal memory;(f) Receptive and expressive language and attention.
For both CNS tumours and ALL, a younger age at time of treatment is associated with an increased
neurocognitive deficit (figure C-I).
Figure C-I. Interpolation of IQ scores after conformal radiation therapy by age for paediatric lowgrade glioma
Adapted from [M29]164

UNSCEAR 2013 REPORT

C20.
Some studies of children treated with radiotherapy for CNS tumours have demonstrated asignificant adverse neurocognitive effect of therapy [P2, R31]. Other studies using lower doses andmore targeted volumes, however, have demonstrated less neurocognitive compromise [M57, P3, R23].
One study supports the hypothesis that medulloblastoma patients demonstrate a decline in IQ values
indicated by an inability to acquire new skills and information, but not a loss of those previously
acquired [P5].
C21.
In a Danish study of children treated for brain tumours, younger age at diagnosis, tumour site
in the cerebral hemisphere, hydrocephalus treatment with shunt, and radiotherapy were predictors oflower cognitive functions [R16]. Similar findings were obtained in a series of 182 five-year survivors ofchildhood low-grade gliomas in which 34% had an IQ below average, and this was associated withyounger age at diagnosis, epilepsy and shunt placement [A26]. Merchant et al. [M29] have shown that
decreases in IQ are very dependent on the age at irradiation for treatment of low-grade gliomas(figure C-I).
C22.
In a large cohort of adult survivors of CNS malignancy (n = 802) reported from the CCSS, therisk of neurocognitive dysfunction was significantly associated with treatment involving cranial
irradiation or placement of a ventriculoperitoneal shunt, and also a history of stroke, paralysis or
auditory difficulties [E11]. In this study, CNS-malignancy survivors with neurocognitive impairment,
when compared with non-CNS-malignancy and sibling-control groups, were found to have deficits inboth the speed of information processing and in working memory Another study evaluated quantitative
tissue volumes from MRI scans, correlating these results with neurocognitive assessments for 40 longterm survivors of paediatric brain tumours treated with radiotherapy with or without chemotherapy 2.6
to 15.3 years earlier (median, 5.7 years) at ages between 1.7 and 14.8 years (median, 6.5 years). The
analyses revealed significant impairment in neurocognitive test performance by the patients on allmeasures. After statistically controlling for age at time of radiotherapy and time from radiotherapy,
significant associations were found between normal-appearing white-matter volumes and both
attentional abilities and IQ. MRI abnormalities were also correlated with deficiencies in academic skills
such as reading, spelling, and solving mathematical problems [R13].
C23.
For children with ALL, studies again show significant neurocognitive impairment [M24, S39]
when cranial irradiation is combined with intrathecal chemotherapy. Reduction in the cranial radiationdose (e.g. from 24 Gy to 12–18 Gy) may result in less neurocognitive impairment [H30, K32, S78, W2,
W1].
C24.
The effects of radiation on the brain are difficult to define, especially when cranial irradiation
is a part of multimodal therapy that may also include surgery, systemic chemotherapy, or intrathecal
chemotherapy. Tumour-related deficits resulting from direct invasion of the brain, seizures andhydrocephalus are confounding factors that must also be considered [K30]. The CCSS reported that inadult survivors of childhood CNS malignancies, neurocognitive impairment was high and proportional
to the radiation dose for specific tumour types. There was a dose-dependent association between
radiotherapy to the frontal/temporal lobes and lower rates of employment and marriage [A24].
C25.
Studies on CNS prophylaxis for ALL, comparing craniospinal radiotherapy with cranialradiotherapy combined with intrathecal methotrexate, showed that children who were younger than five
years at time of treatment and had received radiotherapy and intrathecal chemotherapy had lower IQ
scores than those who received craniospinal radiotherapy alone [B32]. Similarly, another study found asignificant IQ deficit in children treated with a dose of 24 Gy to the cranium combined with intrathecal
methotrexate, compared with children who had received no CNS-directed therapy, and the effect was
greatest among those younger than five years [M24]. A similar effect on cognition with the addition of
intrathecal methotrexate has been found in children treated for medulloblastoma [R26].

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

165

C26.
Systemic methotrexate in high doses and combined with radiotherapy can lead toleukoencephalopathy with severe neurocognitive deficits [B31, C33, D48]. The deleterious effects ofsystemic methotrexate, especially at doses above 1 g/m2, may be no different or even worse than thoseof a cranial radiation dose of 18 Gy [B67, O5]. At lower methotrexate doses, there does not appear to
be a consistent pattern of neurocognitive deficits [B72].
C27.
Neurocognitive abnormalities have been reported in other groups of cancer survivors besides
patients with CNS tumours and ALL. In a study of adult survivors of childhood non-CNS cancers,
13-21% of the survivors had impairment in task efficiency, organization, memory or emotional
regulation. This rate of impairment was approximately 50% higher than that in the sibling comparison.
Factors such as diagnosis at an age younger than six, female sex, cranial radiotherapy, and hearing
impairment were associated with neurocognitive compromise [K2].
C28.
Cognitive consequences of stem cell transplantation in children have also been evaluated. In areport from the St. Jude Children’s Research Hospital in which 268 patients were treated with stem celltransplant, minimal risk of late cognitive and academic sequelae was seen. Subgroups of patients wereat relatively higher risk, including those undergoing unrelated donor transplantation, those receiving
total-body irradiation, and those with graft-versus-host disease (GVHD). However, these differenceswere small relative to differences in premorbid functioning [P31]. The greatest decline inneurocognitive function occurred in patients who received cranial irradiation either as part of theirinitial therapy or as part of their haematopoietic stem cell transplant (HSCT) conditioning [S47]. Most
neurocognitive late effects are thought to be related to white-matter damage in the brain [A17].

2.

Other neurological sequelae

C29.
In a report from the CCSS on 4,151 adult survivors of childhood ALL compared to theirsiblings, survivors were at an elevated risk for late onset coordination problems, motor problems,
seizures and headaches. The overall cumulative incidence was 44% at 20 years after treatment. Serious
headaches were most common, with a cumulative incidence of 25.8% at 20 years after treatment,
followed by focal neurological dysfunction (21.2%) and seizures (7%). Children who were treated withregimens that included cranial irradiation (and also intrathecal methotrexate), and those who sufferedrelapse, were at an increased risk for late-onset neurological sequelae [R12].
C30.
Many survivors of childhood cancer have an inferior quality of life or other adverse
psychological outcomes compared with siblings or age-matched controls. In a study of adult survivorsof childhood cancer, psychological screening was performed during a routine annual evaluation at thesurvivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32% ofsubjects had a positive screen (indicating psychological distress), and 14% reported at least one suicidal
symptom. Risk factors for psychological distress included dissatisfaction with physical appearance,
poor physical health, and treatment with cranial irradiation [B66]. Some authors have indicated acorrelation between calcification and other abnormalities on CT scans and learning disabilities or
seizures [C16], but these conclusions are not confirmed in other studies.

B. Radiotherapy for benign conditions
C31.
There are several published reports evaluating possible changes in mental function after
relatively low doses of radiation. Follow-up studies have been performed and include both Israeli [R34]166

UNSCEAR 2013 REPORT

and American [S60] children who had received a dose of about 1–2 Gy during treatment for tinea
capitis. In the Israeli study, males with multiple irradiations had a higher rate of admissions to mental
hospitals (34.0 observed compared to 17.4 expected per 1,000), but this difference was not seen withfemales. Children irradiated at less than six years of age had a relative risk of mental hospital
admissions of 1.7 (95% CI: 1.1, 2.8), but for older children, there was no increased risk.
C32.
Information on high-school aptitude tests was available for about 1,800 irradiated children,
2,000 matched population controls and 1,000 matched sibling controls. Although the irradiated childrenscored lower on the aptitude test than the population controls, there was no difference compared withthe sibling controls, suggesting that inter-family genetic or environmental factors unrelated to radiation
exposure may have contributed to the difference with regard to the population controls [S60].
C33.
An IQ test administered to military inductees (in a country with universal military service)
showed that a smaller percentage of the irradiated children studied than either the population or sibling
controls, and scored high enough to qualify as officer candidates; however, the average IQ scores of thegroups did not differ significantly. From the Israeli mental-retardation registry, there was no clear
evidence that diagnosed mental retardation was in excess in the irradiated group compared to thecontrol group [R34]. An electroencephalogram (EEG) evaluation did not detect a significantly greater
frequency of abnormalities among the irradiated group (31%) compared to the non-irradiated group(25%) [Y1].
C34.
In the United States series, there was about a 40% excess of reported psychiatric disorders
among the irradiated children; however, a systematic psychological study by Omran et al. [A12, O14]
showed only a borderline difference between the irradiated and non-irradiated groups. There does notappear to be a good biological or pathological basis for such psychiatric effects at these dose levels, andthese results are not supported by follow-up studies of children treated for tumours. As with moststudies of this type, there is the possibility of recall bias and other potential confounders.
C35.
Hall et al. [H9] reported that persons treated for cutaneous haemangioma with radiotherapy ininfancy had some types of lower cognitive function. The male children were treated between 0 and 17
months of age (median, 6 months) and the mean dose to the brain was 52 mGy. They analysed recordsof school attendance and cognitive tests of learning ability and logical reasoning (but not IQ tests) atages 18–19 years. The proportion of boys who attended high school decreased with increasing dosefrom 32% among those not exposed to about 17% in those who received a dose to the brain of>250 mGy. The cognitive tests performed comprised an index of learning ability that was intended tomeasure general verbal ability and be sensitive to education. A test of spatial recognition was the basis
for a logical-reasoning score. Father’s occupation was used as a surrogate to assess the impact ofsocioeconomic, social and educational influences upon cognitive performance. They reported a doserelated decrement in the score for verbal learning ability, but none for logical reasoning. That theyfound a nominal effect for verbal learning ability but not for logical reasoning suggests the possibility
that there may have been residual confounders related to familial, socioeconomic and educational
factors that could not be sufficiently adjusted for by father’s occupation and that affected the verbal
learning-ability results.
C36.
Another possible explanation is that the radiation exposure may have affected thyroid functionthat secondarily impacted cognitive function, although other data do not generally indicate effects on
thyroid function in the dose range of the study [I34]. They had hypothesized that the radiation dose to
the frontal brain would have had a greater impact than that to the posterior part, but the high correlation(r = 0.84) between the two sets of dose estimates made it impossible to see separate effects. Finally, themagnitude of effects suggested here are considerably higher than that noted at doses to the brain over
100 times higher given for CNS prophylaxis of leukaemia. Those studies indicate that doses of 24 Gy

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

167

are associated with about a 10–15 point loss of IQ [O5, T3]. On the other hand, the effects they reported
are quite similar to the reported IQ deficits seen among the survivors of the atomic bombings exposed
in utero at 8–25 weeks post-conception [O23].

C. Accidental exposure
C37.
An accident occurred with a radiotherapy unit in San Jose, Costa Rica [I3], in which an error
was made in the replacement of the 60Co source. The units on the timer were incorrectly interpreted as
seconds instead of hundredths of a minute. As a result, the dose rate was underestimated by a factor of
1.66. As a result, 114 patients were exposed to higher doses than intended. Complications of the CNS
occurred within 24 months in a child who received a dose to the cranium of 58 Gy in 20 fractions. Overthe next nine months, the child lost all ability to speak and was confined to a wheelchair.

III. NEUROENDOCRINE SYSTEM

A. Radiotherapy for malignancies
C38.
Survivors of childhood cancer who have been treated with radiotherapy are at risk for aspectrum of neuroendocrine abnormalities, primarily due to the effect of hypothalamic radiation
exposure [N14].
C39.
The damage to the hypothalamic–pituitary axis generally results from deterministic effects on
the hypothalamus and to a lesser extent on the pituitary [C47, G39, S85]. There are six anterior pituitaryhormones: growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone (FSH),
thyroid stimulating hormone (TSH), and adrenocorticotropin. Clinical manifestations of damage to the
hypothalamic–pituitary axis often include loss of weight, impaired or precocious development of
secondary sexual characteristics and body hair; dry skin, slow pulse, genital atrophy, and low bodytemperature.
C40.
Growth hormone deficiency is the most common neuroendocrinological deficit following
cranial irradiation for brain tumours due to the low threshold dose for this injury. The risk increases
with radiation dose and time after treatment. Growth hormone deficiency is also the earliest hormone
deficiency to arise following exposure and can be observed even following exposure to relatively low
radiation doses. Other hormone deficiencies are manifest only following higher doses and their onset
time is generally longer than for growth hormone deficiency [D11].
C41.
The prevalence in a pooled analysis of survivors of brain tumours in childhood was found tobe approximately 35.6% [M56]. The potential for neuroendocrine damage is lower after current
treatment approaches owing to the use of more focused radiotherapy that reduces hypothalamic
exposure, and a decrease in the dose used for the treatment of some malignancies such as
medulloblastoma. Follow-up studies of patients who received radium therapy applications to treat otitis

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UNSCEAR 2013 REPORT

serosa, resulting in doses to the pituitary of about 11 Gy, did not demonstrate any significant hormonal
deficiencies [R47, R49].

1.

Growth hormone deficiency

C42.
Approximately 60–80% of paediatric patients who were irradiated in the treatment of brain
tumours and received doses greater than 30 Gy will have impaired serum growth hormone response to
provocative stimulation, usually within five years of treatment. The dose–response relationship has athreshold of 18–20 Gy; the higher the radiation dose, the earlier that growth hormone deficiency will
occur after treatment. A study of children who had been treated for tumours of the CNS using
conformal radiotherapy indicates that growth hormone deficiency can usually be demonstrated within
12 months following treatment, depending on hypothalamic dose–volume exposure [M26]. On the basisof data from 118 patients with localized brain tumours that were treated with radiation therapy, peakgrowth hormone was modelled as an exponential function of time after conformal radiotherapy andmean radiation dose to the hypothalamus. The average patient was predicted to develop growth
hormone deficiency within 12 months after a dose of more than 60 Gy; 36 months after 25–30 Gy; and60 months after 15–20 Gy. A cumulative dose of 16.1 Gy to the hypothalamus would be considered themean radiation dose required to achieve a 50% risk of growth hormone deficiency at five years(TD50/5) [M30].
C43.
Children treated with CNS irradiation for leukaemia are also at increased risk of growth
hormone deficiency. One study evaluated 127 children or adolescents with acute lymphocytic
leukaemia treated with 24 Gy, 18 Gy, or no cranial irradiation. The subsequent change in the height ofthe patients, compared with population norms and expressed as the standard deviation score, wassignificant for all three groups with a dose response of −0.49 ± 0.14 for the group that did not receive
radiotherapy, −0.65 ± 0.15 for the group that received a dose of 18 Gy, and −1.38 ± 0.16 for the groupthat received a dose of 24 Gy [S82]. Another study found similar results in 118 survivors of acutelymphocytic leukaemia treated with a dose to the cranium of 24 Gy; 74% had a standard deviation
score of −1 or greater and the remainder had a score of −2 or greater [S35].
C44.
Survivors of acute lymphocytic leukaemia in childhood who are treated with chemotherapy
alone are, however, also at increased risk of diminished growth, though the risk is highest for thosetreated with cranial and craniospinal irradiation at a young age [C23]. In this cross-sectional study,
attained adult height was determined for 2,434 survivors of acute lymphocytic leukaemia participatingin the CCSS. All survivor groups (those who had been treated with chemotherapy alone and those who
had been treated with both chemotherapy and cranial or craniospinal irradiation) had decreased adultheight (standard deviation score <−2) compared with siblings (p <0.001). The risk of short stature inadulthood for the survivors treated with chemotherapy alone was elevated, with an odds ratio of
3.4 (95% CI: 1.9, 6.0). Significant risk factors for short stature included treatment of acute lymphocytic
leukaemia before puberty, magnitude of the dose to the cranium (doses of ≥20 Gy resulted in a higher
risk than doses of <20 Gy), any radiotherapy to the spine, and sex (females had a higher risk thanmales). Growth hormone deficiency has been reported in 14% of survivors of nasopharyngeal
carcinoma in childhood resulting from high dose radiation exposure to the hypothalamic/pituitary axis
[C17]. This incidence is likely to be an underestimate since screening was selective.
C45.
Children who undergo HSCT with whole-body irradiation have a significant risk of both
growth hormone deficiency and impaired bone growth because of the direct effects of radiation on
skeletal development. The risk is increased if: (a) the dose is given in a single fraction rather than in
multiple fractions; (b) pre-transplant cranial irradiation has been given; (c) the patient is female; and (d)ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

169

post-treatment complications such as GVHD develop [O12, W23, W27]. Regimens containing busulfan
and cyclophosphamide appear to increase the risk in some studies [B15, W27] but not others [C13].
Hyperfractionation of the dose markedly reduces the risk in patients who have not undergone pretransplant cranial irradiation for prophylaxis or therapy for CNS leukaemia [H75].
C46.
The late effects that occur after HSCT have been studied and reviewed by the Late EffectWorking Party of the European Group for Blood and Marrow Transplantation. For 181 patients withaplastic anaemia, leukaemia, and lymphomas who underwent HSCT before puberty, an overall decreasein their final height was found compared to what would have been predicted from their parents’ heights.
The mean loss of height is estimated to be approximately one standard deviation score (i.e. 6 cm). The
type of transplantation, graft versus host disease, growth hormone deficiency, or steroid treatment did
not influence the final height. The major factors affecting long-term loss of height were the use of
single dose TBI rather than its administration in multiple smaller fractions, sex of the person (males
were more affected than females), and the age at transplant (the effect was greater at younger ages).
Most patients (140 of 181) reached adult height within the normal range of the general population [C31,
S94].

2.

Gonadal abnormalities

C47.
Pubertal development can be adversely affected by cranial irradiation. Doses greater than
30-40 Gy can result in gonadotropin deficiency, while doses greater than 18 Gy can result in precocious
puberty [N8]. Precocious puberty has been reported in some children, mostly girls, who had received
doses from cranial irradiation of 24 Gy or higher. Earlier puberty and earlier peak height velocity,
however, have been observed in girls treated with doses from cranial irradiation of 18 Gy [D38, S50].
C48.
Another study showed that the age of pubertal onset is positively correlated with age at thetime of cranial irradiation. The impact of early puberty in a child with radiation-associated growth
hormone deficiency is significant, and timing of growth hormone therapy is especially important for
growth hormone deficient females also at risk of precocious puberty [C25]. With higher doses of
cranial irradiation (>35 Gy), deficiencies in the gonadotropins can be seen, with a cumulative incidenceof 10% to 20% at five–ten years post-treatment [A25].

3.

Central hypothyroidism

C49.
Central hypothyroidism in survivors of childhood cancer can have profound clinicalconsequences and is often underappreciated. Symptoms of central hypothyroidism (e.g. asthaenia,
oedema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid
replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism maycause fatigue, dry skin, constipation, increased sleep requirement and cold intolerance. A radiation doseto the hypothalamus in excess of 42 Gy is associated with an increase in the risk of developing TSH
deficiency, 44% ± 19% (for a dose >42 Gy) and 11% ± 8% (for a dose <42 Gy) [L11]. It occurs in as
many as 65% of the survivors of brain tumours in childhood, 43% of the survivors of nasopharyngeal
tumours in childhood, 35% of bone marrow transplant recipients in childhood, and 10–15% of
survivors of leukaemia in childhood [C17, R52].
C50.
Mixed primary and central hypothyroidism can also occur and reflects separate injuries to thethyroid gland and the hypothalamus (e.g. radiation injury can occur in both structures, and sometimes
concomitantly in children irradiated to the cranial-spinal axis). TSH values may be elevated and, in170

UNSCEAR 2013 REPORT

addition, the secretory dynamics of the hormone are abnormal with a blunted or absent surge or adelayed peak response to thyrotropin-releasing hormone (TRH) [C47, R51]. In a study of 208 survivorsof childhood cancer referred for evaluation of possible hypothyroidism or hypopituitarism, mixed
hypothyroidism was present in 15 (7%) patients [R51]. Among the patients who had received wholebody irradiation (fractionated total doses of 12–14.4 Gy) or craniospinal irradiation (fractionated total
doses to the cranium higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children
treated for medulloblastoma, 56% were found to have developed hypothyroidism, including 38% withprimary hypothyroidism, and 19% with central hypothyroidism [P17].

4.

Adrenal-corticotropin deficiency

C51.
Adrenocorticotropic hormone (ACTH) deficiency is less common than other neuroendocrine
deficits but should be suspected in patients who have a history of brain tumour (regardless of therapy
modality), cranial irradiation, growth hormone deficiency, or central hypothyroidism [C46, C47, D11,
K22, L11, P13, R53]. Although uncommon, ACTH deficiency can occur in patients who have received
doses of intracranial irradiation that did not exceed 24 Gy and it has been reported to occur rarely (inless than 3% of patients) after treatment with chemotherapy alone [R53]. Patients with partial ACTH
deficiency may have only subtle symptoms unless they become ill when a stress response is necessary.
Illness can disrupt the usual homeostasis in these patients and cause a more severe, prolonged, orcomplicated course than expected. As in patients with complete ACTH deficiency, partial or
unrecognized ACTH deficiency can be life-threatening during concurrent illness.

5.

Hyperprolactinaemia

C52.
Hyperprolactinaemia has been described in patients who have received doses of radiation
higher than 50 Gy to the hypothalamus or who have undergone surgery that disrupts the integrity of thepituitary stalk. Hyperprolactinaemia may result in delayed puberty. In adult women,
hyperprolactinaemia may cause galactorrhea, menstrual irregularities, loss of libido, hot flushes,
infertility and osteopaenia; in adult men, it may result in impotence and loss of libido. Primary
hypothyroidism may lead to hyperprolactinaemia as a result of hyperplasia of thyrotrophs andlactotrophs, presumably owing to TRH hypersecretion. The prolactin response to the TRH is usually
exaggerated in these patients [C46, C47, D11].

IV. VASCULAR DISEASE/CEREBROVASCULAR ACCIDENT
C53.
A spectrum of vascular morbidities may occur after radiotherapy has been used to treat
malignancies such as lymphomas, head and neck cancers, and brain tumours. Specifically, carotid
artery and cerebrovascular injury occur after cervical and CNS irradiation. The relative risk for
cerebrovascular accident (CVA), i.e. stroke, in the CCSS cohort was almost 10-fold higher than that in
the sibling control [O9]; notably, the risks were highest among the adult survivors of acute lymphocytic
leukaemia, brain tumours, and Hodgkin’s lymphoma in childhood [B57, B56]. Survivors of leukaemia
were six times more likely to suffer a CVA than their siblings, whereas survivors of brain tumours were
29 times more likely to suffer a CVA. Of the cohort of 1,411 patients who had had brain tumours and ahistory of radiotherapy, 69 reported a CVA (4.9%), with a cumulative incidence of 6.9% (95% CI: 4.47,

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

1719.33) at 25 years. Survivors exposed to cranial irradiation greater than 30 Gy had an increased risk for
CVA, with the highest risk being among those who had been treated with doses greater than 50 Gy[M55].
C54.
French investigators observed a significant association with radiation dose to brain and longterm cerebrovascular mortality among 4,227 five-year childhood cancer survivors (median follow-up
29 years). Survivors who received more than 50 Gy to the prepontine cistern had a hazard ratio of
17.8 (95% CI: 4.4, 73) of death from cerebrovascular disease compared to those who had not received
radiotherapy or who had received less than 0.1 Gy in the prepontine cistern region [H1]. In anotherrecent study of children irradiated for brain tumours, the incidence of neurovascular events was
100-fold higher than in the general population [C2]. Adult survivors of Hodgkin’s lymphoma inchildhood who had been treated with radiotherapy to the thorax, including the mediastinum and neck,had a 5.6-fold higher risk for CVA than their siblings (median dose 40 Gy) [B56].
C55.
In another study from the Netherlands of 2,201 five-year survivors of Hodgkin’s lymphoma(of whom 547 were younger than 21 years at the time of treatment), and with median follow-up of 17.5
years, 96 developed cerebrovascular disease—55 with CVA, 31 with transient ischaemic attacks (TIA),
and 10 both CVA and TIA. The median age at diagnosis was 52 years [D24]. Most ischaemic eventswere from large-artery atherosclerosis (36%) or cardioembolism (24%). The SIRs were 2.2 for CVA
and 3.1 for TIA. The cumulative incidence of ischaemic CVA or TIA 30 years after treatment for
Hodgkin’s lymphoma was 7%. For patients younger than 21 years at the time of treatment, the SIRs
were 3.8 for CVA and 7.6 for TIA. These SIRs were greater than those for patients older than 21 years
at the time of treatment. Specifically, the SIRs for CVA were 3.1, 2.0, and 1.4 in the 21–30, 31–40, and
41–50 year-olds, respectively. Similarly, the SIRs for TIA were 4.2, 3.1, and 2.1 in the 21–30, 31–40,
and 41–50 year-olds, respectively. Radiation exposure of the neck and mediastinum was anindependent risk factor for ischaemic cerebrovascular disease, with a hazard ratio of 2.5 (95% CI: 1.1,
5.6) compared to those without radiotherapy. Treatment with chemotherapy was not associated withincreased risk of CVA and TIA.
C56.
There are few studies regarding the risk of stroke in populations exposed to lower doses thanthose used in radiotherapy. Tatsukawa et al. [T7] studied the risks associated with in utero exposure. Of
interest, and for purposes of comparison, it should be noted that this study also included a cohort ofchildren exposed at <10 years of age at the time of the bombings. No significant effects associated withradiation exposure were observed in the cohort exposed in utero. However, a positive association was
found between radiation exposure and hypertension and cardiovascular disease in this cohort ofchildren. Yet, there was no statistically significant difference in relative risks between the two cohorts;
the relative risk for the cohort exposed in utero was 1.20 (95% CI: 0.61, 2.38) and for the childhood
cohort was 1.15 (95% CI: 0.99, 1.34). The median dose in the childhood cohort was 0.13 Gy with arange of 0-3.53 Gy.
C57.
In a more recent study, Shimizu et al. [S57] found an increased risk of circulatory disease in
the survivors of the atomic bombings at doses in excess of 0.5 Gy. The degree of risk at lower doses
was unclear. This study included data on stroke specifically. There was a non-significant indication(p = 0.23) that the risk of stroke associated with radiation may be highest after exposure at young ages:
the ERRs per unit of dose were 36%, 9%, 15% and 5% Gy-1 for those exposed at ages <10, 10–19,
20-39 and >40 years, respectively.

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V. ORBIT AND EYEC58.
Deterministic effects of radiation exposure of the eye were noted as early as 1897, and by 1908
corneal changes were clearly recognized as deterministic effects. In the 1950s, there was extensive
investigation of radiation-induced eye damage, particularly cataract formation. The historical aspects
are well reviewed by Rubin and Casarett [R57]. More recent reviews are also available [A10, A13,
B58, G22, P12, S72].
C59.
Most of the tissues around the eye have the same sensitivity to radiation exposure as skin;however, the lens is particularly radiosensitive. Radiation exposure can produce opacities within thelens and cataract formation. The excretory ducts, particularly in the meibomiam glands, are relatively
sensitive to radiation-induced deterministic effects, as are the equatorial regions of the optic lens andthe basal layer of the cornea. The neurons of the retina probably represent the most radioresistant cells
in the eye. In addition to cataract formation, other late effects of radiation exposure in the eye can
include retinopathy, optic neuropathy and lachrymal gland atrophy. These types of injuries rarely
occur below a dose of 45 Gy, although subclinical indications of retinopathy have been observed
at much lower doses [M41].

A. Radiotherapy for malignancies
C60.
Orbital complications are common following radiotherapy treatment of children for
retinoblastoma, childhood head and neck sarcomas, CNS tumours, and other conditions. For survivorsof retinoblastoma, a small orbital volume may result from either enucleation or radiotherapy. The risk
may be higher at ages younger than one year, but the information on this is not consistent across studies[K15, P30]. Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia,
ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision
following radiotherapy doses of 30–65 Gy. The higher doses (>50 Gy) are associated with lidepitheliomas, keratoconjunctivitis, lachrymal duct atrophy, and severe dry eye. Retinitis and optic
neuropathy may also result from doses of 50–65 Gy, and even at lower total doses if the individual
fractional size of the dose is greater than 2 Gy [K37]. Cataracts are reported following lower
therapeutic doses of 10–18 Gy [H44, O4, P12, P14, P15, R9, R8].
C61.
Survivors of childhood cancer are at increased risk for ocular late effects, related to bothglucocorticoid and radiation exposure. The CCSS reported that survivors of five or more years were at
an increased risk for cataracts, glaucoma, legal blindness, double vision and dry eyes compared tosiblings. The radiation dose was significantly associated with those risks in a dose-dependent manner.
The risk of cataracts was associated with a radiation dose of 30 Gy or more to the posterior fossa andtemporal lobe, and exposure to prednisone. In these situations, the eye is not directly in the radiation
pathway but may still receive some marginal or scattered dose. The cumulative incidence of cataracts,
double vision, dry eyes, and legal blindness continued to increase up to 20 years for those who received
more than 5 Gy to the eye [W19].
C62.
The dose absorbed by the lens when irradiating the cranium for acute leukaemia is associatedwith the induction of cataracts [K38]. The dose to the lens is approximately 15-30% of the midline
dose, depending on the type of treatment fields. Nesbit et al. [N27] found one case of posterior
subcapsular cataracts in 50 survivors of acute leukaemia in childhood. In contrast, Inati et al. [I35]observed a 50% incidence of cataract formation in 69 children with acute leukaemia who had been
given a dose of 24 Gy to the cranium in 13 fractions over 2.5 weeks, intrathecal methotrexate and high

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doses of steroids. All cataracts were small and did not impair vision. In another study of 34 long-term
survivors of acute leukaemia, all 18 patients in the non-irradiated group had normal results on eye
examination, while 4 of 16 of those who had received a dose of 24 Gy to the whole brain in 12 fractions
over 2.5 weeks had ocular abnormalities [W16]. None of the ocular findings could, however, bedefinitely attributed to radiation, and all patients had normal visual acuity.
C63.
Ocular complications such as cataracts and dry-eye syndrome are common after stem celltransplant in childhood. Patients who were treated with single-dose or fractionated whole-body dosecompared to those treated with busulfan or other chemotherapy are at increased risk of cataracts. The
risk ranges from approximately 10% to 60% at 10 years post-treatment, depending on the total dose andfractionation, with a shorter latency period and more severe cataracts noted after single fraction andhigher dose or dose-rate TBI [F1, F7, G41, K4]. Patients receiving whole-body doses of less than 4 Gy
have a less than 10% risk of developing severe cataracts [K4].

B. Radiotherapy for benign conditions
C64.
Qvist and Zachau-Christiansen [Q1] estimated the minimum lenticular dose to produce
cataracts in children to be 13.8 Gy from radium moulds based on a small study in which four cataracts
were observed in 57 irradiated patients; the maximum non-cataract dose for infants was 9.9 Gy and forschool-aged children, 11.4 Gy. The text did not describe the mode of examination (whether
ophthalmoscope or slit-lamp microscope). Notter et al. [N36] conducted a slit-lamp examination andobserved cataracts after considerably lower doses in 234 patients who had been irradiated with 226Ra
containing applicators for skin haemangioma between 1920 and the mid-1950s. An ophthalmologicalexamination was conducted in 1961–1965. Of the 468 eyes examined, cataracts were observed in 51(11%). No cataracts were observed in the 246 eyes which had received a dose to the lens of <2.5 Gy.
The prevalence of cataracts was 8% (out of 100 eyes) after a lenticular dose of 2.5-3.5 Gy and 54% (outof 122 eyes) after higher doses.
C65.
In another study [H8], the prevalence of lens opacities in 484 adults who had been treated as
infants (at median age 4 months; range 0–16 months) with external X-ray (12%) or radium therapy(88%) for haemangiomas of the head, face or neck was compared to that in a control population of
89 unexposed, age-matched persons who presented with skin haemangiomas as infants. These people
had been treated for the condition between 35 and 54 years prior to the study. The exposed subjects hadreceived an average of two treatments with a cumulative mean dose of 0.4 Gy (median 0.2 Gy,
maximum 8.4 Gy, 10% with >1 Gy). Lens opacities of any type were found in 37% of exposed eyes
(357 opacities in 953 eyes) compared to 20% in controls. However, because of the low rate of study
subject participation (39%) for controls and their younger age at examination, the dose–response
analyses were based on only the irradiated group. A dose–response relationship was found which was
independent of age at exposure. When corrected for age at examination, dose rate and steroid use, theauthors reported an odds ratio at 1 Gy of 1.50 (95% CI: 1.15, 1.95) for cortical opacities and 1.49 (95%
CI: 1.07, 2.08) for posterior subcapsular cataracts. In contrast, no dose response was noted for changes
to the nuclear lens.
C66.
A small study of 20 treated infants by Wilde and Sjostrand [W22] noted precataractous
subcapsular lens changes in the eyes of subjects, who were 31–46 years old at the time of examination,on the untreated side of the face, where doses to the lens were estimated to average 0.1 Gy.

174

UNSCEAR 2013 REPORTC67.
In the first half of the twentieth century, before the development of modern antifungal
medication, ringworm of the scalp (tinea capitis) was often treated by epilation using X-ray doses to thescalp ranging from an average 3.3 Gy, up to 6 Gy at the vertex and occasionally as high as 8.5 Gy. As
many as two hundred thousand persons may have been irradiated worldwide [S60]. Despite the fact thatthe eyes of the patients were covered with lead foil, recreation of the original treatment procedures
indicated that the lens had received doses ranging from 0.2 to 0.8 Gy [S41].
C68.
From 1964 to 1965, approximately 15 years after treatment, an increased incidence of early
posterior lens changes characteristic of ionizing radiation exposure was noted after slit-lamp
examination of people given X-ray treatment at a mean age of eight years [S68]. While the overall
severity of such changes was minor, the authors noted an increase in capsular opalescence or sheen andan accumulation of bright dots or micro-opacities, probably corresponding to Merriam-Focht stages
0.5–1.0. Thirteen cases of posterior subcortical opacities were noted in the exposed persons comparedto two cases in the non-irradiated controls. An estimated odds ratio of 5.9 (95% CI: 1.4, 24) was
calculated, adjusted for age at examination. A second follow-up from 1968 to 1973, based on a mailsurvey roughly 25 years after exposure, did not detect any difference in cataract incidence between the
exposed persons and the controls. Unlike the previous detailed ocular examination, which detected
early, radiation-associated lens changes unaccompanied by visual disability, the later survey asked
respondents to self-report on any subsequent cataract diagnosis, surgery or associated visual disability.
This could account for the differences in outcomes between the two studies.
C69.
Patients who had received 224Ra intravenously for treatment of ankylosing spondylitis andtuberculosis had an increased incidence of cataract formation [S103]. This was particularly apparent
since many of the patients were young, and cataract formation was not expected. Stefani et al. [S111]
reported on the development of cataracts in 899 patients who had received multiple injections of 224Ra.
Cataracts were found in 6% of the 218 juvenile patients and in 5% of the 681 adult patients. Those
juveniles who were known have received an injected activity of 224Ra of >1 MBq/kg of body weight,
and had a cataract incidence of 14% (11 patients out of 80) compared to 0.8% (1 patient out of 131)
among those who had received less than that amount. The cataract incidence increased significantlywith the 224Ra activity per unit body weight in both juveniles and adults.
C70.
In a later report, 58 cataracts, including 42 cataract extractions, were found among 831 patients[C20, C19]. The authors reported that the induction of severe cataracts was proportional to the square of
the 224Ra activity per unit body weight and the square of the time since radiation exposure. The data
were also compatible with a linear dose response above a threshold 224Ra activity of 0.5 MBq/kg ofbody weight. In their analysis, no effect of age at exposure was found, but the analysis was primarily interms of cataract acceleration (time from irradiation to cataract diagnosis) rather than magnitude ofcataract induction. Taylor and Thorne [T13] estimated the dose to the anterior surface of the lens to be
0.035–0.22 Gy from an uptake of 1 MBq of 224Ra after injected into the systemic circulation, and alarge uncertainty in the dose from alpha particles to the germinative epithelium.

C. Atomic bombing survivors
C71.
There have been several studies of lens opacities among the survivors of the atomic bombingsin Japan in relation to radiation dose and risk modification by age at exposure. In a study conductedamong subjects of the Adult Health Study (AHS) clinical examination programme in Hiroshima andNagasaki in 1978–1980, a significant excess risk for posterior subcapsular changes was observed inresidents of Hiroshima (but not of Nagasaki) of all ages in the group who had received a dose of >3 Sv

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compared to those in the control group [C21]. The study was based on the 1965 dosimetry system andthe examination was conducted on 2,385 persons, including those with doses of ≥1 Sv, and a matched
unexposed group. Ophthalmological examinations were conducted largely without the use of
mydriatics. The relative risk of cataracts for persons in Hiroshima exposed to a dose of >3 Sv was 4.8
in persons under age 15 years at the time of the bombings, 2.3 in persons aged 15–24 years at the timeof the bombings and 1.4 in persons more than 25 years of age at the time of the bombings. The relativerisk for posterior subcapsular changes in Hiroshima for persons under age 15 years at the time of thebombings was 2.8 in the group with doses of 1–1.9 Sv, 4.3 in the group with doses of 2–2.9 Sv and 5.3
in the group with doses of >3 Sv. A comparison of the 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 the hypothesis that younger are more sensitive than older people to radiationinduced cataracts.
C72.
A reanalysis of the data from the study of Choshi et al. [C21] by [O21, O20], confirmed theprevious findings of a higher sensitivity for radiation-induced cataracts in young persons. The
magnitude of radiation-associated relative risks for cataracts in persons aged 40, 50, 60 and 70 years at
the time of examination was 8.2, 6.4, 4.6 and 2.8-fold higher, respectively, than in persons aged
80 years at the time of examination. However, it is unclear how much the age-comparative ratios ofrisks are due to a younger age at exposure (which correlates with those who were younger at
examination), or to a greater frequency of age-related cataracts among the elderly which could dilutethe dose–response slope for radiation risk.
C73.
Minamoto et al. [M41] reported an examination of 913 persons during 2000–2002, including
mostly persons who were younger than 13 years at the time of the bombings. A variety of potential risk
factors for opacity formation were examined, including ultraviolet exposure, smoking, white blood celland neutrophil counts, serum markers for thyroid dysfunction, inflammation and oxidative stress; thosethat were potentially confounders were included in the analyses. A significant increase in cortical andposterior subcapsular cataracts was reported with increasing radiation dose adjusted for age, sex,
history of diabetes, smoking and a composite index of inflammation–oxidative stress markers.
C74.
A 2006 reanalysis of essentially the same cataract data by Nakashima et al. showed a clear
increase in the dose–effect odds ratio for posterior subcapsular opacity with decreasing age at exposure(p <0.001) (figure C-II) [N6]. The odds ratios at 1 Gy for the age-at-exposure groups of 0–10, 10–20
and >20 years were 1.64 (95% CI: 1.26, 2.14), 1.32 (1.02, 1.72), and 0.87 (0.52, 1.46), respectively.
C75.
The data on the survivors of the atomic bombings prior to 2000 had been based on
ophthalmological screening, and so most of the opacities being analysed were small, subclinicalopacities. A new study examined the prevalence of cataract surgery in 2000–2002 among the AHS
cohort to evaluate the association of radiation with vision-impairing cataracts [N25]. Among 3,761
AHS subjects, 479 had had a cataract extraction. About 70% of those examined were under age of 20 at
the time of irradiation, including 21% who were under 10. With adjustment for city, sex, age at
exposure and diabetes, the odds ratio at 1 Sv was 1.39 (95% CI: 1.24, 1.55). The interaction of age at
exposure and radiation dose was not evaluated.
C76.
Further data on the incidence of cataract extractions in the AHS cohort have indicated an ageat-exposure effect [N26]. A total of 1,028 persons out of the cohort of 6,066 had a first cataract
extraction during 1986–2005. The analysis found no confounding by any of 16 cataract risk factors.
After adjustment for city, sex, diabetes and time since exposure it showed that fifty years after
exposure, the relative risks at 1 Sv were 1.61, 1.32 and 1.15 for those exposed at ages 10, 20 and 30
years, respectively, and the age-at-exposure effect was statistically significant (p = 0.006).

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Figure C-II. Odds ratio per Sv for posterior sub-capsular (PS) versus age at exposure
Adapted from [N6]D. Accidental exposures
C77.
Lens examinations of those exposed as a result of the Chernobyl accident have provided
important epidemiological data for protracted, low-dose exposures of similar magnitudes to thosereceived by the survivors of the atomic bombings [W42]. This is especially important given thatconsiderable animal and human data indicate that dose fractionation of low-LET radiation results in asignificant reduction in the prevalence of cataracts.
C78.
A study of lens changes in a paediatric population exposed as a result of the Chernobyl
accident has been published by Day et al. [D23]. Estimates of cumulative dose ranged from 29 to
86 mSv. A small but statistically significant increase in the incidence of subclinical posterior
subcapsular opacities (2.8%) compared to the unexposed (1.0%), which was greatest among males
12-17 years old at the time of examination, was noted in ~1,000 exposed children, compared to amatched population of ~800 unexposed subjects. The odds ratio for posterior subcapsular opacities was
2.8 (95% CI: 1.3, 6.1). It should be noted, however, that the dose estimates contain large inherent
uncertainties. The authors also noted that the ophthalmologists knew whether the children were exposedor unexposed, though they took precautions to have many of the children with lens changes examinedby a second ophthalmologist to confirm the diagnosis. The presence of posterior subcapsular defects ofa type characteristic of ionizing radiation exposure and not normally found in a paediatric population issuggestive of causal relationship.
C79.
A study of nearly 30,000 residents living near the Techa River at the time of the relatively highradionuclide discharges from the Mayak nuclear plant has shown an exposure-related excess ofdiagnosed cataracts [M38]. However, effects of age at exposure were not reported.

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177

C80.
A study of a paediatric population accidentally exposed while living in 60Co-contaminatedapartments in Taiwan indicated an odds ratio of 1.18 at 1 Gy for subclinical lens changes [C14]. The
mean dose to this population was 170 mGy, with a range of 1 to 1,200 mGy. Annual exposures of>5 mGy, in some cases for more than 10 years, were reported. A recent follow-up of some of the
exposed children, with an estimated mean dose to the eye of 191 mSv received over an average of
7.4 years, indicated that radiation-induced lens changes, measured as subclinical focal lens defects,
continued to increase in size and with the number years after relocation from the contaminatedbuildings and were significantly in excess compared to those in the unexposed control group [H69].
The progressive nature of such changes five years after the children had been removed from thecontaminated environment, supports the earlier findings of radiation-associated lens changes anddemonstrates that such changes may persist and progress with time.

E. Summary
C81.
Survivors of various childhood malignancies who have had radiation treatment are at anincreased risk of cataracts and other ocular pathologies, although the risks per unit dose cannot be
unequivocally quantified because radiotherapy was often administered in conjunction withchemotherapy or other systemic agents (e.g. steroids). Infants who were treated with 224Ra plaques forhaemangiomas have an excess incidence of cataracts. Some older studies suggested that there was adose threshold of ≥3 Sv for the induction of cataracts, but a more recent study has found that cataracts
can be induced by lower doses. The results of studies of persons treated with 224Ra in the second or later
decades of life for ankylosing spondylitis or tuberculosis are unclear as to whether the risk of cataracts
varied with age at exposure. A study of children treated with X-rays for scalp ringworm has suggested
an excess of precataractous changes when the children were examined in their late teens and twenties.
Several studies of cataract induction have been conducted over the years since the atomic bombings in
Hiroshima and Nagasaki. The studies undertaken 30 or more years after the bombings have consistently
shown dose-related excesses of cataracts, and the risk is greater for those exposed at younger ages.
These studies have also suggested that children are about two times more sensitive than adults for the
induction of preclinical posterior subcapsular and cortical opacities, and of vision-impairing cataracts.
Studies of the effects of the protracted radiation exposures as a consequence of the Chernobyl accident
and of the contamination of dwellings by 60Co in Taiwan also indicate a substantial radiosensitivity forearly opacities among children. Much evidence suggests that radiation-induced lens changes may be
progressive after childhood exposure.

VI. EARC82.
The external ear consists of the elastic connective tissue, epithelium, and fibroblasts. The
middle ear has an epithelial lining in the tympanic cavity. The mucous membrane is squamous andepithelial in nature and is composed of reverting post-mitotic cells. The inner ear has many different
cell types, but most of the cells are of the reverting post-mitotic type. The radiosensitivity of theexternal ear, therefore, is similar to that of the skin elsewhere, and the middle and inner ear are
relatively radioresistant. Clinical effects that can be identified as a result of radiation exposure are
primarily due to changes in the fine vasculature, which is moderately radiosensitive.

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C83.
Findings related to radiation effects on the ear may be identified soon after high-dose
irradiation. They include hearing loss, tinnitus and earache [C49, D37, L17, M48]. Tinnitus may occur
with localized radiotherapy at dose levels of 40 Gy. The situation resembles a serous otitis media and isdue to hyperaemia of the capillaries, increased capillary permeability, and serous exudate.
C84.
A conductive hearing loss also may be present. Fractionated doses of 40–60 Gy will cause
acute radiation otitis media in 50% of patients. From six months to a few years after radiotherapy(subacute clinical period), there may be a sudden onset of Meniere's disease [G1]. The aetiology ofthese vestibulocerebellar signs is unknown. Usually, the patient recovers within several weeks.
Sensorineural hearing loss is usually more pronounced at high frequencies [R1] and has a latent periodof 12 months or more.
C85.
There is some information concerning age as a modifying factor in late radiation effects fromradiotherapy. Children treated for malignancies may be at a risk for early- or delayed-onset hearing loss
that can affect learning, communication, school performance, social interaction, and overall quality oflife. Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatinand carboplatin) and cranial irradiation [G35, M19].
C86.
Cranial irradiation, when used as a single modality, results in ototoxicity when the dose to thecochlea exceeds 32 Gy. Young patient age and the presence of a brain tumour/hydrocephalus canincrease susceptibility to hearing loss. The onset of radiation-associated hearing loss may be gradual,
manifesting itself months to years after exposure. When used concomitantly with cisplatin, radiotherapy
can substantially exacerbate the hearing loss [C17, H71, M28, P20]. In a recent report from the CCSS,
five-year survivors were at increased risk of impaired sound perception (RR = 2.3), tinnitus (RR = 1.7),
hearing loss requiring an aid (RR = 4.4) and hearing loss in one or both ears not corrected by a hearingaid (RR = 5.2) when compared with unexposed siblings. These outcomes were associated with doses of>30 Gy to the temporal lobe and >50 Gy to the posterior fossa.

VII. ORAL CAVITY AND PHARYNX
C87.
The epithelial lining of the mouth and pharynx are somewhat more radiosensitive than the skinbecause of the higher renewal rate of their cells. Methotrexate and 5-fluorouracil can produce severe
mucositis and oesophagitis when used in combination with radiation. Because there is increased
sensitivity of the mucosa compared to skin, radiation-induced mucositis will be noted before radiationinduced dermatitis. For these acute changes, the mechanisms of injury are quite similar but vary in timeof expression. Most patients (more than 75%) receiving fractionated radiotherapy schemes totalling60-70 Gy have impairment in taste for several years [K45].
C88.
At the end of the second week of radiotherapy and doses of 20–24 Gy, dysphasia, soreness andpain, and dryness of the mouth occur, and taste deteriorates further. Definite erythema, and patchy
mucositis of the palate may be noted. At doses of 30–36 Gy, the saliva becomes thick, and mucositis is
identified in the region of the tonsils and the posterior pharynx. At doses of 50–60 Gy, mucositis
develops into a pseudomembrane involving all tissues including the tongue. Clearing of these changes
begins in approximately two weeks and is completed within two months. Rubin and Cassarett [R57]
indicate that the same radiotherapy dose schedules are more easily tolerated by children than adults.
The reactivity of children is greater but this is compensated by a more rapid recovery with the end
effect seeming to be less.

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C89.
Delayed effects include progressive fibrosis of the submucosa, telangiectasia, and interstitial
fibrosis of the mucous glands. Chronic ulcers may occur in the mucosa, in a fashion similar to that forthe skin, as the result of arterial intimal fibrosis. They commonly occur along the lateral border of the
tongue, floor of the mouth, and other areas where there is friction or microtrauma. High radiation doses
administered at young ages can cause delayed pharyngeal hypoplasia.

VIII. TEETH
C90.
Adverse long-term abnormalities of dentition can result directly from radiation andchemotherapy effects on growing tooth buds, and indirectly from damage to salivary glands. The
severity and frequency of long-term dental complications due to radiotherapy are related to the type ofradiotherapy given, the total dose, the size and location of radiotherapy fields and the age of the patient.
Tooth bud growth may be arrested by doses of <10 Gy, while doses of >10 Gy can completely destroy
buds. Root shortening, abnormal curvature, dwarfism and hypocalcification are noted with doses of
20-40 Gy [M5, S98]. Both chemotherapy and radiotherapy can cause multiple cosmetic and functional
abnormalities of dentition, most predominantly in children treated before five years of age who have
not yet developed deciduous dentition [A16, H62, H63, K18, K17, K16, O2, P14, P15]. However, evenolder prepubertal children are at risk. More than 85% of survivors of head and neck rhabdomyosarcoma
who receive radiation doses greater than 40 Gy may have significant dental abnormalities, including
mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, andxerostomia [P14, P15]. In Paulino’s study, among children with head and neck rhabdomyosarcoma
receiving radiotherapy to developing teeth, the alveolar portion of the mandible or the lingual surface ofthe maxilla developed dental abnormalities, including microdontia, root stunting and dental caries[P15]. Developing teeth are irradiated in the course of treating head and neck sarcomas, Hodgkin’s
lymphoma, neuroblastoma, CNS leukaemia, and nasopharyngeal cancer, and as a component of wholebody irradiation.
C91.
Whole-body irradiation has been linked to the development of short, V-shaped roots,
microdontia, enamel hypoplasia, and premature apical closure [D2, H62, H63]. Data regarding dental
outcome after bone marrow transplants are limited [D1]. Neuroblastoma patients who received 12 Gy
fractionated TBI-based or non-TBI-based transplants were not different in the incidence of microdontia
and missing teeth, although TBI was associated with more severe root defects and a higher chance of
permanent damage to teeth [H61]. The incidence of tooth abnormalities, including agenesis, was 62.9%
in another study in which most of the children were treated with a TBI-based bone marrow transplant
regimen [U3]. Tooth breakage due to tooth resorption has been common in patients injected with 224Ra,
especially in those injected as teenagers [S99].

IX. SALIVARY GLANDS
C92.
The salivary glands include the parotid, submaxillary, and sublingual glands. They each havesecretions that enter the oral cavity through a duct. Both the parenchymal cells of the gland and the ductcells are relatively resistant to deterministic effects of radiation exposure. The major exceptions are therelatively large excretory ducts of the parotid, which contain stratified epithelium near the main outlet(similar to that of the oral mucosa) which are relatively radiosensitive. The pathological effects of180

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radiation on these glands have been well described by Rubin and Casarett [R56], Fajardo [F4], Scherer[S28] and Ang et al. [A20]. Most of the data concerning these structures are derived from radiotherapy
experience.
C93.
In the months following radiotherapy, the extent of damage varies greatly from person toperson. This may be the result of differences in radiotherapy administration, individual susceptibility,
and other treatment factors such as sensitizing chemotherapy. Yet, it is clear that salivary gland
irradiation incidental to treatment of head and neck malignancies or Hodgkin’s lymphoma causes aqualitative and quantitative change in salivary flow, which can be reversible after doses of less than
40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy isalso administered [J14]. There are few specific data concerning the effects of exposure duringchildhood or adolescence since head and neck tumours are very rare in children. However, available
data does suggest that >25 Gy radiotherapy can reduce secretions of the parotid, submaxillary andsublingual glands with resultant dry mouth, but this is generally not pronounced below doses of 40 Gy.
Permanent xerostomia occurs in about 80% of persons receiving fractionated doses of 40–60 Gy [F20].
Transient dysfunction of the salivary glands is noted in young patients who have received a single
whole-body dose of 10 Gy prior to bone marrow transplantation for leukaemia [D31].
C94.
Following administration of very large doses of 131I, radiation sialitis may be observed.
Goolden et al. [G21] have calculated that after administration of 5.5–7.4 GBq of 131I, doses to thesalivary glands may be as high as 7–9 Gy in 12 hours. Doses from radioiodine therapy for
hyperthyroidism (which sometimes occurs in children and adolescents) almost never result insignificant xerostomia. When higher administered activities of radioiodine are used for the treatment of
thyroid cancer, the doses to the salivary glands are higher. In these circumstances salivary andlachrymal gland dysfunction (sicca syndrome) can occur [S97].

X. THYROID FUNCTION AND THYROIDITIS
C95.
There is extensive clinical experience of thyroid irradiation. Human data are available from thesurvivors of the atomic bombings, from those exposed to fallout from the testing of nuclear weapons,from those exposed as a consequence of accidents, and from those who have undergone radiotherapy
for the treatment of tumours of the thyroid or the adjacent neck, or from the treatment ofhyperthyroidism.
C96.
The deterministic changes in the thyroid following large doses of radiation are primarily
mediated by the vasculature, and presumably less so from direct damage to the fully differentiatedfollicular epithelial cells. Injury may be manifest as inflammatory and oedematous changes, followed
later by obliteration of the fine vasculature and, ultimately, by radionecrosis or atrophy. Primarydamage to the glands can produce either subclinical or clinically evident hypothyroidism. Damage tothe hypothalamic–pituitary axis may produce secondary hypothyroidism.
C97.
Late effects on the thyroid after childhood radiotherapy were reviewed in the UNSCEAR 1993
Report [U8]. However, new data concerning those exposed as a consequence of the Chernobyl accident[U15] and patients who have undergone radiotherapy are now available. A large body of literatureexists regarding the role of radiation in the development of autoimmune thyroiditis, also known as
Hashimoto’s thyroiditis. The literature is complicated by the different tests and methodologies used tomake the diagnosis, the high prevalence of thyroid abnormalities in the general population and nonradiation aetiological factors.

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181

A. Atomic bombing survivors
C98.
Morimoto et al. [M51] reported that in the age group under 20 years of age at the time of thebombings, those who received a dose of 1 Gy or more manifested an increased incidence of thyroid
cancer and nodules but no statistically significant difference with regard to hypothyroidism or markers
of autoimmune thyroiditis. Thyroid disorders were studied 30 years after exposure in 978 persons who
were under 20 years of age at the time of the bombings [M51, M50]. The estimated doses were basedon T65 dosimetry. There were 200 males and 277 females in the group exposed to doses of >1.0 Gy,
and 219 males and 282 females in the unexposed group. Of these, 128 were aged 0–9 years and 349
were aged 10–19 years at the time of the bombings in the group exposed to doses of >1.0 Gy; 139subjects were aged 0–9 years and 362 were aged 10–19 years at the time of the bombings in theunexposed group. There were no significant differences in mean scrum TSH levels or mean serum
thyroglobulin levels between the unexposed and exposed groups.
C99.
In an analysis by Nagataki [N1] of 2,774 subjects of the Nagasaki Adult Health Study cohort,the prevalence of hypothyroidism was 5% in exposed subjects and 2% in controls. Inoue et al. [I37]
studied nearly 2,600 subjects from the same cohort and observed hypothyroidism in 3% of the subjects.
The fitted relative risk increased from one for those who were less than five years of age to three forthose who were 30 years at the time of the bombings.
C100. Fujiwara et al. [F22] reported on the prevalence of various types of immune factors but those
associated with autoimmune thyroiditis did not appear to be dose related. An autopsy study by
Yoshimoto et al. [Y8] of about 3,800 subjects did not reveal a statistically significant increase inchronic thyroiditis, however, the survivors of the atomic bombings who were under 30 years of age at
the time of exposure have shown a dose-dependent excess of thyroid disease, defined to include nontoxic nodular goitre, diffuse goitre, thyrotoxicosis, chronic lymphocytic thyroiditis, and hypothyroidism[W37]. The excess, which became evident within 20 years of exposure and was not detectable in those
exposed at older ages, corresponded to a relative risk of 1.24 at 1 Gy (Sv) (p = 0.003). Although manyof those affected had multiple diagnoses, the exclusion of persons with thyroid cancer or thyroid
adenomas did not modify the risk.
C101. The most recent follow-up of thyroid abnormalities among the survivors of the atomic
bombings has been published by Imaizumi et al. [I34]. Among 4,091 survivors studied there was nodose–response relationship observed for positive antithyroid antibodies or antithyroid antibody-positive
hypothyroidism. There was no analysis by age at exposure.

B. Radiation therapy
C102. While there are a large number of epidemiological studies of persons who had been treatedwith radiotherapy in childhood for various benign conditions—such as tinea capitis, presumed thymic
enlargement, acne and haemangiomas—none of these studies specifically address the incidence ofeither hypothyroidism or autoimmune thyroiditis. Spitalnik and Straus [S105] found evidence forchronic lymphocytic thyroiditis, benign thyroid nodules and papillary thyroid cancers in thyroid glands
removed for palpable thyroid abnormalities in a cohort of 68 patients who received “low dose” externalbeam irradiation for benign disease during childhood (thymus, tonsillitis, adenoiditis, acne, and scalp
conditions). While the radiation dose to the thyroid was not known, the authors noted that all patients
received doses of less than 10 Gy. The NCRP [N18] has pointed out that, given the conditions treated,
it is likely that most of the patients received doses between 0.2 and 1.5 Gy as these were the usual doses

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received by patients with similar conditions in other studies. Regardless of the dose received, themarked selection bias for cases (all with palpable thyroid disease requiring surgical removal) makes theresults not generalizable to patients without palpable thyroid disease. Therefore, no conclusions can be
drawn regarding dose–response relationships from this study.
C103. Thyroid dysfunction is a common delayed effect of high-dose radiotherapy fields that include
the thyroid gland incidentally in the treatment of Hodgkin’s lymphoma, brain tumours, head and necksarcomas, and acute lymphocytic leukaemia. Of the children treated with radiotherapy, most develop
hypothyroidism within the first two–five years post-treatment, but new cases can occur later(figure C-III). Reports of thyroid dysfunction differ depending on the dose of radiation, the length offollow-up, and the biochemical criteria used to make the diagnosis [G15]. The most frequently reported
abnormalities include an elevated TSH, produced by the pituitary in response to a depressed thyroxine
and stimulating the thyroid gland to compensate with increased output of thyroxine If the thyroid glandis unable to compensate with an increased output, then the thyroxine level will decline below normal[C45, H22, O3, S51, S86].
Figure C-III. Probability of developing an underactive thyroid after diagnosis of hypothyroidism
Adapted from [S83]. Patients are grouped according to dose of thyroid irradiation

C104. The incidence of hypothyroidism should decrease with the lower cumulative doses prescribedin newer protocols for radiotherapy. In a study of 1,677 children and adults with Hodgkin’s lymphoma
who were treated with radiotherapy between 1961 and 1989, the risk at 26 years post-treatment for
overt or subclinical hypothyroidism was 47%, with a peak incidence at two–three years post-treatment[H18]. In a study of children and adults with Hodgkin’s lymphoma treated between 1962 and 1979,
hypothyroidism occurred in four of 24 patients who received mantle doses less than 26 Gy but in 74 of
95 patients who received doses greater than 26 Gy. The peak incidence occurred three–five years posttreatment, with a median of 4.6 years [C45].
C105. A cohort of survivors of Hodgkin’s lymphoma in childhood who had been treated between
1970 and 1986 were evaluated for thyroid disease by use of a self-report questionnaire in the CCSSANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

183[S83]. Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid
abnormality. For hypothyroidism, there was a clear dose response, with a 20-year risk of 20% for those
who had received a dose of <35 Gy, 30% for those who had received a dose of 35–44.9 Gy, and 50%
for those who had received a dose of >45 Gy to the thyroid gland. The relative risks for
hypothyroidism, hyperthyroidism and thyroid nodules were 17.1, 8.0 and 27.0, respectively. Elapsed
time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, where the riskincreased in the first three–five years after diagnosis. For nodules, the risk increased beginning at ten
years after diagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.
C106. As might be expected, children treated for head and neck malignancies are also at risk for
primary hypothyroidism if the neck is irradiated. The German Group of Paediatric Radiation Oncology
recently reported on 1,086 patients treated at 62 centres, including 404 patients (median age,
10.9 years) who had received radiotherapy to the thyroid gland/hypophysis. Follow-up information wasavailable for 264 patients (60.9%; median follow-up time was 40 months), with 60 patients (22.7%)
showing pathological values. In comparison to patients treated with prophylactic cranial irradiation(median dose, 12 Gy), patients with radiation doses of 15–25 Gy to the thyroid gland had a hazard ratioof 3.072 (p = 0.002) for the development of pathological thyroid blood values. Patients with a dose
greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had ahazard ratio of 3.768 (p = 0.009) and 5.674 (p <0.001), respectively. The cumulative incidence of
thyroid hormone substitution therapy did not differ between defined subgroups [B46].
C107. Paediatric patients who have undergone HSCT are at risk of thyroid dysfunction, which ismuch lower (15–16%) after fractionated whole-body irradiation, as opposed to single-dose irradiation(46–48%). Previously, regimens that did not involve whole-body irradiation were not associated withan increased risk. However, in a report from the Fred Hutchinson Cancer Research Centre, theincreased risk of thyroid dysfunction was not different between children receiving whole-body
irradiation and those receiving a busulfan-based regimen (p = 0.48) [S19]. Other high-dose therapies
have not been studied. While mildly elevated TSH is common, it is usually accompanied by normal
thyroxine concentration [B50, S17].
C108. According to the UNSCEAR 1993 Report [U8], the effect of age at the time of radiotherapy on
the development of hypothyroidism 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 of treatment had elevated TSHlevels compared to 33% of older patients [G14]. Green et al. [G27] observed that 7 out of 15 children
with Hodgkin’s disease and irradiated at the age of less than 13 years developed hypothyroidism,
compared to 3 out of 12 among those who had been older than 13 years. In a study by Tarbell et al. [T6]of patients irradiated for Hodgkin’s disease, the 15-year risk for hypothyroidism was 64% among
patients aged 16 years or less, as compared to 29% among those older than 16 years. Constine et al. also
identified an influence of age at exposure [C45]. However, other investigators have not identified age
as a contributory factor [D36, K9, N23, S92].

C. Fallout
C109. In 1954, a thermonuclear explosion accidentally deposited large amounts of radioiodine on the
Marshall Islands [C43, L7, R27]. The estimated thyroid dose varied from 0.3 to 3.4 Gy among those
aged ≥18 years to 0.6–20 Gy among those aged <10 years. Many uncertainties were involved in thecalculation of doses to the thyroid. The most widespread late effects of radiation exposure among the
Marshallese have been related to radiation injury to the thyroid gland.

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C110. The incidence of subclinical hypothyroidism was 31% among children of <10 years of age at
exposure after an estimated dose to the thyroid of >2 Gy. No case of hypothyroidism occurred in thisage group at lower doses. Among subjects who were ≥10 years at exposure, one case (1%) of
hypothyroidism was observed in those who had received an estimated dose to the thyroid of <1 Gy, onecase (8%) in those who had received a dose of 1 to 2 Gy and four cases (9%) in those who had received
a dose of >2 Gy. Only two of the subjects exposed at less than 10 years of age had clinicalhypothyroidism. The incidence of hypothyroidism began to increase approximately one decade after
exposure. A thorough re-evaluation of the absorbed dose in the thyroid was done by Lessard et al.
[L21]. The recalculated cumulative external doses of gamma rays were close to the initial estimates, but
the doses from internally deposited radionuclides were much higher. Most of the thyroid dose resulted
from short-lived radionuclides. The re-evaluated absorbed doses to the thyroid make the observed
results compatible with those of other studies with similar doses [R29].
C111. Long-term follow-up by Takahashi et al. [T1, T2] of the Marshall islanders who received
doses to the thyroid up to 4 Gy from the fallout from the testing of nuclear weapons did not show anincrease in autoimmune hypothyroidism.

1.

NevadaC112. Although there was an early report by Rallison et al. [R5] of an excess of autoimmune
thyroiditis in Nevada and Utah compared to Arizona, a subsequent age- and sex-adjusted study by
Kerber et al. [K27] showed no evidence of a relationship between autoimmune thyroiditis or otherthyroid diseases and individual doses. After a thorough review of the dosimetry and diagnoses in thisstudy, Lyon et al. [L44] reported a statistically significant association with estimated radiation dose forthyroiditis (ERR Gy-1 of 4.9; 95% CI: 2.0, 10.0) and a suggestive association for thyroiditis withhypothyroidism (ERR Gy-1 of 2.9; 95% CI: 0.0, 11.7; p = 0.09).

2.

Chernobyl

C113. The Chernobyl accident also released very large quantities of radioiodine to the environment.
Unfortunately, the distribution of radioiodines in the environment and the doses to those exposed as aconsequence are not well known. The International Chernobyl Project [I2] did examine the thyroid
function of hundreds of persons living in nearby heavily contaminated villages and compared thefindings with those of persons living in clean settlements. Five years after the accident, there was noevidence of thyroid hypofunction in the general population as a result of the accident. A large numberof subsequent studies have been done on children in the contaminated regions. The majority of the dose
initial to the thyroid was from 131I (about 80%) and to a lesser extent from the shorter-lived
radioisotopes of iodine. The data is complicated by potential effects of iodine deficiency in some areas
and also continuing exposure from 137Cs.
C114. Ostroumova et al. [O19] recently reported on thyroid function among 10,827 children andadolescents exposed to 131I from the accident at the Chernobyl nuclear plant. They reported an
association between thyroid dose and hypothyroidism but not for other outcomes including
hyperthyroidism and autoimmune thyroiditis. Hypothyroidism was diagnosed on the basis of elevated
TSH and not on serum thyroxine levels. As a result, the findings largely refer to subclinicalhypothyroidism. The authors mentioned that a linear-quadratic dose-response model fit the data best,
but they used a linear model to estimate an excess odds ratio per Gy of 0.34 (95% CI: 0.15, 0.62) forANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

185

hypothyroidism. Inspection of the data reveals that there was no statistically significant increase in
hypothyroidism at thyroid doses less than about 5 Gy.
C115. The large screening programme conducted by the Chernobyl Sasakawa Health and Medical
Cooperation Project from 1991 to 1996 involving 160,000 children who were less than 10 years of age
at the time of the accident, found no increased risk of hypothyroidism, hyperthyroidism or goitre that
could be related to ionizing radiation [I42, Y4]. Neither was there an increase in thyroid antibodies,
which is in contradiction to some other smaller studies. There are quite a number of smaller studies
which typically have less than 200 subjects. They are ecological studies based on caesium deposition
and are of questionable value. A study from the Russian oblast of Orelby, Kasatkina et al. [K14] foundsignificantly higher antithyroid peroxidase and antithyroglobulin antibody levels in the contaminatedregion but for those who had a fine needle aspiration performed, the prevalence of autoimmune
thyroiditis was the same in the contaminated and control areas.
C116. Studies by Vykhovanets et al. [V19] covered 1,000 children who lived in contaminated areas
and were medically screened. However, only 53 had blood tests performed and the results werecompared with those obtained with 45 children living in other areas. Differences were reported as
significant but inspection of the actual data indicated that this was probably not so. For example, one
reported significant finding was that the level of TSH in the controls was 1.6 ± 1.3 and in the group thatwas presumed to have been exposed it was 6.1 ± 6.2. There are also data on thyroid echogenicity which
are subjective and apparently obtained by the observers from a knowledge of where the children were
living. Vykhovanets et al. have also reported that there was an increase in thyroid autoimmune disease
after Chernobyl in all exposed children in the first decade, but that this effect decreased fourfold andessentially disappeared in the second decade post-exposure in persons who had been exposed to dose of>0.5 Gy [V19].
C117. Pacini et al. [P1] have reported on the prevalence of thyroid autoantibodies in children living
around Chernobyl. The blood samples were drawn six–eight years post-exposure. Whether these
persons will have a persistent elevation in antibody levels and whether this truly represents autoimmune
thyroiditis and might lead to hypothyroidism is unclear. Vermiglio et al. [V17] measured the prevalenceof antithyroglobulin antibody and antithyroid peroxidase in 143 children from a contaminated region
and compared them with 40 controls. There were statistically significant increases of autoimmune
thyroiditis in the exposed group. They also pointed out the possible effects of iodine deficiency on
increasing the incidence of thyroid autoimmunity in the Russian Federation.
C118. Increasing the availability of non-radioactive iodine to the thyroid gland can precipitate
autoimmune thyroiditis. There were programmes in the former Soviet Union that supplied stable iodine
tablets (to combat goitre) to school children even before Chernobyl. In addition, potassium iodide wasdistributed to the population for use as a thyroid blocking agent in the days after the accident. All these
aspects complicate any analysis of the data. The expert summary of the Chernobyl Project based on areview of the literature up to that date concluded that there was no consistent or conclusive evidence ofradiation thyroiditis in the populations exposed to the radionuclides released during the Chernobyl
accident [W21].
C119. The UNSCEAR 2008 Report [U15] indicated that there had been few studies of significant
size addressing the relationship between autoimmune thyroiditis and exposure to radiation from the
Chernobyl accident. Some studies report an association between radiation and serum thyroid antibodies,but not with the prevalence of autoimmune thyroiditis [A8]. The largest study by Tronko et al. [T38]
could not demonstrate any conclusive evidence of a relationship between dose to the thyroid andautoimmune thyroid disease This is consistent with the findings from studies of other exposed
populations.

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3.

Hanford

C120. A analysis was conducted relative to releases of radioiodine from the Hanford nuclear facility
in the United States. The study by Davis et al. [D17] included 3,447 persons who were born between
1940 and 1946 and resident near the Hanford plant. No increased incidences of hypothyroidism or
autoimmune thyroiditis related to the estimated doses to the subjects compared to unexposed controls
were found. For hypothyroidism and autoimmune thyroiditis, the slopes of the dose–response curves
were negative (-0.006 and 0.026, respectively).

4.

Mayak

C121. Mushkacheva et al. [M59] have studied those who were exposed to 131I as children as aconsequence of discharges from the Mayak weapon facility in the Russian Federation. The study
included 894 subjects born in 1952 and 1953. There were 581 subjects born in Ozyorsk and 313 who
moved to the area after the exposure had ended. The relative risk for autoimmune thyroiditis was notelevated. The relative risk in males was 0.6 (95% CI: 0.2, 2.1) and for females the relative risk was
0.7 (95% CI: 0.4, 1.2).

D. Radioiodine thyroid therapy
C122. A large amount of information is available on the health effects of exposure of the thyroid
gland in humans to 131I, particularly in the treatment of Graves’ disease and toxic multinodular goitres.
One problem is that the natural course of Graves’ disease often terminates in hypothyroidism, whether
treated with 131I or not.
C123. The actual absorbed dose to the thyroid is often difficult to calculate in these patients becauseof uncertainties in the exact size and weight of the gland. Another uncertainty is the biological half-lifeof the radioiodine in a hyperthyroid and radiation-damaged gland. Hypothyroidism, when it resultsfrom high-dose 131I treatment, is usually evident three to four months after therapy; then the patientmust be given replacement thyroid hormone. Transient hyperthyroidism due to release of stored
hormone following radioiodine therapy for thyrotoxicosis has also been described.
C124. There are only very limited data on the effects of absorbed doses to the thyroid from 131I of<25 Gy, in particular in children. The NCRP Report No. 55 [N15] cited unpublished data from
Hamilton and Tompkins, who observed that 8 out of 443 subjects (2%) less than 16 years old andjudged to have normal thyroids became hypothyroid after diagnostic 131I tests. The incidence of
hypothyroidism was 0% per year in 146 subjects who received a dose of <0.3 Gy to the thyroid, 0.15%
per year in 146 subjects who received a dose of 0.3–0.8 Gy and 0.23% per year in 151 subjects after adose of >0.8 Gy. A linear model with a threshold was postulated for hypothyroidism; owing to the large
functional capacity of the thyroid gland, a large number of cells would have to be affected to result in
hypothyroidism. Hayek et al. [H36] observed hypothyroidism in 8 out of 30 (26%) patients between theages of 8 and 18 years who received 131I therapy for hyperthyroidism. The mean amount of 131I
administered was 240 MBq, and the mean follow-up was nine years. Freitas et al. [F15] found a 92%
prevalence of hypothyroidism in 51 patients aged 6–18 years after 131I therapy for hyperthyroidism(mean 131I activity, 520 MBq). There is one very early report from 1952 that children have more

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187

sensitive glands with regard to the induction of hypothyroidism after repeated diagnostic doses ofradioiodine than adults [W18].

E. Summary
C125. Thyroid dysfunction may result from irradiation of the thyroid gland or the hypothalamic–
pituitary axis. A substantial proportion of patients receiving radiotherapy for various paediatric tumours
have impaired thyroid function. The incidence of hypothyroidism varies with the definition used; it ishighest when elevated TSH levels are used to define the impairment. On the basis of very limited
external beam radiotherapy data, 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 in leukaemic children who have received doses of 18–24 Gy to thecranium from radiotherapy over a period of 2–2.5 weeks. The doses to the thyroid in these cases havebeen calculated to be 3–8% of those to the brain (i.e. 1–2 Gy). However, the children also received
associated chemotherapy, which may affect the risk for hypothyroidism.
C126. No epidemiological study has demonstrated hypothyroidism in children after a thyroid dosefrom external irradiation of <1 Gy. There is limited evidence that dose rate may be of importance andthat the risk of hypothyroidism is reduced when fraction size is reduced. There are insufficient data on
the effects of 131I to determine whether there is a threshold dose for the induction of hypothyroidism.
Some data from the Chernobyl accident do indicate an increase in antithyroid antibodies in the morecontaminated regions. The available data, which are well documented, indicate that autoimmune
thyroiditis is unlikely to have been induced by exposure to radiation in childhood. This includes recent
data from the survivors of the atomic bombings, those exposed in the Marshall Islands following thetesting of a nuclear weapon, those exposed as a consequence of the Chernobyl accident and those
exposed as a consequence of discharges from the Mayak facility.

XI. BENIGN THYROID NODULES
C127. There are a large number of studies regarding the induction of benign thyroid nodules inchildren. These include those related to the use of radiotherapy for benign and malignant conditions, thesurvivors of the atomic bombings, environmental exposures, and medical use of 131I. A recent review
was published in 2008 by the NCRP [N18]. The data on risk for radiation-induced benign nodules has
greater uncertainty than the data for induction of thyroid cancer. This is due to the high spontaneous
rate of thyroid nodules in the population (which increases with age), differences in detection methods,
and somewhat poorer characterization of the doses to the thyroid.
C128. In the general population, thyroid nodules are more common in adults than in children andabout twice as common in females as in males. The prevalence of palpable nodules in non-exposedchildren ranges between 0.2% and 1.5%. In adults, palpable nodules are present in 4–7% of the
population. The prevalence of nodules detected by ultrasound can be three–tenfold higher than whenbased on data from physical examinations.

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UNSCEAR 2013 REPORTA. Atomic bombing survivors
C129. In a study of the incidence of non-cancer disease in the survivors of the atomic bombings by
Yamada et al. [Y2], dose–response relationships were found for thyroid disease. The radiation risk was
highest for subjects exposed at younger ages. The relative risk at 1 Gy for subjects exposed at less than
20 years of age was 1.54 (p <0.0001; 95% CI: 1.33, 1.81). For those exposed after 20 years of age, therelative risk at 1 Gy was not statistically significant, being 1.11 (95% CI: 0.96, 1.30; p <0.18).
C130. Imaizumi et al. [I34] studied thyroid disease in a cohort of 4,091 survivors of the atomic
bombings 55–58 years after exposure. A significant dose response was found for all solid nodules,
cancer and benign nodules. Nodules were all 1 cm or larger. There was a clear age-at-exposure effectwith those exposed at younger ages being more at risk for both solid nodules (p <0.001) and benign
nodules (p = 0.002) (see figure C-IV). The excess odds ratio for benign nodules was 2.89 (95% CI:
1.32, 5.77) for those exposed at 0–9 years of age, 0.83 (95% CI: 0.28, 1.70) for those exposed at 10–19
years of age, and 0.25 (95% CI: –0.20, 1.21) for those exposed at or above 20 years of age.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

Figure C-IV. Trend at age of exposure in radiation response of thyroid diseases
Adapted from [I34]. P values are calculated by likelihood ratio test; * indicates detectable limit

189

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UNSCEAR 2013 REPORT

B. Medical radiation uses
1.

Tinea capitis

C131. Ron et al. [R39] studied the incidence of thyroid neoplasia among 10,834 Israeli persons who
received X-ray therapy for ringworm of the scalp. All were less than 16 years old at the time oftreatment. The mean dose to the thyroid was estimated to be 90 mSv, the relative risk for adenomas was
2.3 and the ERR per unit dose was 14.4 (95% CI: 2.9, 35) Gy-1. In 1992, Shore et al. [S71] studied New
York children who were treated with X-rays for tinea capitis. The mean dose to the thyroid wasestimated to be 60 mSv. The relative risk for adenomas was 6.6 and the ERR per unit dose was 93 (95%
CI: 1.7, 647) Gy-1.

2.

Presumed thymic enlargement

C132. Janower and Miettinen [J13] studied children treated for presumed thymic enlargement. The
estimated dose to the thyroid was about 400 mSv and the relative risk was 4.6 and the ERR per unit
dose was 8.9 (95% CI: 2.3, 25) Gy-1. Shore et al. [S66, S67, S63] studied a cohort of 2,657 exposedchildren compared to 4,833 siblings using a questionnaire. There were 86 cases in the irradiated groupand 11 in the sibling controls. The estimated thyroid dose was 1,360 mSv. The ERR per unit dose was
6.3 (90% CI: 3.7, 11.2) Gy-1. Elevation in risk was seen even in the group exposed to a dose of<0.25 Gy. There was no increase in risk of nodules in less than 13 years after exposure; the meanlatency was 38 years.

3.

Lymphoid hyperplasia

C133. Children who had been irradiated for lymphoid hyperplasia between 1938 and 1969 were
followed up by Pottern et al. [P40] and compared with surgically treated subjects. The mean dose to thethyroid was estimated to be 240 mGy. This was a very interesting study in that the results wereobtained both by questionnaire and by clinical examination. A much higher relative risk of thyroid
nodules was estimated from the questionnaire (RR = 15.8) than from clinical examination (RR = 2.7).
This study indicates that there are major differences in risk estimates that can be obtained solely upon
the basis of the study design and that questionnaire studies may substantially overestimate the true risk.
Palpation by two physicians was used for the clinical evaluation, and nodules were found in 10.3% of
the exposed persons compared with 4.2% in the controls. The ERR was estimated to be 7% (95% CI:
3, 20) per 0.01 Gy. This can be compared with risks of 10–30% per 0.01 Gy obtained in the Israeli tinea
capitis study.
C134. Wong et al. [W38] reported the results of a telephone interview with 590 adults who, as
children, had received head and neck (tonsillar) irradiation with an estimated dose to the thyroid of
570 mSv. The ERR per unit dose for nodules was 11.0 Gy-1. There was a strong effect of age at
irradiation (p = 0.006).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

4.

191

Haemangioma

C135. A cohort of 5,032 patients who were treated by radiotherapy for skin haemangioma between
1941 and 1973 in France was studied by de Vathaire et al. [D26]. Approximately 1,480 of these patientswere less than 14 years old at the time of irradiation and were considered to have received exposure of
thyroid (they were treated with 32P, 90Sr or 90Y for haemangiomas that were located less than 5 cm fromthe thyroid or with 226Ra or X-rays at other locations of the haemangioma). The authors calculated theabsolute risk of thyroid nodules (benign and malignant) to be 1.8 × 10−3 PY Gy. Two studies from
Sweden examined the risk of benign nodules following the treatment of skin haemangiomas with 226Ra
during infancy [L26, L40]. The mean estimated doses to the thyroid were 116 and 260 mGy,
respectively. The ERRs per unit dose were 7.5 (95% CI: 0.4, 18.1) Gy-1 and 4.92 (95% CI: 1.26,
10.19) Gy-1, respectively.

5.

Hodgkin’s disease

C136. Treatment of Hodgkin’s disease with radiotherapy during childhood has been the subject ofstudy relative to thyroid nodules. Hancock et al. [H18] have reported on 1,787 patients treated at
Stanford University with radiation alone (810 patients), radiation and chemotherapy (920 patients), andchemotherapy alone (57 patients). Palpable abnormalities were found in 48 patients, 1.5–25 years after
therapy. Thyroidectomy was performed on 26 patients. The patients had benign adenomas, six had
adenomatous nodules, 4 had multinodular goitres, and six had cancer. The cancers occurred 9–19 years
after therapy. No risk estimates for nodule induction were given. In a limited ultrasound study of the
thyroids of 30 patients who had previous treatment for Hodgkin’s disease using mantle radiotherapy,
abnormalities were described in 24 patients [S115]. Nine of these appeared to have nodular lesions thatwould meet usual criteria. Other abnormalities included atrophy of the gland.
C137. A cohort of survivors of Hodgkin’s lymphoma in childhood who were treated between 1970
and 1986 were evaluated for thyroid disease by use of a self-report questionnaire in the CCSS. Among
1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality. The
relative risk for thyroid nodules was 27.0 with the risk increase beginning at 10 years after diagnosis.
Females were at increased risk for both hypothyroidism and thyroid nodules [S83].
C138. In a recent study of children treated with fractionated TBI between 1989 and 2009 for thetreatment of haematological diseases, and with a median age of 8.2 years (5.7–11.4), the 10 year
cumulative incidence of benign and malignant thyroid nodules was 16% and 8%, respectively [V18].

6.

Radioiodine in diagnosis

C139. Hamilton et al. [H14] conducted a cohort study of 3,503 persons who had received diagnostic
doses of radioiodine as children. The mean and median thyroid doses were estimated to be about 0.9 and0.30 Gy, respectively, but the authors stated that the doses were probably higher because examinations forwhich some data were lacking were not included in the dosimetric calculations. In addition, the number oftumours was too small to estimate the ERR for benign nodules. Hall et al. [H7] examined 1,005 women who
had received a diagnostic dose of 131I. Within the exposed group there was a dose–response relationship with
an ERR per unit dose of 0.9 (95% CI: 0.2, 2.3) Gy-1. The ERR was similar for those irradiated before andafter age 20.

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C. Environmental and accidental exposures
1.

Fallout from nuclear weapon testing

C140. The 1954 BRAVO thermonuclear test exposed residents of the Marshall Islands to fallout. A
number of reports [C43, R29] indicated a higher than expected incidence of thyroid cancer and thyroid
nodules. Data through 1986 indicated that 51 patients had nodules in the exposed group and 10 in thecontrol group. The first nodule was found in a nine-year-old girl after the accident. Nodules were
palpated in 2.6% of the control group of children under the age of 10 and in 7.8% of those over the ageof 10. On Rongelap Atoll, nodules were palpated in over 60% of persons exposed at age less than 10
and in 13% of those over age 10 at exposure. The percentages were smaller for the Ailingae and Utirik
atolls. Analysis of these data reveals virtually no excess of nodules at doses to the thyroid of less than
3 Gy. The risk in females was about 3.7 times that of males. Pathological diagnosis of the nodules
indicated that most were adenomatous and frequently multiple.
C141. In another study, Hamilton et al. [H15] screened 2,273 Marshall Islanders using palpation,
defining a nodule as being 1 cm or greater. The prevalence of thyroid nodules ranged from 0.9 to 10.6%
and decreased with distance from the test site. A risk estimate was reported of 1,100 cases per Gy per
year per million persons (11 excess cases per rad per year per million persons). This risk factor iscomplicated by the fact that there are wide variations in the natural incidence of thyroid cancer in
Polynesian populations, and the spontaneous prevalence of thyroid nodules is not well known. Given
these factors, the risk estimates from this population should be viewed with caution.
C142. An analysis of thyroid nodules in Utah has been conducted to examine the potential effect of
fallout from the Nevada Test Site. Using palpation, Rallison et al. [R4] did not find any significant
difference between 5,179 children in Utah and Nevada exposed to fallout and 3,453 in a control group.
Many of the study participants were subsequently screened again for thyroid disease. Lyon et al. [L44]conducted a thorough review of the dosimetry and diagnoses in that study. They found that about 7% of
the study participants had estimated thyroid doses of ≥400 mGy and another 10% had doses of
250-400 mGy. For the revised data they reported an ERR Gy-1 of 4.65 (95% CI: 1.1, 12.3) for thyroid
nodules.

2.

Hanford

C143. An analysis was conducted relative to releases of radioiodine from the Hanford nuclear facility
in the United States. The study included 3,447 subjects who were children at the time of exposure, born
between 1940 and 1946 and resident near the Hanford plant. The result reported by Davis et al. [D16,D17, K44] did not find an increased incidence of benign nodules. The estimated slope per unit dose wasactually negative at −0.008 (95% CI: <0.022, 0.041) Gy-1. The relative risk detectable with an 80% or
greater power at 170 mGy was 1.37.

3.

Mayak

C144. Mushkacheva et al. [M59] evaluated data on those who had been exposed as children to 131I
that had been discharged from the Mayak weapon facility in the Russian Federation. The study included
894 subjects who were born in 1952–1953. There were 581 subjects born in Ozyorsk and 313 who

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moved to the area after the exposure had ended. The prevalence of nodular disease was significantly
higher in the exposed group (20.7%) than in the control group (14.4%) with a relative risk of 1.4 (95%
CI: 1.1, 1.9).

4.

Semipalatinsk

C145. Land et al. [L6] reported the results of ultrasound findings of thyroid nodules among a groupof 2,994 residents of villages close to the Semipalatinsk test site who were children at the time of themain radioiodine fallout event from the testing of a nuclear weapon in 1949. Nodules—diagnosed ifthey were above 3 mm—were found in 30.6% of the subjects. The vast majority were benign. The
prevalence of nodules increased with dose (p = 0.001) and the linear-model excess odds ratio per unit
dose was 0.74 (95% CI: 0.22, 1.24) Gy-1. Of interest is that estimates of both external and internalradiation doses were strongly and independently associated with nodule prevalence and that internal
irradiation was about one quarter to one third as causative (per unit exposure) as external photons but
the data were consistent with ratios anywhere from 0.3 to 2.

5.

Chernobyl

C146. The population living in the contaminated areas around the Chernobyl nuclear power plant
were studied as part of the International Chernobyl Project [I2] and additional results were reported byMettler et al. [M34]. Both palpation and high-resolution ultrasound were performed in seven highly
contaminated villages and compared with results from five clean villages. In contaminated and control
populations, both methods yielded less than 1.2% of children at five and ten years of age with a thyroid
nodule. This, however, was at about only five years post-exposure. Longer follow-up was conducted asa part of the Sasakawa Project [I42, Y4]. Ivanov et al. [I46] reported on non-cancer thyroid diseases
among 2,457 persons exposed as children in the Kaluga and Bryansk regions of the Russian Federation.
Thyroid nodules were diagnosed if their diameter exceeded 3 mm. Solid nodules were found in 2.5% of
those examined; however, the ERR for risk of nodules was not estimated.

D. Summary
C147. The incidence of benign thyroid nodules increases following radiation exposure. Those
exposed at younger ages and females appear to be at greater risk. The estimated dose associated with
the induction of benign nodules varies widely among the many published epidemiological studies. Thisis, in part, due to differences in the low signal-to-noise ratio, the detection methods used, the criteria fordiagnosis and the uncertainties in the estimation of dose to the thyroid. On the basis of data from thesurvivors of the atomic bombings, the excess odds ratios per unit dose at different ages for thyroid
cancer and benign nodules are broadly similar. The major difference occurs in prevalence as a result thelarge background of spontaneous benign nodules in unexposed populations. The vast majority of benign
thyroid nodules do not become malignant.

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C148. In spite of the extensive experience from studies of the effects of neck irradiation for thetreatment of the thyroid for both benign and malignant conditions, no clinically-significant
deterministic effects upon the parathyroid glands have been identified. Both Rubin and Casarett [R57]
and Fajardo [F4] have reviewed the literature; the only effect reported has been atrophy of some glands
embedded within the thyroid tissue when large doses of radioiodine had been administered. This result
indicates the relative resistance of the parathyroid parenchymal cells to radiation, and perhaps asignificant reserve capacity such that minor injury is well compensated. There have been reports ofhyperfunction of the parathyroids following irradiation of the neck for benign and malignant conditions[C28].
C149. Fujiwara et al. [F23] reported increased levels of parathyroid hormone of 6.8% per unit dose(grays) but the dose response levelled off at a dose of about 1 Gy. Calcitonin levels were also increased.
The mechanism remains unclear, and there is little, if any, clinical significance since normal individual
variation is much greater than the potential radiation effect. There are occasional reports of calcitonin
deficiency after radioiodine therapy [B35]; however, in most of these cases, there had been previous
surgery for thyroid carcinoma and the removal of parathyroid glands. There is no literature specificallyrelated to children that addresses susceptibility.

XIII.FEMALE BREAST
C150. Effects of radiation on breast tissue following radiotherapy have been well described. In
general, adult breast tissue is quite radioresistant, with the major changes occurring in the skin,although ultimately atrophy of the gland may occur. Breast development is readily inhibited byradiotherapy in infancy and severe hypoplasia of the breast has been reported in women who have had ahistory of breast irradiation in childhood [D22, G34, K41, U5]. Doses to the breast of an infant inexcess of 2–3 Gy may produce later deformity or hypoplasia. Rubin and Casarett [R58] reported that ininfants and children, a dose exceeding 10 Gy of conventionally fractionated radiotherapy may result in
absence of breast development in 1–5% of patients, but with hypoplasia occurring in most patients.
This observation is supported by experience treating young children with doses of greater than 12 Gy
for metastatic Wilms’ tumour.
C151. Furst et al. [F26] reviewed the effect of radiation on the breast in 129 women who hadreceived about 2.3 Gy to the chest as children for the treatment of haemangioma. The children weretreated with flat 226Ra applicators and were less than four years of age at the time of treatment. The
mean absorbed dose to the breast for the cohort was 2.3 Gy (range 0.01–18.3 Gy). Breast hypoplasia
was reported on the treated side by 57% of the patients and on the contralateral side by 8% of patients.

XIV. HEART
C152. All structural and functional components of the heart including the pericardium, myocardium,valves, conduction system, and coronary arteries are susceptible to deterministic effects by irradiation

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195

although the thresholds are slightly different. No effects are evident at doses below 0.5 Gy. The
pathophysiology of radiation-induced injury has been extensively studied and reviewed [A4].
C153. Myocardial injury is marked by non-specific, diffuse interstitial fibrosis [F2]. Lesions canmeasure from a few millimetres to several centimetres in diameter but usually do not involve the entire
myocardium. Severity of fibrosis from one region to another can be markedly different. At amicroscopic level, collagen not only increases as a whole but the proportion of type I collagen increases
proportionally to type III [C11]. This change is thought to alter the compliance of the myocardium, andthus, contribute to the diastolic dysfunction seen after cardiac irradiation. Cells of the myocardium
involved with conduction also appear to be sensitive to radiation-induced fibrosis, as demonstrated by
the multiple reports of arrhythmias occurring after chest radiotherapy [C34, O16], and also correlations
between pathological and electrophysiological changes [C11]. A common pathophysiological pathway
of damage to the heart appears to be microcirculatory damage.
C154. Essentially all studies document an increased incidence or mortality from cardiovasculardisease after exposure to ionizing radiation; however, these studies are complicated by significant
limitations. Prominent among these is the fact that there is a wide range of cardiovascular andcirculatory diseases, which may or may not be interrelated (including stroke, valvular disease, arteritis,
atherosclerosis, hypertension, ischaemic disease, myocardial hypertrophy, myocardial infarction,
myocarditis, hypercholesterolemia and pericarditis). Many studies use self-reported surveys, and thosewhich examine the subjects often do not provide the criteria used for diagnosis of specific end points.
There are also many confounding factors which are rarely accounted for, including misclassification of
injury, and detailed analysis of other known cardiac risk factors such as family history, hypertension,
obesity, and diabetes. Other risk factors are also clearly relevant, such as socioeconomic status, tobaccouse, cardiotoxic medications, diet and genetics.
C155. Cardiovascular effects after exposure to ionizing radiation have been reviewed in the
UNSCEAR 1993 Report (annex I) [U8], which summarized the late cardiovascular effects after
irradiation of childhood cancer patients. It was concluded that radiation exposure causes occlusion ofboth small and large blood vessels. Cardiac abnormalities were observed particularly following
irradiation of the mediastinum. The few data available at that time suggested that a dose of 40 Gy
with conventional fractionation can be considered as a critical dose for clinical cardiomyopathy
in both children and adults.
C156. The UNSCEAR 2006 Report (annex B) [U12] reviewed the epidemiological evidence of
cardiovascular disease after radiation exposure and indicated that there was clear evidence of
cardiovascular disease after absorbed doses in the radiotherapeutic range, but that the only evidence forfatal cardiovascular disease at doses of less than 1–2 Gy came from the data on the survivors of theatomic bombings. More recent reviews are available from Darby et al. [D9] and the NCRP [N19]. The
review by Darby et al. [D9] indicates that there is a higher risk with younger age at irradiation. The data
related to children is derived from studies of the survivors of the atomic bombings and the survivors ofchildhood cancer. Data related to stroke and cerebrovascular disease are discussed elsewhere in thisannex.

A. External exposure
C157. Non-cancer disease mortality in the survivors of the atomic bombings was studied in the AHS
by Yamada et al. [Y2], who found it to be increased for some categories of disease, including

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cardiovascular. In particular, they reported a statistically significant quadratic association of radiationdose and myocardial infarction among those who were under age 40 at the time of irradiation. Positiveeffects of radiation exposure have also been reported for the incidence of hypertension andcardiovascular disease in the cohort exposed in childhood [T7]. For hypertension, the ERR/Gy was
0.15 (95% CI: −0.01, 0.34; p = 0.06) and for cardiovascular disease (which included both heart disease
and stroke) it was 0.72 (0.24, 1.40).
C158. More recently, mortality from heart disease was studied in the LSS cohort [S57], based on
about 8,400 heart disease deaths. It was found that possible confounders—smoking, alcohol intake,education, occupation, obesity and diabetes—had almost no impact on the risk estimate althoughadjusting for the misdiagnosis of cancers as heart disease slightly reduced the risk estimate but it was
still statistically significant. They found an approximately linear dose response over the dose range of
0 to about 3 Gy; a test for quadratic curvature yielded a p-value >0.5. The estimated linear doseresponse risk estimate was an ERR Gy-1 of 0.14 (95% CI: 0.06, 0.23; p<0.001), and EAR of 3.2 (1.3,
5.2) (104 PY Sv)-1. The dose response over the dose range 0 to 1 Gy was statistically significant, but
over the range 0 to 0.5 Gy it was not. A formal analysis for a dose-effect threshold gave a best estimateof 0 Gy (95% CI: <0, 0.5 Gy), suggesting no dose threshold. Nevertheless, the erratic nature of the data
points in the lower dose range leaves considerable uncertainty about dose effects below about 0.5 Gy.
There was no significant modification of risk by age at exposure. The risk estimates (ERR/Gy) were0.24, 0.08, 0.10 and 0.17 for exposure ages of <10, 10–19, 20–40 and >40 years, respectively.
C159. Late effects of radiotherapy on the cardiovascular system include cardiomyopathy, coronary
artery disease, pericardial effusions, valvular injury, conduction defects and pericarditis [S38].
Radiation, chemotherapy, and biological agents, both independently and in combination, increase therisk of cardiovascular disease in survivors of childhood cancer. In fact, cardiovascular disease is theleading cause of non-cancer mortality among the survivors of some cancers such as Hodgkin’s
lymphoma [H74, H73, R18]. The highest risks are from therapeutic exposures involving the use of theanthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone) and thoracic
irradiation. The risks to the heart are related to the cumulative dose from anthracycline, the method ofadministration, the amount of radiation delivered to different depths of the heart, the volume andspecific areas of the heart irradiated, the total and fractional irradiation dose, the age at exposure, thelatency period, and the sex.
C160. The effects of thoracic irradiation are difficult to separate from those of anthracyclines because
few children undergo thoracic irradiation without the use of anthracyclines. However, the pathogenesisof injury differs, with radiation primarily affecting the fine vasculature of the heart and anthracyclines
directly damaging the myocytes [F3].
C161. Mulrooney et al. [M58] recently conducted a very large study of cardiac outcomes among
14,358 survivors of childhood and adolescent cancer. This group was found to be significantly more
likely than a group of siblings to report congestive heart failure, myocardial infarction and pericardial
disease or valvular abnormalities. The risk was slightly higher with younger age at exposure. Treatment
with anthracyclines and cisplatin caused some of the increased risk. However, a dose to the heart of
15 Gy or more increased the relative hazard of congestive heart failure, myocardial infarction,
pericardial disease and valvular abnormalities by two- to sixfold compared to non-irradiated survivors.
The hazard ratios for congestive heart failure at doses of <5 Gy, 5–<15 Gy, 15–<35 Gy and >35 Gy
were 0.9 (95% CI: 0.6, 1.4), 1.3 (95% CI: 0.7, 2.5), 2.2 (95% CI: 1.4, 3.5), and 4.5 (95% CI: 2.8, 7.2),
respectively. The hazard ratios for myocardial infarction with the same dose intervals were 0.7 (95%
CI: 0.4, 1.4), 0.6 (95% CI: 0.1, 2.5), 2.4 (95% CI: 1.2, 4.9) and 3.6 (95% CI: 1.9, 6.9), respectively. The
values for pericardial disease were 0.7 (95% CI: 0.4, 1.1), 1.9 (95% CI: 0.9, 3.9), 2.2 (95% CI: 1.3, 3.9)
and 4.8 (95% CI: 2.8, 8.3), respectively. For valvular abnormalities, the values were 0.6 (95% CI: 0.4,

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

1971.0), 1.4 (95% CI: 0.7, 2.9), 3.3 (95% CI: 2.1, 5.1) and 5.5 (95% CI: 3.5, 8.6), respectively. The risk of
incurring these effects continued to increase for at least 30 years (see figure C-V).
Figure C-V. Cumulative incidence of cardiac disorders among childhood cancer survivors by average
cardiac radiation doses
Adapted from [M58]

C162. A European study of 4,122 five-year survivors of childhood cancer diagnosed before 1986 also
provides evidence for an association between radiation dose and risk of cardiovascular disease [T50].
After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall
standardized mortality ratio was 8.3-fold (95% CI: 7.6, 9.0) higher in relation to the general populationsof France and the United Kingdom. Thirty-two patients had died of cardiovascular disease, and this isfivefold (95% CI: 3.3, 6.7) greater than expected. The risk of dying of cardiac disease (n = 21) was
significantly higher in people who had received a cumulative dose of anthracyclines greater than
360 mg/m2 (RR = 4.4; 95% CI: 1.3, 15.3), with or without irradiation, and following radiation doses
between 5 and 14.9 Gy (RR = 12.5) and greater than 15 Gy (RR = 25.1) to the heart. A linear
relationship was found between the average dose of radiation to the heart and the risk of cardiac
mortality (ERR at 1 Gy is 60%).
C163. Subclinical cardiac dysfunction was evaluated by a group from the Netherlands. Of 601
eligible adult five-year survivors of childhood cancer, 525 (87%) had an echocardiogram performed, of
which 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF) [V2]. The

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median overall LVSF in the whole group of survivors of childhood cancer was 33.1% (range 13.0–
56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a
multivariate linear regression model, the LVSF was reduced with younger age at diagnosis, higher
cumulative anthracycline dose, and higher radiation dose to the thorax. High-dose cyclophosphamide
and ifosfamide were not associated with a reduction of the LVSF. This group also studied theoccurrence of symptomatic cardiac abnormalities in a hospital-based cohort of 1,362 five-year
childhood cancer survivors diagnosed between 1966 and 1996 and treated in the Netherlands [V3].
Fifty cardiac events, including 27 cases of congestive heart failure, were observed in 42 survivors at a
median attained age of 27.1 years. The 30 year cause-specific cumulative incidence of cardiac eventswas significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%;
95% CI: 4.3, 20.3), after anthracyclines (7.3%; 95% CI: 3.8, 10.7), and after cardiac irradiation (4.0%;
95% CI: 0.5, 7.4) compared to other treatments; an exponential relationship between anthracycline andirradiation doses with risk was observed.
C164. Because cardiovascular disease is a leading cause of morbidity and mortality in survivors ofchildhood Hodgkin’s lymphoma, this disease deserves special attention. An early case–control study by
Boivin et al. [B44] of Hodgkin’s lymphoma patients found the relative risks of myocardial infarction
associated with mediastinal irradiation to be relatively homogenous among subgroups categorized byage at diagnosis of Hodgkin’s lymphoma (0–39, 40–59 and 60+ years) or by number of years after
diagnosis (0–4, 5–9, and 10+ years). However, variations in the radiation-related risk of heart disease
were evident in the Stanford Hodgkin’s lymphoma data [H21], which included a large number ofpatients treated at a wide range of ages and followed for varying time intervals. Most remarkably, therelative risk of acute myocardial infarction was highest (RR = 44) among those treated at age <20 years
and decreased significantly with increasing age at irradiation. The absolute risk (i.e. the excess numberof cases per 10,000 persons) increased significantly with increasing age at treatment, reflecting theincreasing background rate for this disease with increasing age. The relative risk of acute myocardial
infarction was already significantly elevated during the first five years after the initiation of therapy andremained increased 20 years or more after treatment, and the risk increased with time after treatment.
Generally, similar patterns were observed for the risk of heart diseases other than myocardial infarction.
The relative risk of heart disease other than myocardial infarction was highest among patients treated atage <20 years, decreasing significantly with increasing age at treatment, and increased significantlywith increasing years after treatment.
C165. With current techniques and the fact that reduced doses are now used in radiotherapy for
Hodgkin’s lymphoma and other paediatric malignancies, these effects are unlikely to be so frequently
observed following treatment for childhood cancer. Recent data from the German-Austrian DAL–HD
studies show a dose response for cardiac diseases in children treated for Hodgkin’s lymphoma withcombined radiation and anthracycline-based chemotherapy (cumulative doxorubicin dose was
uniformly 160 mg/m2). The 25-year cumulative incidence of cardiac diseases was 3% with noradiotherapy, 5% after a dose of 20 Gy, 6% after a dose of 25 Gy, 10% after a dose of 30 Gy, and 21%
after a dose of 36 Gy [S27]. An older study of 635 patients treated for childhood Hodgkin’s lymphoma
confirms the risks that occur after higher-dose radiation therapy that is no longer used in current
treatment regimens. Yet, in that study’s report, the risk of pericarditis requiring pericardiectomy was
4% at 17 years post-treatment (occurring only in children treated with higher radiation doses). Only 12
patients died of cardiac disease, including seven deaths from acute myocardial infarction; however,these deaths occurred only in children treated with a dose of 42–45 Gy [H19]. In an analysis of 48
patients treated for Hodgkin’s lymphoma from 1970 to 1991 with mediastinal therapy (median dose
40 Gy), 43% had valvular abnormalities, 75% had a conduction abnormality or arrhythmia, and 30%
had reduced oxygen consumption during exercise testing. Among children treated with a dose of 15–

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199

26 Gy, none developed radiation-associated cardiac problems [A5] although this finding is contradictedby the much larger Mulrooney study discussed previously[M58].
C166. Data from the CCSS demonstrate the significant cardiovascular morbidity that occurs after
treatment of a large variety of childhood cancers in addition to Hodgkin’s lymphoma, with the caveatthat the data were based on self-reporting. In a study of self-reported late effects among 1,607 survivorsof childhood brain tumours [G39], 18% reported a heart or circulatory late effect. The risk was higher
among those treated with combined surgery, radiotherapy, and chemotherapy compared to those treatedwith surgery and radiotherapy alone, suggesting a potential added vascular injury from chemotherapy.
Children who received spinal irradiation for the treatment of CNS tumours have been demonstrated toshow a low maximum cardiac index on exercise testing and pathological Q-waves in inferior leads onelectrocardiogram testing, and higher posterior-wall stress [J10]. Among survivors of non-Hodgkin’s
lymphoma, the standard mortality ratio for cardiac disease was 6.9. A recent follow-up study ofsurvivors of Wilms’ tumour reported a cumulative risk of congestive heart failure of 4.4% at 20 years
for those who had received doxorubicin as part of their initial therapy, and 17.4% at 20 years where
doxorubicin was received as part of the therapy for relapsed disease. The risk factors for congestive
heart failure in this cohort included female sex, lung irradiation with doses of 20 Gy or higher, leftsided abdominal irradiation, and doxorubicin dosage of 300 mg/m2 or more [G28]. Finally, cardiac
complications after bone marrow transplantation may occur with arrhythmias, pericarditis, andmyopathies predominating. High-dose cyclophosphamide is clearly a causative agent. Whole-body
irradiation is a secondary contributing factor [A23, E1, H55, S27].
C167. There have been a number of claims in the popular media concerning “Chernobyl heart diseasein children” with the allegation that this is due to caesium contamination. Similar concern has also beenraised as a result of caesium contamination from Fukushima. Extensive review of the health effects of
the Chernobyl accident was included in both annex D of the UNSCEAR 2008 Report [U15] and the2005 Chernobyl Forum Report [W21]. There was neither scientific evidence nor apparent biologicalmechanism to support such an entity.

XV. RESPIRATORY SYSTEM
C168. The lung is the most radiosensitive organ in the thorax. The data on lung injury following
childhood exposure are almost exclusively derived from information obtained from radiotherapy treatedpatients, and interpretation of these data is complicated because of the use of chemotherapeutic agentsin most of these patients. The mechanism for radiation-induced respiratory damage in young children
may be different from that in adults or in adolescents. Specific radiation effects in children can include
the impaired formation of new alveoli or failure in the development of the thoracic skeleton (chest wall)and thus a reduced size of the lung [B13, R59]. Overall, respiratory damage in young children issomewhat less than in adults at the same doses. The reasons for this are that children have less preexisting disease, fewer co-morbid conditions and better repair capability. Children are able to develop
additional alveoli up to the age of two years. No deterministic effects are seen at doses of less than
1 Gy.
C169. Acute and chronic pulmonary complications reported after treatment for paediatricmalignancies include radiation pneumonitis, pulmonary fibrosis, and spontaneous pneumothorax. These
sequelae are uncommon following contemporary therapy and most often result in subclinical injury thatis detected only by imaging or formal pulmonary function testing. Chemotherapy agents with potential

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pulmonary toxicity commonly used in the treatment of paediatric malignancies include bleomycin,
busulfan, and the nitrosoureas (carmustine and lomustine). These agents induce lung damage on theirown or potentiate the damaging effects of radiation to the lung. Thus, the potential for acute or chronic
pulmonary sequelae must be considered in the context of the specific chemotherapeutic agents and theradiation dose administered, the volume of lung irradiated, and the fractionation of the doses used inradiotherapy [N14].
C170. Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow
radiotherapy alone at doses greater than 40 Gy to focal lung volumes, or after lower doses whencombined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after radiotherapy alone
at doses to the whole lung greater than 20 Gy, but is possible after lower doses when combined withchemotherapy. Infection, GVHD in the setting of bone marrow transplant, and pre-existing pulmonary
compromise (e.g. asthma) all may influence this risk. Changes in lung function have been reported inchildren treated with whole-lung radiotherapy for metastatic Wilms’ tumour. A dose of 12–14 Gy
reduced the total lung and vital capacity to about 70% of the predicted values and even lower if thepatient had undergone thoracotomy.
C171. In a study of 48 survivors of paediatric malignant solid tumours with a median follow-up of
9.7 years following median whole lung irradiation doses of 12 Gy (range 10.5–18 Gy), only ninepatients (18.8%) reported respiratory symptoms. However, abnormalities in forced vital capacity,
forced expiratory volume in one second, total lung capacity, and diffusion capacity were common(58-73%). Focal boost irradiation was also significantly associated with additional abnormalities[M53]. Reducing the size of the daily radiation fractions (e.g. from 1.8 Gy per day to 1.5 Gy per day)decreases this risk [M15, M16]. Administration of bleomycin alone can produce pulmonary toxicity
and, when combined with radiotherapy, can intensify its effects. Chemotherapeutic agents such as
doxorubicin, dactinomycin, and busulfan are radiomimetic agents and can reactivate latent radiation
damage [K51, M15, M16].
C172. The development of bleomycin-associated pulmonary fibrosis with permanent restrictive
disease is dose dependent, usually occurring at doses of bleomycin greater than 200–400 U/m2, which
is higher than those used in most treatment protocols for paediatric malignancies [B51, F21, K51].
Nevertheless, more current paediatric regimens for Hodgkin lymphoma using radiotherapy andadriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) have shown a significant
incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time
[H72, H76, M6]. However, more severe and symptomatic grade 3 and 4 pulmonary toxicity has beenreported in 9% of children receiving 12 cycles of ABVD (an amount no longer used) followed by aradiation dose of 21 Gy [F21]. In addition, ABVD-related pulmonary toxicity may result from fibrosis
induced by bleomycin or “radiation recall” (terminology for the first manifestation or re-expression of
subclinical or clinical radiation-induced injury, respectively, when certain chemotherapeutic agents areadministered) pneumonitis related to administration of doxorubicin. Pulmonary veno-occlusive diseasehas been observed rarely and has been attributed to bleomycin chemotherapy [P37].
C173. Patients undergoing HSCT are at increased risk of pulmonary toxicity related to: (a) preexisting pulmonary dysfunction (e.g. asthma, pre-transplant therapy); (b) the preparative regimen that
may include cyclophosphamide, busulfan, carmustine; (c) whole-body irradiation; and (d) the presenceof GVHD [C10, K8, L20, M7, N24, N46]. Although most survivors of transplant are not clinicallycompromised, restrictive lung disease may occur. Obstructive disease is less common, as is late onset
pulmonary syndrome, which includes the spectrum of restrictive and obstructive disease. Bronchiolitis
obliterans with or without organizing pneumonia, diffuse alveolar damage, and interstitial pneumonia
may occur as a component of this syndrome, generally between 6 and 12 months post-transplant.

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Cough, dyspnea, or wheezing may occur with either normal chest X-rays or diffuse/patchy infiltrates;
however, most patients are symptom free [L20, S40, U4, Y7].
C174. Additional factors contributing to chronic pulmonary toxicity include superimposed infection,
underlying pneumonopathy (e.g. asthma), cigarette use, respiratory toxicity, chronic GVHD, and theeffects of chronic pulmonary involvement by tumour or reaction to tumour. Lung lobectomy duringchildhood appears to have no significant impact on long-term pulmonary function [K50] but the longterm effect of lung surgery for children with cancer is not well defined.
C175. The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is
not clear. For children treated with HSCT, there is significant clinical disease. No large cohort studies
have been performed with clinical evaluations coupled with functional and quality-of-life assessments.
An analysis of self-reported pulmonary complications of 12,390 survivors of common childhood
malignancies has been reported by the CCSS [M31]. This cohort includes children treated with bothconventional and myeloablative therapies. Compared with siblings, the survivors had an increased
relative risk of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygentherapy, abnormal chest wall, exercise-induced shortness of breath, and bronchitis, with RRs ranging
from 1.2 to 13.0 (highest for lung fibrosis and lowest for bronchitis). The 25-year cumulative incidenceof lung fibrosis was 5% for those who had received chest irradiation and less than 1% for those who
had received pulmonary toxic chemotherapy. With changes in the doses of radiotherapy used since thelate 1980s, the incidence of these abnormalities is likely to decrease.

XVI. OESOPHAGUS
C176. The squamous epithelium of the oesophagus has approximately the same turnover rate as oral
mucosa. In spite of this, the oesophagus is extremely resistant to radiation when compared with theremainder of the gastrointestinal tract. Oesophagitis, dysphasia, and later stricture following
radiotherapy have been reported. Early changes are primarily due to mucosal damage while latedamage is primarily related to changes in the muscle wall although mucosal changes may be present.
C177. The appearance of mucositis in the oesophagus is very similar to its appearance in theoropharynx. There is little information on early effects after irradiation of the oesophagus in children to
indicate a significant difference in sensitivity from adults. There is a report of a child with ataxia
telangiectasia being more sensitive during radiotherapy for Hodgkin’s disease [P57].
C178. Early symptoms include mild to moderate substernal burning and difficulty in swallowing,
beginning in the second or third week after initiation of radiotherapy at absorbed dose levels as low as
20 Gy. Doses of 20–30 Gy over 2 weeks lead to clinical symptoms of oesophagitis; however, they aretransient. The oesophagus can tolerate fractionated doses up to 60 Gy. Strictures have been reported todevelop 4–8 months after completion of radiotherapy at doses from 30 Gy in 2 weeks to 65 Gy in
6.5 weeks. Strictures may occur at lower doses in very young patients. Rare late delayed effects
including tracheoesophageal fistula and stricture have been reported after radiotherapy for Hodgkin’s
disease [H2, M52].

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C179. Donaldson et al. [D42] reviewed the late complications in children after whole abdominal
radiotherapy for Wilms’ tumour, teratoma, or lymphoma. Of 14 long-term survivors, five developed
severe radiation injury, with small bowel obstruction, within two months of the completion of therapy.
The average age at treatment was six years, and the dose was 31 Gy in 7–20 fractions over 11–39 days.
Coia and Hanks [C35] reviewed the complications in 1,026 patients treated with large-field
infradiaphragmatic radiotherapy for Hodgkin’s disease and seminoma. The most frequent
complications were gastrointestinal injury, such as peptic ulceration, haemorrhage, chronic diarrhoea,
and intestinal obstruction. The bowel complications occurred in 1% of patients at doses of <35 Gy and
3% at doses of ≥35 Gy. Major bowel complications were increasingly likely when large portions of thebowel received fractionated doses above 50–55 Gy. Histologically, during the subacute and chronic
period, the villae of the mucosa are often blunt and thickened, and the mucosal cells are often flattened.
The lamina propria may be normal or may demonstrate severe fibrosis. Telangiectasia may occasionallyoccur as well. Overall, collagen deposition throughout the submucosa is demonstrated mostconsistently.
C180. Upper gastrointestinal, hepatic, and lower gastrointestinal adverse outcomes were assessed incases from participants in the CCSS of 14,358 survivors of childhood cancer who were diagnosed
between 1970 and 1986. Data were compared with those from randomly selected siblings. The medianage at cancer diagnosis was 6.8 years (range, 0–21.0 years), and the median age at outcome assessment
was 23.2 years (5.6–48.9 years) for survivors and 26.6 years (1.8–56.2 years) for siblings. Rates of selfreported late gastrointestinal complications (occurring five or more years after cancer diagnosis) were
determined and associated with patient characteristics and cancer treatment, adjusting for age, sex, andethnic group. Older age at diagnosis, intensified therapy, abdominal radiation, and abdominal surgery
increased the risk of certain gastrointestinal complications [G19].

XVIII. HEPATOBILIARY AND PANCREAS

A. LiverC181. Data on hepatobiliary effects following childhood radiation exposure are derived primarily
from its therapeutic use for malignancies. At fractionated absorbed doses to the liver of <10 Gy, noradiation-induced clinical effects (i.e. in the absence of chemotherapy) have been reported. Radiationand specific chemotherapeutic agents may produce hepatic toxicity that is acute and transient in mostaffected patients but, rarely, can be delayed in onset and be persistent. Recipients of HSCT are theexception to this rule as these persons frequently experience chronic liver dysfunction related tomicrovascular, immunological, infectious, metabolic, and toxic aetiologies. Acute radiation-induced
liver disease also causes endothelial cell injury that is characteristic of veno-occlusive disease/sinusoidal obstruction syndrome [D20].
C182. Tefft [T14] observed liver abnormalities in children after radiotherapy that included a dose to
the liver of 12–30 Gy. The whole liver in adults has a tolerance of up to 30–35 Gy with conventional
fractionation. Chou et al. [C22] reported that about 75% of children receiving 7–12 Gy whole-body

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irradiation for conditioning in the setting of bone marrow transplant develop acute liver dysfunction,
and about 25% show signs of hepatic veno-occlusive disease. Thomas et al. [T21, T22] reported hepatic
fibrosis in 3 of 26 long-term survivors of Wilms’ tumours who had received a dose of at least 30 Gy in
1.5 to 2 Gy fractions.
C183. On the basis of limited data from paediatric cohorts treated in the 1970s and 1980s, persistentradiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors
without predisposing conditions such as viral hepatitis or iron overload [P7]. The risk of injury inchildren increases with radiation dose, hepatic volume, younger age at treatment, prior partial
hepatectomy, and concomitant use of radiomimetic chemotherapy like dactinomycin and doxorubicin[B23, F8, K54, T14]. Survivors who received radiation doses of 40 Gy to at least one third of the liver
volume, or doses of ≥30 Gy to the whole abdomen or to the upper abdomen that included the entire
liver, are at the highest risk for hepatic dysfunction.
C184. Hepatitis following irradiation and chemotherapy at doses and volumes of irradiation
ordinarily considered within the tolerance of hepatic function has been reported [K54]. Fatal liver
damage occurred in a 13-year-old boy who had received adriamycin before and during radiotherapy
involving a dose of 24 Gy in 17 fractions over 28 days to the upper abdomen including the entire liver.
A 13-year-old girl had moderate clinical liver changes following a dose of 25 Gy in 23 fractions over
32 days with adriamycin administered before and during irradiation. In this case, much of the right lobe
was shielded during radiotherapy. About 20 patients have been reported to have developed liver disease
after fractionated radiotherapy involving a total dose of 12–40 Gy to the liver in childhood together
with chemotherapy [C7, J16]. Viral hepatitis B and C may complicate the treatment course ofchildhood cancer and result in chronic hepatic dysfunction.
C185. Nodular regenerative hyperplasia (NRH) is a rare condition characterized by the developmentof multiple monoacinar regenerative hepatic nodules and mild fibrosis. The pathogenesis is not wellestablished, but may represent a non-specific tissue adaptation to heterogeneous hepatic blood flow
[W14]. NRH has rarely been observed in survivors of childhood cancer treated with chemotherapy,
with or without liver irradiation [B63, C29]. Biopsy may be necessary to distinguish NRH from asecond malignancy.
C186. In a cohort who recently completed intensified therapy for ALL, histological evidence of fatty
infiltration was noted in 93% and siderosis in up to 70% of the patients [H11]. Fibrosis developed in
11% and was associated with a higher serum low-density lipoprotein cholesterol level.
C187. Prospective studies are needed to define whether acute post-therapy fatty liver change
contributes to the development of steatohepatitis or the metabolic syndrome in this population.
Likewise, information about the long-term outcomes of transfusion-related iron overload is lacking,especially among cohorts of survivors who did not undergo haematopoietic cell transplantation.

B. Pancreas
C188. The pancreas has been thought to be relatively radioresistant because of a paucity of
information on late pancreatic-related effects. However, children and young adults treated with total
body or abdominal radiation are known to have an increased risk of insulin resistance and diabetes
mellitus. A retrospective cohort study, based on self-report, on 2,520 five-year survivors of childhood
cancer treated in France and the United Kingdom investigated the relation between radiation dose to the204

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pancreas and risk of a subsequent diabetes diagnosis. Sixty-five cases of diabetes were validated withthe risk increasing with radiation dose to the tail of the pancreas where the islets of Langerhans areconcentrated. Risk increased up to 20–29 Gy and then plateaued. The estimated relative risk at one Gy
was 1.61, and the relative risk of diabetes was 11.5 in patients who received more than 10 Gy to the tailof the pancreas. Radiation dose to the other parts of the pancreas did not have a significant effectcompared with patients who did not receive radiation. Children younger than two at the time of
exposure were more sensitive compared with older patients (relative risk at one gray was 2.1 for thisyoung age group versus 1.4 for older patients). For the 511 patients who received more than 10 Gy, thecumulative incidence of diabetes was 16% [D29, N14].

XIX. REPRODUCTIVE SYSTEM AND FERTILITY

A. Testes
C189. The effects of radiation on the testes are age and dose dependent. Radiation appears to have its
greatest effect on the germ cells rather than on Leydig cells. Testicular function may be compromised atdoses as low as 0.5 Gy. Leydig cell function appears more resistant to radiation, and impaired function
occurs after a dose of ≥10 Gy. Testicular function is also impaired by chemotherapy and may beabnormal prior to therapy for malignancy that does not involve the testes. Irradiation to the prepubertal
gonads may not always result in irreversible damage. Whole-body irradiation has been shown to
produce primary gonadal failure of various degrees in the majority of boys who had received doses of
10 Gy, regardless of pubertal status. In most of these patients, Leydig cell function appeared adequate.
A recent review of this was reported by members of the United States Children’s Oncology Group[K26].

1.

Radiotherapy

C190. Surgery, radiotherapy, and/or chemotherapy may damage testicular function. Patients who
undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term
follow-up [A21, T43]. Retrograde ejaculation is a frequent complication of bilateral retroperitoneal
lymph node dissection performed on males with testicular neoplasms [N9, N31] and impotence may
occur following extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate [S30].
C191. Most data on the sensitivity of the testes to radiation are historical, but demonstrate that men
treated with whole-abdomen irradiation during childhood frequently develop gonadal dysfunction. For
example, in one study, five of ten men evaluated at ages 17–36 years were azoospermic, and two wereseverely oligospermic, after whole-abdomen irradiation for Wilms’ tumour at ages 1–11 years. Thisoccurred even though the penis and scrotum were either excluded from the treatment volume, orshielded with 3 mm of lead. The doses to the testes varied from 7.96 Gy to 9.83 Gy [S49]. Others
reported azoospermia in 100% of ten men 2–40 months after radiotherapy doses of 1.4–3 Gy to bothtestes [S100]. Similarly, azoospermia was demonstrated in 100% of ten men following radiotherapy
doses to the testes of 1.18–2.28 Gy. Recovery of spermatogenesis occurred after 44–77 weeks in 50%of the men, although three of the five with recovery had sperm counts below 20 × 106 ml-1 [H3].

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Oligospermia or azoospermia was reported in 33% of 18 men evaluated 6–70 months after receiving
testicular radiation doses of 0.28–1.35 Gy [P23].
C192. In another report, none of five men who had received doses to the testes of <0.20 Gy becameazoospermic. By contrast, two who had received doses to the testes of 0.55–0.70 Gy developed
temporary oligospermia, with recovery to sperm counts greater than 20 × 106 ml-1 18–24 months after
treatment [K34]. In summary, a decrease in sperm counts can be seen three–six weeks after irradiation
and, depending on the dose, recovery may take one–three years. The germinal epithelium is damagedby much lower doses (<1 Gy) than those that damage Leydig cells (20–30 Gy). Complete sterilization
may occur with fractionated irradiation above doses of 2 to 4 Gy.
C193. Administration of higher radiation doses, such as 24 Gy, which was used for the treatment of
testicular relapse of ALL, results in both sterilization and Leydig cell dysfunction [B28]. Craniospinal
irradiation produced primary germ cell damage in 17% of 23 children with ALL [S84] but in none offour children with medulloblastoma [A9]. This difference may be related to the concurrent
administration of chemotherapy in the children with ALL, and also to techniques used to shield or
avoid the testes in the medulloblastoma children. Whole-body irradiation involving doses of
9.50-15.75 Gy combined with cyclophosphamide (60 mg/kg each day for two days) produced
azoospermia in almost all men treated [S15]. Male survivors of non-Hodgkin’s lymphoma who
underwent pelvic radiotherapy and received a cumulative cyclophosphamide dose greater than 9.5 g/m2
were at increased risk for failure to recover spermatogenesis [N14, P61].

2.

Accidents and incidents

C194. A case of child abuse involving industrial radiography sources has been reported by Collins
and Gaulden [C36]. In this particular instance, a divorced petroleum engineer had intermittent custodyof his two sons. He had possession of at least a 37 GBq 137Cs source used for oil and gas well logging.
The dose rate in contact with such a source is approximately 5 Gy/min. One of the sons was subjected
to various occasions in which “shiny silver pellets” were placed in the earpieces of headphones that hewas told to wear, in a pillow he was told to use, and in a sock he found on his bed. After more than a
year, a plastic surgeon recognized the lesions as radiation necrosis. Both testes had effectively been
destroyed and the boy had been functionally castrated.

B. Ovary
C195. The majority of post-pubertal females who receive whole-body irradiation prior to bonemarrow transplantation develop amenorrhea. Recovery of normal ovarian function occurred in only 9 of
144 patients in one series and was highly correlated with age at irradiation; those who demonstrated
recovery were younger than 25 years [S16]. In a series restricted to patients who were prepubertal at thetime of bone marrow transplantation, 44% (7 out of 16) had clinical and biochemical evidence ofovarian failure [M12].
C196. As previously suggested, the frequency of ovarian failure following abdominal radiotherapy isrelated to both the age of the woman at the time of irradiation, and the radiotherapy dose received by
the ovaries. Whole-abdomen irradiation produces severe ovarian damage. Seventy-one per cent of
women in one series failed to enter puberty, and 26% had premature menopause following whole-

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abdominal radiotherapy doses of 20 to 30 Gy [W9]. Other studies reported similar results in women
treated with whole-abdomen irradiation [S45] or craniospinal irradiation [H17, W10] during childhood.
C197. Of 3,390 eligible participants in the CCSS, 215 (6.3%) developed acute ovarian failure (AOF).
Survivors with AOF were older at cancer diagnosis (aged 13–20 years versus those aged 0–12 years),
more likely to have been treated for Hodgkin’s lymphoma, or to have received abdominal or pelvic
radiotherapy than survivors without AOF [C12]. Of the survivors who developed AOF, 75% hadreceived abdominal–pelvic irradiation. Radiation doses to the ovary of at least 20 Gy were associatedwith the highest rate of AOF, with over 70% of such patients developing AOF [C12]. In a multivariablelogistic regression model, increasing doses of ovarian irradiation, exposure to procarbazine at any age,and exposure to cyclophosphamide at 13–20 years of age were independent risk factors for AOF.
C198. The presence of apparently normal ovarian function at the completion of chemotherapy should
not be interpreted as evidence that no ovarian injury has occurred. Premature menopause is well
documented in survivors of childhood cancer, especially in women treated with both an alkylating
agent and abdominal irradiation [B74, C18, S87]. A total of 126 survivors of childhood cancer and 33
control siblings who participated in the CCSS developed premature menopause. Of these women, 61
survivors (48%) and 31 siblings (94%) had surgically-induced menopause (RR = 0.8; 95% CI: 0.52,
1.23). However, the cumulative incidence of non-surgical premature menopause was substantiallyhigher for survivors than for siblings (8% versus 0.8%; RR = 13.21; 95% CI: 3.26, 53.51; p <0.001)[S87].
C199. A multiple Poisson regression model showed that the risk factors for non-surgical prematuremenopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing
alkylating agent dose score, and a diagnosis of Hodgkin’s lymphoma. For survivors who were treatedwith alkylating agents plus abdominal–pelvic irradiation, the cumulative incidence of non-surgicalpremature menopause approached 30% [S87]. A recent review of ovarian function following cancer
therapy in children was performed by Metzger et al. [M36].

C. Fertility
C200. Fertility was evaluated among the 6,224 male CCSS participants aged 15–44 years who were
not surgically sterile. They were less likely to sire a pregnancy than siblings (hazard ratio = 0.56; 95%
CI: 0.49, 0.63). Among survivors, the hazard ratio of siring a pregnancy was decreased by radiotherapy
doses greater than 7.50 Gy to the testes (hazard ratio = 0.12; 95% CI: 0.02, 0.64). Compared withsiblings, the hazard ratio for ever siring a pregnancy for survivors who had not been treated withalkylating agents, and had no measureable radiation doses to the hypothalamic/pituitary axis or testes,
was 0.91 (95% CI: 0.73, 1.14; p = 0.41) [G32].
C201. Fertility was evaluated among the 5,149 female CCSS participants and 1,441 female siblingsof CCSS participants, aged 15–44 years. The RR for ever being pregnant was 0.81 (95% CI: 0.73, 0.90;
p <0.001) compared with female siblings. In multivariate models among childhood cancer survivors,
those who had received a hypothalamic/pituitary radiation dose greater than 30 Gy (RR = 0.61; 95%
CI: 0.44, 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever beenpregnant (RR = 0.56 for a uterine dose of 5–10 Gy; 95% CI: 0.37, 0.85; RR = 0.18 for a uterine dose
>10 Gy; 95% CI: 0.13, 0.26).

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207

C202. Fertility may be impaired by factors other than the absence of sperm and ova. Conception
requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur,
and appropriate conditions in the uterus for implantation. Retrograde ejaculation occurs with significant
frequency in men who undergo bilateral retroperitoneal lymph node dissection. Uterine structure may
be affected by abdominal irradiation. A recent study demonstrated that uterine length was significantly
shorter in ten women with ovarian failure who had been treated with whole abdomen irradiation.
Endometrial thickness did not increase in response to hormone replacement therapy in three women
who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasoundthrough either uterine artery in five women, and through one uterine artery in three additional women[G30].
C203. In summary, fertility and reproduction can be reduced by a number of factors, including thoseoutlined above for the testes, ovary and uterus. Other factors would include patency of fallopian tubes
and dysfunction of the pituitary/hypothalamic axis. While there is no data that radiation susceptibilityof the neuroendocrine axis is greater at younger age, uterine development is clearly compromised bypelvic irradiation and is, thus, age dependent. Conversely, the ovary, and perhaps the testes, may be
more resistant to radiation at younger age [K26, M36].

D. Reproduction
C204. For survivors of childhood cancer who maintain fertility, numerous investigations haveevaluated the prevalence of and risk factors for pregnancy complications in adulthood. Pregnancy
complications including hypertension, foetal malposition, foetal loss/miscarriage, pre-term labour, andlow birth weight have been observed in association with specific diagnostic and treatment groups [B73,
C18, C26, C52, C60, G32, G33, H32, M4, M54, R17, W31]. Studies regarding heritable effects were
presented earlier in the annex.
C205. In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63%
live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation. Risk of
miscarriage was 3.6-fold higher in women treated with craniospinal irradiation and 1.7-fold higher inthose treated with pelvic irradiation. Chemotherapy exposure alone did not increase the risk of
miscarriage. Compared with siblings, survivors were less likely to have live births, more likely to havemedical abortions, and more likely to have low birth-weight babies [C52]. In the same cohort, anotherstudy evaluated pregnancy outcomes of partners of male survivors. Among 4,106 sexually active males,
1,227 reported that they had sired 2,323 pregnancies, which resulted in 69% live births, 13%
miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis. Compared withpartners of male siblings, there was a decreased incidence of live births (RR = 0.77), but no significant
differences of pregnancy outcome by treatment [G32].
C206. In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of morethan 20-weeks duration. In this group, there were 955 single live births. Hypertension complicating
pregnancy, early or threatened labour, malposition of the foetus, lower birth weight (<2,500 g), andpremature delivery (<36 weeks) were more frequent among women who had received flank irradiation,
in a dose-dependent manner [G33]. Results from a Danish radiotherapy study confirm the associationof uterine irradiation with spontaneous (but not other types of abortion). Thirty-four thousand
pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish
Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in
the population were identified. No significant differences were seen between survivors and comparison

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women in the proportions of live births, stillbirths, or all types of abortions combined. Survivors with ahistory of neuroendocrine or abdominal radiotherapy had an increased risk of miscarriage. Thus, thepregnancy outcomes of survivors were similar to those of comparison women with the exception of
miscarriage [W31].
C207. Preservation of fertility and successful pregnancies may occur after HSCT, though theconditioning regimens that include whole-body irradiation, and treatment with cyclophosphamide, andbusulfan are highly gonadotoxic. In a group of 21 females who had received bone marrowtransplantation in the prepubertal years, 12 (57%) were found to have ovarian failure when examined
between ages 11 and 21 years, and the association with busulfan was significant [T15]. One study
evaluated pregnancy outcomes in a group of females who had undergone bone marrow transplantation.
Among 708 women who were post-pubertal at the time of transplant, 116 regained normal ovarianfunction and 32 became pregnant. Among 82 women who were prepubertal at the time of transplant, 23
had normal ovarian function and nine became pregnant. Of the 72 pregnancies in these 41 women, 16
occurred in those treated with whole-body irradiation and 50% resulted in early termination. Among the
56 pregnancies in women treated with cyclophosphamide without either whole-body irradiation ortreatment with busulfan, 21% resulted in early termination. There were no pregnancies among the 73
women treated with both busulfan and cyclophosphamide, and only one retained ovarian function[S18].
C208. For survivors of childhood cancer who have offspring, there is concern about congenital
anomalies, genetic disease, and risk of cancer in the offspring. In an early analysis [G29] of informationfrom the National Wilms Tumor Study Group, congenital anomalies were marginally increased inoffspring of females who had received radiotherapy of the flank. In a later analysis [G33], the offspringof the partners of males who had received radiotherapy to the flank raised the possibility that one orboth findings were spurious.
C209. In a report on 2,198 offspring of adult survivors who were treated for childhood cancer
between 1945 and 1975 compared with 4,544 offspring of sibling controls, there were no differences in
the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations.
There was similarly no effect on the occurrence of genetic disease in the offspring regardless of thetype of treatment for childhood cancer that had been used. A population-based study of 2,630 live-bornoffspring of the survivors of childhood cancer versus 5,504 live-born offspring of the siblings of thesurvivors found no differences in the proportion of abnormal karyotypes or incidence of Down’s
syndrome or Turner’s syndrome between the two groups [W30]. Survivors treated with abdominal
radiotherapy and/or alkylating agents did not have an increased risk of offspring with genetic disease,
compared with survivors not exposed to these agents [B75].
C210. In a study of 5,847 offspring of survivors of childhood cancer treated in five Scandinavian
countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was
no increased risk of cancer [S22]. A study by Byrne et al. also indicated no excess risk of single-gene
disorders, congenital malformations, or chromosomal syndromes among the offspring of former
patients compared with the offspring of siblings [B75].
C211. In summary, treatment for childhood malignancy with select chemotherapeutic agents,
primarily alkylators, or radiation therapy that exposes the ovaries or testes, is associated with animpairment in fertility and this is both chemotherapy and radiation-dose related. Radiation therapy that
exposes the uterus is associated with miscarriages and premature or small-for-date babies, and this isalso dose related.

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XX. SKIN
C212. The skin is considered to be a body organ. It serves not only as a barrier against theenvironment but is also involved in immune function, in control of the body’s temperature, and as a
medium to provide sensory input. A vast literature describes the effects of radiation exposure on theskin. In general, children’s skin is not significantly more radiosensitive than that of adults [F5, I12,
R56, T42]. When large areas of skin are exposed, the “cutaneous radiation syndrome” [G24, P26] may
appear.
C213. Single acute doses of low-LET radiation of 0–2 Gy to the skin produce no clinicallyobservable effects in adults. At a dose of 2–5 Gy, there is transient erythema followed by temporary
epilation in 2-8 weeks. Doses of 5–10 Gy result in transient and delayed erythema and permanent
partial epilation. Acute single doses of 10–15 Gy will cause the same erythematous changes but withdry or moist desquamation and long-term telangiectasia and dermal atrophy. With single acute doses>15 Gy, moist desquamation at 2–8 weeks followed by ulceration and necrosis may occur [B3].
Erythema in children has been documented as a result of accidental overexposures from CT scans.
Children appear to be less sensitive than adults for some skin effects such as moist desquamation(perhaps owing to the faster repair by the skin cells) [G16].
C214. With radiotherapy, temporary loss of hair (epilation) occurs in about three weeks with doses of
3-5 Gy; hair begins to return during the second month and continues for up to one year. Single doses of
7 Gy may cause permanent epilation, with the latent period being less than three weeks. Not all bodyareas have the same radiosensitivity for epilation. Hair follicles of children are more sensitive thanthose of adults. Exacerbated acute skin reactions can be seen when radiotherapy is combined withchemotherapy. Late effects of radiotherapy include telangiectasia, pigmentation changes and skin
atrophy. There is significant individual variation in expression of these effects.
C215. Skin effects have been reported in children following accidental exposure to radionuclides.
The circumstances have included fallout from the testing of atomic weapons in the Marshall Islands, theGoiania accident involving a source of 137Cs and many accidents with orphan industrial radiographysources. Most reports, however, do not provide information on the difference in skin reactions by age ofpatient.
C216. The effects on the skin of various deposited radionuclides depend significantly on the half-lifeof the radionuclide and the energy spectrum of the emitted radiation. A number of reports and books on
the occurrence and treatment of such lesions are available [G43, I1, O13].

XXI. MUSCULOSKELETAL SYSTEM
C217. The majority of data concerning deterministic effects on the musculoskeletal system arederived from studies of those who had undergone external beam radiotherapy; some were previously
summarized in the UNSCEAR 1993 Report [U8]. Essentially all forms of cancer therapy, including
surgery, chemotherapy, and radiotherapy, can affect the musculoskeletal system of a growing child or
adolescent. Outcomes affecting the musculoskeletal system are discussed below, including late effects
on the bone and joints (abnormal bone and muscle growth, amputation/limb-sparing surgery, joint
contracture, osteoporosis/fractures, osteonecrosis) and changes in body composition (obesity and bodyfatness). There are a few studies of childhood exposure relating to growth and the musculoskeletal

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system involving those exposed to 224Ra, the survivors of the atomic bombings and those exposed as aconsequence of radiation in the environment (e.g. following the Chernobyl accident).

A. Abnormal bone growth
C218. Otake et al. [O22] have studied growth retardation as a potential radiation effect following inutero exposure of the survivors of the atomic bombings. Overall, the effect, if any, was small. Similar
results have been reported by Nakashima [N5]. There are no data among the survivors of the atomic
bombings indicating that there was a direct effect on the musculoskeletal system in those who were
exposed as children.
C219. Anthropometric analyses were performed in 1990 on children who were living in the former
Soviet Union at the time of the accident at the Chernobyl nuclear plant in 1986, and in children bornin 1989 [I2]. The main conclusion from these studies was that there were no significant differences inheight or weight between those living in the control and contaminated regions.
C220. In cancer patients up to six years of age, a dose of 10 Gy produces mild osseous changes,
whereas a dose of 10–20 Gy in fractionated radiotherapy produces severe changes (impaired growthand development, including asymmetrical bone growth if only part of the bone is irradiated). In general,the higher the dose and the younger the child, the more deformity results. Although animal data indicatethat irradiation of bone causes a reduction in the number of blood vessels, it is not thought to be theprimary cause of reduction in growth.
C221. In an age- and dose-dependent fashion, radiotherapy can inhibit normal bone and muscle
maturation and development. Radiation to the head (e.g. cranial, orbital, infratemporal, nasopharyngeal
radiotherapy) can cause craniofacial abnormalities, particularly in children treated before the age of fiveor with radiation doses of 20 Gy or more [D34, E13, G9, K13, K15]. Soft tissue sarcomas, such as
orbital rhabdomyosarcoma, and retinoblastoma are two of the more common cancer groups with thesehead and neck radiation fields. Often, in addition to the cosmetic impact of the craniofacialabnormalities, there can be related dental and sinus problems as previously discussed.
C222. Radiotherapy can also directly affect the growth of the spine and long bones (and associatedmuscle groups), and can cause premature closure of the epiphyses, leading to short stature,scoliosis/kyphosis, or limb-length discrepancy depending on the radiation field treated [F9, H56, K19,
M27, P58, W25]. Orthovoltage, commonly used before 1970, delivered higher doses of radiation to thebone and was commonly related to abnormalities in bone growth. However, even with contemporary
radiotherapy, if the location of the solid tumour is near an epiphysis or the spine, alterations in normalbone development can be difficult to avoid.
C223. The effects of radiation on stature in survivors of Wilms’ tumour was assessed in the National
Wilms Tumor Studies [H56]. Stature loss in 2,778 children treated on these studies was evaluated.
Repeated height measurements were collected during long-term follow-up. The effects of radiationdose, chemotherapy, and age at treatment on stature were analysed using statistical models that
accounted for the normal variation in height with sex and advancing age. Predictions from the model
were validated by descriptive analysis of heights measured at age 17–18 years for 205 patients. For
those under 12 months of age at diagnosis who received a dose of more than 10 Gy, the estimateddeficit in adult height was 7.7 cm when contrasted with the unexposed group. For those who received adose of 10 Gy, the estimated shortening of the trunk was 2.8 cm or less. Among those whose heightANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

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measurements in the teenage years were available, patients who received a dose of more than 15 Gy
were 4–7 cm shorter on average than their unexposed counterparts, and there was an evident dose–
response relationship. Chemotherapy did not confer an additional risk.
C224. The effects of radiation on the development of scoliosis have also been recently re-evaluated.
In a group of 42 children treated for Wilms’ tumour from 1968 to 1994, scoliosis was seen in 18, with
only one patient needing orthopaedic intervention [P16]. Median time to development of scoliosis was
102 months (range 16–146 months). A clear dose–response relationship was seen, with children treatedwith lower doses (<24 Gy) having a significantly lower incidence of scoliosis than those who received adose of more than 24 Gy. There was also a suggestion that the incidence was lower in patients who
received a dose of 10–12 Gy, the doses that are currently used for the treatment of Wilms’ tumour.
Also, cranial and whole-body radiotherapy damages the hypothalamic–pituitary axis in an age– anddose–response fashion, often leading to growth hormone deficiency. This has been discussed in the text
on neuroendocrine effects.
C225. In children, radiotherapeutic fractionated doses in excess of 25 Gy to the ends of long bones
have occasionally been shown to cause slipped capital epiphyses. Slippage is rare with fractionateddoses of less than 25 Gy [B5, W7]. The risk in children irradiated under the age of four is about 47%,
and about 5% in older children [S79]. This effect apparently results from an arrest in chondrogenesis
and vascular changes. Chemotherapy may play a minor role because many patients have received
doxorubicin, which has been shown to arrest chondrogenesis temporarily [E7, P9, S79, W7]. In
addition to slippage of the femoral epiphysis, there also can be aseptic necrosis in some patients.
Usually, these are children who have received doses in excess of 30–40 Gy and chemotherapy [P54].
C226. Growth retardation has also been observed in children injected with 224Ra for the treatmentof tuberculosis of bone and soft tissue [M13, S104]. Spiess et al. [S104] obtained the adult heights of
133 patients injected as juveniles. 224Ra-induced growth retardation was greatest in young
children, who had the greatest amount of potential growth after exposure. The growth retardation
increased with radiation dose, and there was a 2% decrease in potential growth post-irradiation
per Gy for average skeletal doses up to 20-25 Gy.

B. Osteoporosis/fractures
C227. Chemotherapy (e.g. methotrexate) can have a cytotoxic effect on osteoblasts, resulting in a
reduction of bone volume and the formation of new bone. This effect may be exacerbated by thechronic use of corticosteroids [P36]. Radiation-related endocrinopathies, such as growth hormone
deficiency or hypogonadism, may contribute to ongoing bone-mineral loss. Radiation-induced fractures
can occur with fractionated doses of radiation of 50 Gy or more, as is often used in the treatment ofEwing’s sarcoma of the extremity [P18, W3].

C. Osteochondroma
C228. Radiation-induced osteochondromas have been reported in 6% of long-term surviving children
who received radiotherapy. These benign “tumours” have been noted in the spine, pelvis, scapula, andribs [N28]. Approximately 5% of children undergoing myeloablative stem cell transplantation will

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develop osteochondroma, which most commonly presents in the metaphyseal regions of long bones.
Osteochondroma generally occurs as a single lesion; however, multiple lesions may develop in thecontext of hereditary multiple osteochondromatosis [B55]. A large Italian study reported a 6.1%
cumulative risk of developing osteochondroma at 15 years post-transplant, with increased risk
associated with younger age at transplant (≤3 years) and use of whole-body irradiation [F6]. Growth
hormone therapy may influence the onset and pace of growth of osteochondromas [B48]. Malignant
degeneration of these lesions is exceptionally rare.

D. Joints and muscle
C229. Cartilage, like adult bone, is fairly radioresistant. Doses of 60 to 70 Gy in a prolonged
radiotherapy treatment scheme can be tolerated by cartilage. Unless there is stress to the cartilage,
clinical manifestations of deterministic radiation effects are rare with the exception of delayed necrosisof the larynx.
C230. Deterministic effects of radiation on muscle are distinctly unusual. Acute radionecrosis ofskeletal muscle requires absorbed doses in excess of 500 Gy [G7]. The most common late effect on
developing muscle tissues secondary to irradiation is their diminished development (hypoplasia). The
muscles treated are smaller and functionally not as strong as the patient’s non-irradiated muscle tissues.
Studies have shown that the functional outcome after radiotherapy to the limb is related to theradiotherapy volume and the size of the non-irradiated corridor [A15]. The total dose and dose per
fraction of radiotherapy used is also significant in determining range of movement, muscle power, andlimb function [K28]. At lower fractionated doses, from 22 to 54 Gy, atrophy of fibres can be identified.
Finally, ischaemia due to arterial narrowing may result in fibrosis [Z4]. The ultimate clinical result ofmuscle irradiation probably depends not only on the absorbed dose but on the length of the muscle
segment irradiated. If the muscle is short and is entirely included in the radiation field, the resultant
detriment may be substantially greater than if only a portion of a long muscle is irradiated. Heterotopic
calcification of soft tissue has been reported as a late radiation effect although it is usually seen in
combination with other late effects such as tissue ulceration, fibrosis, nerve damage or bone necrosis[C5].

E. Changes in body composition
C231. The primary cancer groups recognized with an increased incidence of treatment-related obesity
are survivors of acute lymphocytic leukaemia [C24, G5, M40, O8, R11, W36] and of CNS tumour inchildhood treated with cranial radiotherapy [G39, P34]. In addition, craniopharyngioma survivors also
have a substantially increased risk of extreme obesity [C47, M22, N10]. Moderate-dose cranialradiotherapy (18–24 Gy) among survivors of acute lymphocytic leukaemia is associated with obesity,
particularly in females treated at a young age [D39, G5, O8].
C232. Female adult survivors of acute lymphocytic leukaemia in childhood who were treated withcranial radiotherapy with a dose of 24 Gy prior to the age of five are four times more likely to be obese
in comparison with women who have not been treated for cancer [O8]. In addition, women treated withcranial radiotherapy with doses of 18–24 Gy prior to the age of 10 have a substantially greater rate ofincrease in their body mass index through their young adult years in comparison with women who were

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treated for acute lymphocytic leukaemia with only chemotherapy or with women in the general
population [G5]. It appears that these women also have a significantly increased visceral adiposity andassociated insulin resistance [J11, O11]. These outcomes are attenuated in males. Interestingly, among
survivors of brain tumours treated with higher doses of cranial radiotherapy, only females treated at a
younger age appear to be at increased risk for obesity [G40].
C233. The development of obesity following cranial radiotherapy is multifactorial, with factors
including growth hormone deficiency, leptin sensitivity, reduced levels of physical activity, and energy
expenditure [B59, G5, O10]. Importantly, survivors of childhood cancer treated with whole-body
irradiation in preparation for an allogenic HSCT have increased measures of body fatness (percentage
of fat) while often having a normal body mass index [N29, N47]. It remains controversial whether
contemporary acute lymphocytic leukaemia therapy, without cranial radiotherapy, is associated with asustained increase in body mass index.

F. Metabolic syndrome
C234. The metabolic syndrome is highly associated with cardiovascular events and mortality.
Definitions of the metabolic syndrome are evolving, and generally include a combination of central(abdominal) obesity with at least two other components, namely:−

hypertension;−

atherogenic dyslipidemia (elevated triglycerides, reduced high-density level cholesterol);−abnormal glucose metabolism (fasting hyperglycaemia, hyperinsulinism, insulin resistance,
diabetes mellitus type II) [N12].

C235. An increased risk of metabolic syndrome or its components has been observed in cancer
survivors. Long-term survivors of acute lymphocytic leukaemia, especially those treated with cranial
irradiation, may have a higher prevalence of some, potentially modifiable, risk factors for
cardiovascular disease such as impaired glucose tolerance or overt diabetes, dyslipidemia, hypertension,and obesity [C27].
C236. In a young adult cohort of survivors of acute lymphocytic leukaemia (mean age 30 years),
62% had at least one cardiovascular risk factor and 30% had two or more [O7]. Another study observed
no difference in prevalence of metabolic syndrome in 75 survivors of acute lymphocytic leukaemia
compared to a population-based control group [G42]. However, survivors with metabolic syndrome
were more likely to have growth hormone insufficiency or deficiency. Those treated with cranialradiotherapy also had an association with growth hormone abnormalities and were more likely to have
two or more components of the metabolic syndrome compared to survivors who were not treated withcranial radiotherapy.
C237. A high frequency of cardiovascular risk factors has also been observed among haematopoietic
cell transplant recipients [S52]. French investigators reported an overall 9.2% (95% CI: 5.5, 14.4)
prevalence of metabolic syndrome in a cohort of 184 survivors of acute lymphocytic leukaemia(median age 21.2 years) [O24]. Sex, age at diagnosis, corticosteroid therapy or cranial irradiation were
not significant predictors of metabolic syndrome. However, haematopoietic cell transplantation withwhole-body irradiation was a major risk factor for metabolic syndrome (OR = 3.9; p = 0.03).

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C238. Other investigators have reported a significantly increased risk of hyperinsulinemia, impaired
glucose tolerance, or diabetes mellitus associated with exposure to whole-body irradiation [N29]. The
association between whole-body irradiation and excess risk for diabetes has also been observed byother investigators [N14].

G. Summary
C239. No radiation-related effect on height has been observed in children living in the former Soviet
Union at the time of the Chernobyl accident nor among those exposed as children to the atomic
bombings. In childhood cancer patients, growth can be adversely affected by direct radiation damage
and by malnutrition, other treatment modalities, the presence of residual tumour, and endocrine chronic
radiation effects. Most clinical data are based on small and heterogeneous groups of patients treated indifferent ways at varying ages. The skeletal effects have also been assessed in a variety of ways, and it
is not possible to give any estimates of late deterministic effects based on large-scale epidemiological
data.
C240. Skeletal changes in children generally occur at doses exceeding fractionated doses of 20 Gy
and include scoliosis, kyphosis, slipped femoral epiphyses, hypoplasia, growth retardation, and dental
problems. However, even doses lower than 20 Gy can impair muscle and skeletal development inyoung children and infants. Absolute shortening of the long bone depends on the absorbed radiationdose and the age at the time of irradiation. Scoliosis and kyphosis are common after spinal or flank
irradiation with doses of >20 Gy. Slipped femoral capital epiphysis does not occur below a dose of
20 Gy, and this late effect is more common in children under four years of age at the time of irradiation.
A dose exceeding 20 Gy is required to arrest endochondral bone formation, and doses of 10–20 Gy
cause the partial arrest of bone growth. There is little alteration in bone growth below a fractionateddose of 10 Gy to the bone. Exposure at less than six years of age and during puberty appears to have thegreatest effect on growth retardation. Clearly, several factors—including radiation dose, radiation
volume, age at irradiation, concomitant chemotherapy, and patient genetics (i.e. the expected size towhich the patient might grow)—are all important variables in determining final growth.

XXII. URINARY SYSTEM
C241. The urinary system shows a wide range in radiosensitivity, with the kidney being the mostsensitive organ, the bladder having an intermediate sensitivity and the urethra being more resistant. Allavailable data on deterministic effects comes from high doses associated with radiotherapy and arecomplicated by chemotherapy and by the primary tumour.

A. Kidney
C242. The kidney is a relatively radiosensitive organ when compared with the other intra-abdominalorgans and tissues. The kidney consists of three major cell groups of interest, those forming: (a) the
glomerulus; (b) the renal tubules; and (c) the vascular supply system. The vascular system isANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

215

particularly important because about one fifth of the body’s blood passes through the kidneys eachminute. The arterioles supply a rich network about the glomeruli and the renal tubules. The epithelia of
the tubules and the glomerular capsule are long-lived, composed of reverting post-mitotic cells thatrarely divide. The nephrons themselves are unable to regenerate and are constantly being reduced in
number with age and injury; however, if an injury is focal, the remaining nephrons may hypertrophy.
Acute nephritis may occur in 6–13 months associated with proteinuria and hypertension. Chronic
radiation nephritis (associated with protein casts in the urine) and hypertension usually has a latent
period of 1.5–4 years [D21, P16].
C243. Cancer treatment predisposing to late renal injury and hypertension includes specificchemotherapeutic drugs (cisplatin, carboplatin, and ifosfamide), renal radiotherapy, and nephrectomy[J17]. The tolerance dose for the adult kidney appears to be approximately 23 Gy in five weeks to theparenchyma of both kidneys. Doses of 28 Gy to both kidneys in five weeks carry a high risk of severeradiation nephritis [L43]. In some studies, renal injury appears to be more severe in children, and they
have limited tolerance for combined chemotherapy and radiotherapy. Reduced creatinine clearance has
been reported by Mitus et al. [M42] in 18% of 108 children who had nephrectomy for malignant
disease and received a dose of less than 12 Gy to the remaining kidney, and in 33% of those who
received a dose of 12–24 Gy. Doses greater than 20 Gy can result in significant nephropathy [D21]. In a
recent report from the German Registry for the Evaluation of Side Effects after Radiation in Childhoodand Adolescence (RISK consortium), 126 patients who underwent radiotherapy to parts of the kidneys
for various cancers were evaluated. All patients also received potentially nephrotoxic chemotherapy.
Whole kidney volumes exposed to doses greater than 20 Gy (p = 0.031) or 30 Gy (p = 0.003) wereassociated with a greater risk for mild degrees of nephrotoxicity [B45].
C244. The effect of radiotherapy on the kidney has best been examined in the survivors of paediatricWilms’ tumour. Generally, studies have shown that the risk of renal insufficiency is higher amongchildren receiving higher doses of radiation [B2, R25, S88]. A correlation between functional
impairment and the dose to the kidneys was reported in a study of 100 children treated for Wilms’
tumour. The incidence of impaired creatinine clearance was significantly higher for children receiving
doses of more than 12 Gy to the remaining kidney, and all cases of overt renal failure occurred after adose of more than 23 Gy [M42]. In a cohort of survivors of Wilms’ tumour evaluated five years after
receiving abdominal irradiation, the prevalence of renal insufficiency, as defined by hypertension, wasapproximately 7% [P16].
C245. Data from the National Wilms Tumor Study Group and the United States renal data system
indicate that the 20-year cumulative incidence of end-stage renal disease in children with unilateralWilms’ tumour and Denys–Drash syndrome is 74%, 36% for those with WAGR (Wilms’ tumour,aniridia, genitourinary abnormalities, mental retardation) syndrome, 7% for male patients withgenitourinary anomalies and 0.6% for 5,347 patients with none of these conditions [B61]. For patientswith bilateral Wilms’ tumours, the incidence of end-stage renal disease is 50% for the Denys-Drash
syndrome, 90% for WAGR syndrome, 25% for genitourinary anomaly and 12% for patients for allothers [B61, H16]. End-stage renal disease in patients with WAGR syndrome and genitourinary
anomalies tended to occur relatively late, and often during or after adolescence. Treatment for Wilms’
tumour without flank or abdominal radiotherapy was not associated with significant nephrotoxicity in astudy of 40 survivors of Wilms’ tumour treated in England [B2].
C246. Radiation nephropathy has also been reported in children receiving bone marrowtransplantation therapy [T6, V11]. After a dose of 12–14 Gy given in six–eight fractions over three–four days, there was haematuria and elevated creatinine. This is probably the result of both radiationand chemotherapy since long-term studies revealed abnormalities in less than 10% of patients receiving
doses of only 12 Gy in six fractions to the whole body [B49]. The risk is related to the nephrotoxic

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agents used and the total dose to the whole body, fractionation scheme and interfraction interval. Morespecifically, the radiation-associated risk rises when the total dose exceeds 12 Gy, or the individual
fraction size is greater than 2 Gy, or the interval-fraction is less than four–six hours [A2, E12, H54,
L20]. Obviously, if only one kidney is irradiated, there is substantially less clinical effect. Radiation of
only one kidney did not cause radiation nephropathy in any of 13 patients receiving doses between
25 Gy in six weeks and 49 Gy in five weeks [K31].

B. Urethras and bladderC247. The bladder is relatively more radioresistant than the kidneys, with the most resistant portionof the genitourinary system being the urethras. Survivors of childhood cancer treated with pelvic or
CNS surgery, alkylator-containing chemotherapy including cyclophosphamide or ifosfamide, or pelvic
radiotherapy may experience late effects in the urinary bladder including haemorrhagic cystitis, bladderfibrosis, neurogenic/dysfunctional bladder, and bladder cancer [R24]. Bladder dysfunction after
irradiation for bladder and prostate sarcomas (median dose of 40 Gy) is reported to be 27% [R7]. This
includes incontinence, urinary frequency and nocturia. It should be noted that most of these patients
also received cyclophosphamide. Bladder damage, including haemorrhagic cystitis, fbrosis andoccasional bladder shrinkage, can occur following chronic administration of alkylating agents such as
cyclophosphamide [L23].
C248. In summary, late effects following irradiation of the kidney include nephritis, tissue
necrosis and fibrosis, 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 14 Gy, and decreased creatinine clearance has occurred after doses
around 12 Gy. The seemingly higher sensitivity of the kidney in children can probably be
explained by the combination of radiotherapy and chemotherapy, which can enhance the side effects inthe kidney [R60].

XXIII. IMMUNE FUNCTION
C249. The effects of radiation on the immune system have been extensively reviewed in the
UNSCEAR 2006 Report (annex D) [U13]. The material presented here summarizes the information
contained in that report and from newer data sources relative to potential differences that may result
from exposure during adulthood versus that during childhood. Those studies that relate to the possible
interaction of the immune system and autoimmune thyroiditis and cardiovascular disease are discussed
elsewhere in this annex.

A. Atomic bombing survivors
C250. Immune mechanisms have consistently been associated with either resistance to or
development of numerous tumours. Also, an association between non-cancer mortality and radiationdose has been observed among the survivors of the atomic bombings, cardiovascular, thyroid and liverANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

217

diseases being the more frequently reported causes. Kusunoki et al. [K56] have suggested that longlasting inflammation may be considered an important contributory factor for the development of someof these diseases.
C251. While there are several studies showing increased changes in the immune system withincreasing age, few studies have examined the effect of age at exposure. Several studies indicate anincreased perturbation of the immune system in survivors exposed at older age compared to those
exposed as children. Investigating T-cell immunity among the survivors of the atomic bombings, in an
early paper Akiyama et al. [A11] looked at the responsiveness of peripheral blood lymphocytes to allogenic
antigens in mixed lymphocyte cultures (MLCs) from 139 survivors. This study revealed a significant
decrease in MLC response with increasing radiation dose and increasing age. The decline was mostmarked in the survivors who were >15 years old at the time of the initial exposure. These results wereinterpreted as an impaired thymic function as it affects the immune system.
C252. The numbers of peripheral blood lymphocytes belonging to different subsets were studied in
1,328 survivors of the atomic bombings using immunocytochemistry (fluorescent antibodies) [K55].
The number of CD5+ B-lymphocytes was significantly lower in those persons exposed to doses >1 Gy
within the group exposed at the age of 30 or later. A similar tendency towards decreased numbers of
CD4+, CD8+, and CD19+ cells was observed in these older survivors, although the differences were
not statistically significant. These results suggest that ageing of the T-cell-related immune system isaccelerated in people irradiated at advanced age. Due to the age-related decrease in thymic function,subjects who were older at the time of the bombings may have decreased functional capability of theimmune system for recovery after radiation injury.
C253. The major histocompatibility complex (MHC) gene seems to be a particularly important
genetic factor that can affect host immune responses. Significant differences in type 2 diabetes
prevalence were found by Hayashi et al. [H35] between heavily exposed (those who received doses of>1.5 Gy) and low-dose/non-exposed survivors of the atomic bomb dropped on Hiroshima with different
class II MHC DQA1 and DRB1 alleles. The prevalence was higher for heavily-exposed people who
were less than 20 years old at the time of the bombings and who presented DQA1*0401 and DRB1*08
alleles or DQA1*0301 and DRB1*09. These results suggest that certain class II MHC genes regulate
one or more components of the immune system related with the risk of diabetes development among
the younger and more heavily-exposed survivors.

B. Chernobyl
C254. Studies relating to the immune system of those exposed as a consequence of the Chernobyl
accident have yielded conflicting results and are often at variance with the results reported in survivorsof the atomic bombings. Also, children evacuated from Pripyat did not have significant differences in
immunological parameters from those of the control groups [B9, B8]. Children examined two years
after the accident from Mogilev and Gomel did not show abnormalities in levels of T-lymphocytes, butshowed a minor increase in B-lymphocytes [G3]. The UNSCEAR 2000 Report (annex J) [U10] pointed
out that: (a) the levels of radiation that Chernobyl populations were exposed to had not been shown toaffect the immune system in prior non-Chernobyl studies; (b) the findings of Chernobyl studies were
not consistent with the known mechanisms and temporal effects of radiation on the immune system.
The UNSCEAR 2000 Report concluded that immunological effects in the general population could not
be associated with Chernobyl and, when observed, were likely due to other causes [U10].

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C255. Titov et al. [T27] investigated the production of immunoglobulins in children living around theChernobyl nuclear power plant. They found a decrease in B-cell numbers, a transient decrease of
immunoglobulin M (IgM) and immunoglobulin G (IgG) and an increase of immunoglobulin A (IgA)
levels (both in serum and saliva) during the first months following the accident. Over a six-year period,
children living in the contaminated areas exhibited increasing production of IgG and IgM.
C256. Chernyshov et al. [C15] examined peripheral blood lymphocyte subsets in children living
around the Chernobyl nuclear power plant eight years after the accident. Differences were found inchildren who had recurrent respiratory disease. Children with this disease from the contaminated areas had
higher levels of CD3– CD56+ CD16+ natural killer (NK) cells compared to children withrecurrent respiratory disease living in non-contaminated areas. Healthy children without recurrent
respiratory disease from contaminated areas had the same mean values for lymphocyte subsets as
healthy children from non-contaminated areas.
C257. Koike et al. [K39] compared NK cell activity from children living in Gomel, a highly
contaminated area, with that of children living in non-contaminated areas. While children living in noncontaminated areas exhibited a narrow range of NK cell cytotoxicity percentages, a wider range of NK
cell cytotoxicity percentages was found in children from contaminated areas. NK cell cytotoxicity ofthese children was correlated with neither NK cell number nor with the amount of internal
contamination by 137Cs. The authors interpreted these findings as a loss of normal regulatory
mechanism to maintain a correlation between the cytotoxic activity and the number of NK cells. This
seems to be a rather speculative conclusion for this ecological study. Even if such dysregulation exists,
the Committee concluded it cannot be attributed to ionizing radiation. There are few if any
immunological studies of residents of the contaminated areas that have shown a significant difference
in immune function as a result of age at exposure.

C. Techa River
C258. About 30,000 inhabitants living near the Techa River were exposed, predominantly during theearly 1950s, to external gamma radiation from fission products associated with discharges of high andmedium level wastes from the Mayak nuclear facility into the river. In the early period, cases of chronic
radiation sickness (940 people in total, including 242 under the age of 19 years) were diagnosed. The
diagnosis was based on occurrence of changes in blood parameters (leucopoenia, thrombocytopenia,
granulocytopoenia); nervous system disorders; ostealgia; cardiovascular syndrome; and changes in
immunity (inhibition of innate immunity, autoimmunity). The subjects who were initially exposed inutero or at one–two years of age showed the greatest changes in the immune system parameters.
Haematopoietic disturbances developed almost at the same time as the signs of immune insufficiency[K47]. Complete recovery from the haematological and neurological effects, respectively, occurred
within 13–16 and 14–20 years following the beginning of exposure. The duration of the disease waspresumably dependent on the patient age at exposure. A specific feature of chronic radiation syndromein children was the prevalence of neurological disorders while in adults it was haemopoiesis that wasmost frequently recorded. Recovery processes developed more slowly in children and teenagers who
received the highest doses.

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D. Radiotherapy
C259. Blomgren et al. [B33] studied the lymphocyte count and serum immunoglobulin level inchildren irradiated for treatment of either Wilms’ tumour or non-Hodgkin’s lymphoma. Doses to thetumours were from 7 to 32 Gy, and all children received chemotherapy. With the exception of a slightly
decreased serum level of immunoglobulin E (IgE) in patients treated for lymphoma, there was nodifference from healthy controls in immunoglobulin levels, lymphocyte count, or frequency of rosetteforming cells.
C260. A long-term deficit in total CD4+ T-cell counts after radiation treatment for Hodgkin’s disease wasreported by Posner et al. [P38]. Watanabe et al. [W15] found a marked depletion in both CD4+ andCD8+ naive T-cell counts in patients who received mediastinal irradiation for Hodgkin’s disease, which
persisted up to 30 years after completion of treatment. In contrast, CD4+ and CD8+ memory T-cell subsets andtotal CD8+ T-cells recovered to normal or above normal levels by five years post-treatment with different
kinetics (early expansion of CD8+ memory T-cells versus gradual recovery of the others). Thus, thelong-term deficit in total CD4+ T-cell counts in irradiated patients with Hodgkin’s disease was due tospecific depletion of naive T-cell subset. Similarly, total CD8+ T-cell counts return to normal values
within five years, particularly because CD8+ memory T-cells expand to higher than normal levels. As thethymus is the main source of naive T-cells, these findings suggest that mediastinal irradiation results in along-term depletion of the CD4+ naive cell pool, probably because of thymus impairment. This
dysregulation of T-cell subset homeostasis may explain the altered T-cell function observed in patients who
were treated for Hodgkin’s disease, including the poor response to immunization after treatment. An
extrathymic (peripheral) expansion of mature T-cells may partially compensate for the loss of thymicderived T-cells, but this expansion is restricted primarily to the memory population, thus resulting in a
selective expansion of memory T-cells, while the naive T-cell number remains low [W15].
C261. Although the immune system appears to recover from the effects of active chemotherapy andirradiation, there is some evidence that lymphoid subsets may not always normalize. Innate immunity,
thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors ofchildhood leukaemia [S43]. Antibody levels resulting from previous vaccinations are also reduced inpatients who have completed chemotherapy for ALL for at least one year [A29, L22].
C262. In summary, there is only sparse literature concerning potential differences in immune
function following exposure in adulthood and childhood. The data from the survivors of the atomic
bombings suggest that some effects are greater during exposure at older ages. The data from those
exposed as a consequence of the Chernobyl accident generally do not compare adults and children and,
when age at exposure is considered, the results are often contradictory. The radiotherapy data arecomplicated by concurrent disease and chemotherapy. Overall, there does not appear to be a major or
clinically significant difference regarding age at exposure.

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REFERENCES
A1
A2
A3
A4
A5
A6
A7
A8

A9
A10
A11
A12
A13
A14
A15
A16
A17
A18

AAPM. The measurement, reporting, and management of radiation dose in CT. Report of
AAPM Task Group 23 of the Diagnostic Imaging Council CT Committee. AAPM report no.
96. American Association of Physicists in Medicine, One Physics Ellipse, MD, 2008.
Abboud, I., R. Porcher, M. Robin et al. Chronic kidney dysfunction in patients alive without
relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow
Transplant 15(10): 1251-1257 (2009).
Abylkassimova, Z., B. Gusev, B. Grosche et al. Nested case-control study of leukemia among
a cohort of persons exposed to ionizing radiation from nuclear weapon tests in Kazakhstan(1949-1963). Ann Epidemiol 10(7): 479 (2000).
Adams, M.J., P.H. Hardenbergh, L.S. Constine et al. Radiation-associated cardiovasculardisease. Crit Rev Oncol Hematol 45(1): 55-75 (2003).
Adams, M.J., S.R. Lipsitz, S.D. Colan et al. Cardiovascular status in long-term survivors of
Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 22(15): 3139-3148 (2004).
Adams, M.J., A. Dozier, R.E. Shore et al. Breast cancer risk 55+ years after irradiation for anenlarged thymus and its implications for early childhood medical irradiation today. Cancer
Epidemiol Biomarkers Prev 19(1): 48-58 (2010).
Adams, M.J., R.E. Shore, A. Dozier et al. Thyroid cancer risk 40+ years after irradiation for anenlarged thymus: an update of the Hempelmann cohort. Radiat Res 174(6): 753-762 (2010).
Agate, L., S. Mariotti, R. Elisei et al. Thyroid autoantibodies and thyroid function in subjects
exposed to Chernobyl fallout during childhood: evidence for a transient radiation-induced
elevation of serum thyroid antibodies without an increase in thyroid autoimmune disease. J
Clin Endocrinol Metab 93(7): 2729-2736 (2008).
Ahmed, S.R., S.M. Shalet, R.H. Campbell et al. Primary gonadal damage following treatmentof brain tumors in childhood. J Pediatr 103(4): 562-565 (1983).
Ainsbury, E.A., S.D. Bouffler, W. Dorr et al. Radiation cataractogenesis: a review of recent
studies. Radiat Res 172(1): 1-9 (2009).
Akiyama, M., O.L. Zhou, Y. Kusunoki et al. Age and dose related alteration of in vitro mixed
lymphocyte culture response of blood lymphocytes from A-bomb survivors. Radiat Res
117(1): 26-34 (1989).
Albert, R.E., R.E. Shore, N. Harley et al. Follow-up studies of patients treated by x-ray
epilation for tinea capitis. p. 1-25 in: Radiation Carcinogenesis and DNA Alterations (F. J.
Burns et al., eds.). Plenum Press, New York, 1986.
Alberti, W. Effects of radiation on the eye and ocular adnexa. p. 269-282 in: Radiopathologyof Organs and Tissues (E. Scherer et al., eds.). Springer, Berlin, 1991.
Albo, V.C., D.R. Miller, S. Leiken et al. Nine brain tumors as a late effect in children "cured"of acute lymphoblastic leukemia from a single protocol study (141). Proc Am Soc Clin Oncol
4: 172 (1985).
Alektiar, K.M., M.J. Zelefsky and M.F. Brennan. Morbidity of adjuvant brachytherapy in soft
tissue sarcoma of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 47(5):1273-1279 (2000).
Alpaslan, G., C. Alpaslan, H. Gogen et al. Disturbances in oral and dental structures in patientswith pediatric lymphoma after chemotherapy: a preliminary report. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 87(3): 317-321 (1999).
Anderson, F.S., A.S. Kunin-Batson, J.L. Perkins et al. White versus gray matter function as
seen on neuropsychological testing following bone marrow transplant for acute leukemia inchildhood. Neuropsychiatr Dis Treat 4(1): 283-288 (2008).
Andersson, M. and H.H. Storm. Cancer incidence among Danish Thorotrast-exposed patients.
J Natl Cancer Inst 84(17): 1318-1325 (1992).

222

A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10

B11

UNSCEAR 2013 REPORT

Andersson, M., B. Carstensen and H.H. Storm. Mortality and cancer incidence after cerebral
arteriography with or without Thorotrast. Radiat Res 142(3): 305-320 (1995).
Ang, K.K., L.C. Stephens and T.E. Schultheiss. Oral cavity and salivary glands. p. 283-312 in:Radiopathology of Organs and Tissues (E. Scherer et al., eds.). Springer, Berlin, 1991.
Arap, M.A., F.C. Vicentini, M. Cocuzza et al. Late hormonal levels, semen parameters, andpresence of antisperm antibodies in patients treated for testicular torsion. J Androl 28(4): 528532 (2007).
Arhan, D.P., G. Devroede, B. Jehannin et al. Segmental colonic transit time. Dis Colon
Rectum 24(8): 625-629 (1981).
Armenian, S.H., C.L. Sun, L. Francisco et al. Late congestive heart failure after hematopoietic
cell transplantation. J Clin Oncol 26(34): 5537-5543 (2008).
Armstrong, G.T., Q. Liu, Y. Yasui et al. Long-term outcomes among adult survivors ofchildhood central nervous system malignancies in the Childhood Cancer Survivor Study. J
Natl Cancer Inst 101(13): 946-958 (2009).
Armstrong, G.T., J.A. Whitton, A. Gajjar et al. Abnormal timing of menarche in survivors ofcentral nervous system tumors: A report from the Childhood Cancer Survivor Study. Cancer
115(11): 2562-2570 (2009).
Armstrong, G.T., H.M. Conklin, S. Huang et al. Survival and long-term health and cognitive
outcomes after low-grade glioma. Neuro Oncol 13(2): 223-234 (2011).
Astakhova, L.N., L.R. Anspaugh, G.W. Beebe et al. Chernobyl-related thyroid cancer inchildren of Belarus: a case-control study. Radiat Res 150(3): 349-356 (1998).
Auvinen, A., M. Hakama, H. Arvela et al. Fallout from Chernobyl and incidence of childhood
leukaemia in Finland, 1976-92. BMJ 309(6948): 151-154 (1994).
Aytac, S., S.S. Yalcin, M. Cetin et al. Measles, mumps, and rubella antibody status andresponse to immunization in children after therapy for acute lymphoblastic leukemia. Pediatr
Hematol Oncol 27(5): 333-343 (2010).
BAG. Diagnostische Referenzwerte in der Computertomographie. Merkblatt R-06-06.
Eidgenössisches Departement des Innern EDI, Schweizerische Eidgenossenschaft. Bundesamt
für Gesundheit, Bern, Switzerland, 2010. (German).
Bailey, S., A. Roberts, C. Brock et al. Nephrotoxicity in survivors of Wilms' tumours in the
North of England. Br J Cancer 87(10): 1092-1098 (2002).
Balter, S., J.W. Hopewell, D.L. Miller et al. Fluoroscopically guided interventional
procedures: a review of radiation effects on patients' skin and hair. Radiology 254(2): 326-341(2010).
Barnes, R.M. Childhood soil ingestion: how much dirt do kids eat? Anal Chem 62(19):1023A-1026A, 1030A-1033A (1990).
Barrett, I.R. Slipped capital femoral epiphysis following radiotherapy. J Pediatr Orthop 5(3):268-273 (1985).
Bartley, K., C. Metayer, S. Selvin et al. Diagnostic X-rays and risk of childhood leukaemia. Int
J Epidemiol 39(6): 1628-1637 (2010).
Bauer, S., B.I. Gusev, L.M. Pivina et al. Radiation exposure due to local fallout from Soviet
atmospheric nuclear weapons testing in Kazakhstan: solid cancer mortality in the
Semipalatinsk historical cohort, 1960-1999. Radiat Res 164(4 Pt 1): 409-419 (2005).
Bebeshko, V., A. Chumak, D. Bazyka et al. Immuno-biology and psychosocial aspects of thehealth of children after the Chernobyl. Disaster Prehospital and Disaster Medicine 11: 104-107(1996).
Bebeshko, V., D. Bazyka, A. Chumak et al. Acute and remote immunohematological effects
after the Chernobyl accident. Environ Sci Pollut Res 10(1 (Special issue)): 85-94 (2003).
Bebeshko, V.G., E.M. Bruslova and V.I. Klimenko. Leukemias and lymphomas in Ukraine
population exposed to chronic low dose irradiation. p. 337-338 in: Low Doses of Ionizing
Radiation: Biological Effects and Regulatory Control. Contributed Papers, International
Conference held in Seville, Spain. International Atomic Energy Agency, Vienna, 1997.
Becker, N., D. Liebermann, H. Wesch et al. Mortality among Thorotrast-exposed patients andan unexposed comparison group in the German Thorotrast study. Eur J Cancer 44(9): 12591268 (2008).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30

B31
B32

223

Beimfohr, C., S. Klugbauer, E.P. Demidchik et al. NTRK1 re-arrangement in papillary thyroid
carcinomas of children after the Chernobyl reactor accident. Int J Cancer 80(6): 842-847(1999).
Benoist, M.R., J. Lemerle, R. Jean et al. Effects of pulmonary function of whole lung
irradiation for Wilm's tumour in children. Thorax 37(3): 175-180 (1982).
Beres, J., G. Papp, I. Pazonyi et al. Testicular volume variations from 0 to 28 years of age. Int
Urol Nephrol 21(2): 159-167 (1989).
Bernard, F., P. Bordigoni, M.C. Simeoni et al. Height growth during adolescence and final
height after haematopoietic SCT for childhood acute leukaemia: the impact of a conditioning
regimen with BU or TBI. Bone Marrow Transplant 43(8): 637-642 (2009).
Bernstein, J.L., R.W. Haile, M. Stovall et al. Radiation exposure, the ATM Gene, andcontralateral breast cancer in the women's environmental cancer and radiation epidemiology
study. J Natl Cancer Inst 102(7): 475-483 (2010).
Bernstein, J.L., D.C. Thomas, R.E. Shore et al. Contralateral breast cancer after radiotherapy
among BRCA1 and BRCA2 mutation carriers: A WECARE Study Report. Eur J Cancer
49(14): 2979-2985 (2013).
Bertin, M. and J. Lallemand. Increase of cancers of the thyroid gland in children in Byelarus.
Ann Endocrinol 53(5-6): 173-177 (1992). (French).
BfS. Dosiskoeffizienten bei äußerer und innerer Strahlenexposition. Bundesamt fürStrahlenschutz. Bundesanzeiger 160a/b: (2001). (German).
BfS. Bekanntmachung der diagnostischen Referenzwerte für radiologische undnuklearmedizinische Untersuchungen. Bundesamt für Strahlenschutz. Bundesanzeiger 143:
17503-17504 (2003). (German).
BfS. Bekanntmachung der aktualisierten diagnostischen Referenzwerte für diagnostische undinterventionelle Röntgenuntersuchungen. Bundesamt für Strahlenschutz. Bundesanzeiger 111:2594-2596 (2010). (German).
BfS.
Bekanntmachungderaktualisierten
diagnostischen
Referenzwerte
fürnuklearmedizinische Untersuchungen. Bundesamt für Strahlenschutz. Bundesanzeiger:(2012). (German).
Bhanot, P., B. Cushing, A. Philippart et al. Hepatic irradiation and adriamycin cardiotoxicity. J
Pediatr 95(4): 561-563 (1979).
Bhatia, S., A.D. Louie, R. Bhatia et al. Solid cancers after bone marrow transplantation. J Clin
Oncol 19(2): 464-471 (2001).
Bhatia, S., Y. Yasui, L.L. Robison et al. High risk of subsequent neoplasms continues withextended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group.
J Clin Oncol 21(23): 4386-4394 (2003).
Bhatti, P., L.H. Veiga, C.M. Ronckers et al. Risk of second primary thyroid cancer afterradiotherapy for a childhood cancer in a large cohort study: an update from the childhood
cancer survivor study. Radiat Res 174(6): 741-752 (2010).
Bithell, J.F. and G.J. Draper. Uranium-235 and childhood leukaemia around Greenham
Common airfield. J Radiol Prot 19(3): 253-259 (1999).
Blatt, J., R.J. Sherins, D. Niebrugge et al. Leydig cell function in boys following treatment for
testicular relapse of acute lymphoblastic leukemia. J Clin Oncol 3(9): 1227-1231 (1985).
Blettner, M., B. Schlehofer, F. Samkange-Zeeb et al. Medical exposure to ionising radiationand the risk of brain tumours: Interphone study group, Germany. Eur J Cancer 43(13): 19901998 (2007).
Bleyer, W.A. and T.W. Griffin. White matter necrosis, mineralizing microangiopathy andintellectual abilities in survivors of childhood leukemia. p. 155-174 in: Radiation Damage to
the Nervous System: A Delayed Therapeutic Hazard (H. A. Gilbert et al., eds.). Raven Press,
New York, 1980.
Bleyer, W.A. Neurologic sequelae of methotrexate and ionizing radiation: a new classification.
Cancer Treat Rep 65(Suppl 1): 89-98 (1981).
Bleyer, W.A., J. Fallavollita, L. Robison et al. Influence of age, sex, and concurrent intrathecal
methotrexate therapy on intellectual function after cranial irradiation during childhood: areport from the Children's Cancer Study Group. Pediatr Hematol Oncol 7(4): 329-338 (1990).

224

B33
B34
B35
B36
B37
B38
B39
B40
B41
B42
B43
B44
B45
B46

B47

B48
B49
B50
B51
B52
B53

UNSCEAR 2013 REPORT

Blomgren, H., S. Hayder, I. Lax et al. Studies on the lymphatic system in longterm survivors
treated for Wilms' tumour or non-Hodgkin's lymphoma during childhood. Clin Oncol 6(1): 313 (1980).
Bloom, H.J. Intracranial tumors: response and resistance to therapeutic endeavors, 1970-1980.
Int J Radiat Oncol Biol Phys 8(7): 1083-1113 (1982).
Body, J.J., N. Demeester-Mirkine and J. Corvilain. Calcitonin deficiency after radioactive
iodine treatment. Ann Intern Med 109(7): 590-591 (1988).
Boice, J. and B. Stone. Interaction between radiation and other breast cancer risk factors. p.
231-247 in: Late Biological Effects of Ionizing Radiation. Vol. I. International Atomic Energy
Agency, Vienna, 1978.
Boice, J.D., Jr., G. Engholm, R.A. Kleinerman et al. Radiation dose and second cancer risk inpatients treated for cancer of the cervix. Radiat Res 116(1): 3-55 (1988).
Boice, J.D., Jr., D. Preston, F.G. Davis et al. Frequent chest X-ray fluoroscopy and breast
cancer incidence among tuberculosis patients in Massachusetts. Radiat Res 125(2): 214-222(1991).
Boice, J.D., Jr., W.L. Bigbee, M.T. Mumma et al. Cancer incidence in municipalities near twoformer nuclear materials processing facilities in Pennsylvania. Health Phys 85(6): 678-690(2003).
Boice, J.D., Jr., M. Mumma, S. Schweitzer et al. Cancer mortality in a Texas county with prioruranium mining and milling activities, 1950-2001. J Radiol Prot 23(3): 247-262 (2003).
Boice, J.D., Jr., M.T. Mumma, W.J. Blot et al. Childhood cancer mortality in relation to the St
Lucie nuclear power station. J Radiol Prot 25(3): 229-240 (2005).
Boice, J.D., Jr., M.T. Mumma and W.J. Blot. Cancer mortality among populations residing incounties near the Hanford site, 1950-2000. Health Phys 90(5): 431-445 (2006).
Boice, J.D., Jr., M.T. Mumma and W.J. Blot. Cancer incidence and mortality in populations
living near uranium milling and mining operations in Grants, New Mexico, 1950-2004. Radiat
Res 174(5): 624-636 (2010).
Boivin, J.F., G.B. Hutchison, J.H. Lubin et al. Coronary artery disease mortality in patientstreated for Hodgkin's disease. Cancer 69(5): 1241-1247 (1992).
Bolling, T., I. Ernst, H. Pape et al. Dose-volume analysis of radiation nephropathy in children:
preliminary report of the risk consortium. Int J Radiat Oncol Biol Phys 80(3): 840-844 (2011).
Bolling, T., A. Geisenheiser, H. Pape et al. Hypothyroidism after head-and-neck radiotherapy
in children and adolescents: preliminary results of the "Registry for the Evaluation of Side
Effects After Radiotherapy in Childhood and Adolescence" (RiSK). Int J Radiat Oncol Biol
Phys 81(5): e787-e791 (2011).
Book, S.A. Age-related variation in thyroidal exposures from fission-produced radioiodines.
CONF-771017. p. 330-343 in: Developmental Toxicology of Energy-Related Pollutants (D. D.
Mahlum et al., eds.). Technical Information Center, U.S. Department of Energy, Virginia,
1978.
Bordigoni, P., R. Turello, L. Clement et al. Osteochondroma after pediatric hematopoietic
stem cell transplantation: report of eight cases. Bone Marrow Transplant 29(7): 611-614(2002).
Borg, M., T. Hughes, N. Horvath et al. Renal toxicity after total body irradiation. Int J Radiat
Oncol Biol Phys 54(4): 1165-1173 (2002).
Borgstrom, B. and P. Bolme. Thyroid function in children after allogeneic bone marrowtransplantation. Bone Marrow Transplant 13(1): 59-64 (1994).
Bossi, G., I. Cerveri, E. Volpini et al. Long-term pulmonary sequelae after treatment ofchildhood Hodgkin's disease. Ann Oncol 8(Suppl 1): 19-24 (1997).
Boukheris, H., E. Ron, G.M. Dores et al. Risk of radiation-related salivary gland carcinomas
among survivors of Hodgkin lymphoma: a population-based analysis. Cancer 113(11): 31533159 (2008).
Boukheris, H., M. Stovall, E.S. Gilbert et al. Risk of salivary gland cancer after childhood
cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys
85(3): 776-783 (2013).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

B54
B55
B56
B57
B58
B59
B60
B61
B62
B63
B64
B65
B66
B67
B68
B69
B70
B71
B72
B73
B74
B75

225

Bounacer, A., R. Wicker, B. Caillou et al. High prevalence of activating ret proto-oncogene
rearrangements, in thyroid tumors from patients who had received external radiation.
Oncogene 15(11): 1263-1273 (1997).
Bovee, J.V. Multiple osteochondromas. Orphanet J Rare Dis 3: 3 (2008).
Bowers, D.C., D.E. McNeil, Y. Liu et al. Stroke as a late treatment effect of Hodgkin's
Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol 23(27): 6508-6515(2005).
Bowers, D.C., Y. Liu, W. Leisenring et al. Late-occurring stroke among long-term survivors ofchildhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J
Clin Oncol 24(33): 5277-5282 (2006).
Brady, L.W., J. Shields, J. Augusburger et al. Complications from radiation therapy to the eye.
Front Radiat Ther Oncol 23: 238-250; discussion 251-234 (1989).
Brennan, B.M., A. Rahim, W.F. Blum et al. Hyperleptinaemia in young adults following
cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin
Endocrinol (Oxf) 50(2): 163-169 (1999).
Brenner, A.V., M.D. Tronko, M. Hatch et al. I-131 dose response for incident thyroid cancers
in Ukraine related to the Chornobyl accident. Environ Health Perspect 119(7): 933-939 (2011).
Breslow, N.E., A.J. Collins, M.L. Ritchey et al. End stage renal disease in patients with Wilms
tumor: results from the National Wilms Tumor Study Group and the United States Renal Data
System. J Urol 174(5): 1972-1975 (2005).
Brincker, H., H.S. Hansen and A.P. Andersen. Induction of leukemia by 131-I treatment of
thyroid carcinoma. Br J Cancer 28(3): 232-237 (1973).
Brisse, H., V. Servois, B. Bouche et al. Hepatic regenerating nodules: a mimic of recurrent
cancer in children. Pediatr Radiol 30(6): 386-393 (2000).
Broeks, A., L.M. Braaf, A. Huseinovic et al. Identification of women with an increased risk ofdeveloping radiation-induced breast cancer: a case only study. Breast Cancer Res 9(2): R26(2007).
Brooks, J.D., J.D. Boice, Jr., M. Stovall et al. Reproductive status at first diagnosis influences
risk of radiation-induced second primary contralateral breast cancer in the WECARE study. Int
J Radiat Oncol Biol Phys 84(4): 917-924 (2012).
Brouwers, P. and D. Poplack. Memory and learning sequelae in long-term survivors of acutelymphoblastic leukemia: association with attention deficits. Am J Pediatr Hematol Oncol
12(2): 174-181 (1990).
Brown, R.T., A. Madan-Swain, R. Pais et al. Chemotherapy for acute lymphocytic leukemia:
cognitive and academic sequelae. J Pediatr 121(6): 885-889 (1992).
Bruenger, F.W., R.D. Lloyd and S.C. Miller. The influence of age at time of exposure to
226Ra or 239Pu on distribution, retention, postinjection survival, and tumor induction inbeagle dogs. Radiat Res 125(3): 248-256 (1991).
Bucci, A., E. Shore-Freedman, T. Gierlowski et al. Behavior of small thyroid cancers found by
screening radiation-exposed individuals. J Clin Endocrinol Metab 86(8): 3711-3716 (2001).
Burch, J.D., K.J. Craib, B.C. Choi et al. An exploratory case-control study of brain tumors in
adults. J Natl Cancer Inst 78(4): 601-609 (1987).
Busby, C. and M. Scott. Increases in leukemia in infants in Wales and Scotland following
Chernobyl: Evidence for errors in statuatory risk estimates. Energy Environ 11(2): 127-139(2000).
Butler, R.W., J.M. Hill, P.G. Steinherz et al. Neuropsychologic effects of cranial irradiation,
intrathecal methotrexate, and systemic methotrexate in childhood cancer. J Clin Oncol 12(12):2621-2629 (1994).
Byrne, J., J.J. Mulvihill, R.R. Connelly et al. Reproductive problems and birth defects insurvivors of Wilms' tumor and their relatives. Med Pediatr Oncol 16(4): 233-240 (1988).
Byrne, J., T.R. Fears, M.H. Gail et al. Early menopause in long-term survivors of cancer
during adolescence. Am J Obstet Gynecol 166(3): 788-793 (1992).
Byrne, J., S.A. Rasmussen, S.C. Steinhorn et al. Genetic disease in offspring of long-term
survivors of childhood and adolescent cancer. Am J Hum Genet 62(1): 45-52 (1998).

226

C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22

UNSCEAR 2013 REPORT

Caldwell, G.G., D. Kelley, M. Zack et al. Mortality and cancer frequency among military
nuclear test (Smoky) participants, 1957 through 1979. J Am Med Assoc 250(5): 620-624(1983).
Campen, C.J., S.M. Kranick, S.E. Kasner et al. Cranial irradiation increases risk of stroke inpediatric brain tumor survivors. Stroke 43(11): 3035-3040 (2012).
Cardis, E., A. Kesminiene, V. Ivanov et al. Risk of thyroid cancer after exposure to 131I inchildhood. J Natl Cancer Inst 97(10): 724-732 (2005).
Cardis, E., D. Krewski, M. Boniol et al. Estimates of the cancer burden in Europe fromradioactive fallout from the Chernobyl accident. Int J Cancer 119(6): 1224-1235 (2006).
Carl, U.M. and K.A. Hartmann. Heterotopic calcification as a late radiation effect: report of 15
cases. Br J Radiol 75(893): 460-463 (2002).
Carr, Z.A., R.A. Kleinerman, M. Stovall et al. Malignant neoplasms after radiation therapy for
peptic ulcer. Radiat Res 157(6): 668-677 (2002).
Castellino, S., A. Muir, A. Shah et al. Hepato-biliary late effects in survivors of childhood andadolescent cancer: a report from the Children's Oncology Group. Pediatr Blood Cancer 54(5):663-669 (2010).
Castellino, S.M., A.M. Geiger, A.C. Mertens et al. Morbidity and mortality in long-term
survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood
117(6): 1806-1816 (2011).
CERRIE. Report of the committee examining radiation risks of internal emitters. Committee
Examining Radiation Risks of Internal Emitters, London, 2004.
Cerveri, I., P. Fulgoni, G. Giorgiani et al. Lung function abnormalities after bone marrowtransplantation in children: has the trend recently changed? Chest 120(6): 1900-1906 (2001).
Chello, M., P. Mastroroberto, R. Romano et al. Changes in the proportion of types I and III
collagen in the left ventricular wall of patients with post-irradiative pericarditis. Cardiovasc
Surg 4(2): 222-226 (1996).
Chemaitilly, W., A.C. Mertens, P. Mitby et al. Acute ovarian failure in the childhood cancer
survivor study. J Clin Endocrinol Metab 91(5): 1723-1728 (2006).
Chemaitilly, W. and C.A. Sklar. Endocrine complications of hematopoietic stem celltransplantation. Endocrinol Metab Clin North Am 36(4): 983-998 (2007).
Chen, W.L., J.S. Hwang, T.H. Hu et al. Lenticular opacities in populations exposed to chronic
low-dose-rate gamma radiation from radiocontaminated buildings in Taiwan. Radiat Res
156(1): 71-77 (2001).
Chernyshov, V.P., E.V. Vykhovanets, I. Slukvin et al. Analysis of blood lymphocyte subsets
in children living on territory that received high amounts of fallout from Chernobyl accident.
Clin Immunol Immunopathol 84(2): 122-128 (1997).
Chessells, J.M., T.C. Cox, B. Kendall et al. Neurotoxicity in lymphoblastic leukaemia:
comparison of oral and intramuscular methotrexate and two doses of radiation. Arch Dis Child65(4): 416-422 (1990).
Cheuk, D.K., C.A. Billups, M.G. Martin et al. Prognostic factors and long-term outcomes ofchildhood nasopharyngeal carcinoma. Cancer 117(1): 197-206 (2011).
Chiarelli, A.M., L.D. Marrett and G. Darlington. Early menopause and infertility in females
after treatment for childhood cancer diagnosed in 1964-1988 in Ontario, Canada. Am J
Epidemiol 150(3): 245-254 (1999).
Chmelevsky, D., C.W. Mays, H. Spiess et al. An epidemiological assessment of lens
opacifications that impaired vision in patients injected with radium-224. Radiat Res 115(2):238-257 (1988).
Chmelevsky, D., C.W. Mays, H. Spiess et al. The cataract response in radium-224 patients.
BIR Report 21. p. 21-25 in: Risks from Radium and Thorotrast (D.M. Taylor et al., eds.).
British Institute of Radiology, London, 1989.
Choshi, K., I. Takaku, H. Mishima et al. Ophthalmologic changes related to radiation exposureand age in adult health study sample, Hiroshima and Nagasaki. Radiat Res 96(3): 560-579(1983).
Chou, R.H., G.B. Wong, J.H. Kramer et al. Toxicities of total-body irradiation for pediatricbone marrow transplantation. Int J Radiat Oncol Biol Phys 34(4): 843-851 (1996).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

C23
C24
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C29
C30
C31
C32
C33
C34
C35
C36
C37
C38
C39
C40
C41
C42

227

Chow, E.J., D.L. Friedman, Y. Yasui et al. Decreased adult height in survivors of childhood
acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr
150(4): 370-375, 375.e371 (2007).
Chow, E.J., C. Pihoker, K. Hunt et al. Obesity and hypertension among children after
treatment for acute lymphoblastic leukemia. Cancer 110(10): 2313-2320 (2007).
Chow, E.J., D.L. Friedman, Y. Yasui et al. Timing of menarche among survivors of childhood
acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr
Blood Cancer 50(4): 854-858 (2008).
Chow, E.J., A. Kamineni, J.R. Daling et al. Reproductive outcomes in male childhood cancer
survivors: a linked cancer-birth registry analysis. Arch Pediatr Adolesc Med 163(10): 887-894(2009).
Chow, E.J., J.H. Simmons, C.L. Roth et al. Increased cardiometabolic traits in pediatricsurvivors of acute lymphoblastic leukemia treated with total body irradiation. Biol Blood
Marrow Transplant 16(12): 1674-1681 (2010).
Christensson, T. Hyperparathyroidism and radiation therapy. Ann Intern Med 89(2): 216-217(1978).
Chu, W.C. and D.J. Roebuck. Nodular regenerative hyperplasia of the liver simulating
metastases following treatment for bilateral Wilms tumor. Med Pediatr Oncol 41(1): 85-87(2003).
Clark, D.E. Association of irradiation with cancer of the thyroid in children and adolescents. J
Am Med Assoc 159(10): 1007-1009 (1955).
Cohen, A., A. Rovelli, B. Bakker et al. Final height of patients who underwent bone marrowtransplantation for hematological disorders during childhood: a study by the Working Party for
Late Effects-EBMT. Blood 93(12): 4109-4115 (1999).
Cohen, A., A. Rovelli, M.T. van Lint et al. Secondary thyroid carcinoma after allogeneic bonemarrow transplantation during childhood. Bone Marrow Transplant 28(12): 1125-1128 (2001).
Cohen, M.E. and P.K. Duffner. Long-term consequences of CNS treatment for childhood
cancer, Part I: Pathologic consequences and potential for oncogenesis. Pediatr Neurol 7(3):157-163 (1991).
Cohen, S.I., S. Bharati, J. Glass et al. Radiotherapy as a cause of complete atrioventricular
block in Hodgkin's disease. An electrophysiological-pathological correlation. Arch Intern Med
141(5): 676-679 (1981).
Coia, L.R. and G.E. Hanks. Complications from large field intermediate dose
infradiaphragmatic radiation: an analysis of the patterns of care outcome studies for Hodgkin's
disease and seminoma. Int J Radiat Oncol Biol Phys 15(1): 29-35 (1988).
Collins, B.P. and M.E. Gaulden. A case of child abuse. p. 198 in: The Medical Basis for
Radiation Accident Preparedness (K. F. Hubner et al., eds.). Elsevier, North Holland, New
York, 1980.
Colman, M., L.R. Simpson, L.K. Patterson et al. Thyroid cancer associated with radiation
exposure. Dose-effect relationship. p. 285-289 in: Biological and Environmental Effects of
Low-Level Radiation. Vol.II. International Atomic Energy Agency, Vienna, 1976.
Colman, M., M. Kirsch and M. Creditor. Tumours associated with medical x-ray therapy
exposure in childhood. p. 167-180 in: Late Biological Effects of Ionizing Radiation. Vol. I.
International Atomic Energy Agency, Vienna, 1978.
COMARE. The incidence of childhood cancer around nuclear installations in Great Britain.
Tenth Report. Committee on Medical Aspects of Radiation in the Environment, UK, 2005.
COMARE. Further consideration of the incidence of childhood leukaemia around nuclear
power plants in Great Britain. Fourteenth Report. Committee on Medical Aspects of Radiationin the Environment, UK, 2011.
Conard, R.A. Acute myelogenous leukemia following fallout radiation exposure. J Am Med
Assoc 232(13): 1356-1357 (1975).
Conard, R.A., D.E. Paglia and P.R. Larsen. Review of medical findings in a marshallese
population twenty-six years after accidental exposure to radioactive fallout. Bookhaven
National Laboratory, New York, 1980.

228

C43
C44
C45
C46
C47
C48
C49
C50
C51
C52
C53
C54
C55
C56
C57
C58
C59
C60
D1
D2
D3
D4

UNSCEAR 2013 REPORT

Conard, R.A. Late radiation effects in Marshall Islanders exposed to fallout 28 years ago p. 5771 in: Radiation Carcinogenesis: Epidemiology and Biological Significance (J. D. Boice Jr.,eds.). Raven Press, New York, 1984.
Constine, L., M. Morris, I. Ding et al. Late effects of cancer treatment on normal tissues. p.
357-390 in: Principles and Practice of Radiation Oncology (C. Perez et al., eds.). Lippincott
Williams & Wilkins, Philadelphia, 2004.
Constine, L.S., S.S. Donaldson, I.R. McDougall et al. Thyroid dysfunction after radiotherapy
in children with Hodgkin's disease. Cancer 53(4): 878-883 (1984).
Constine, L.S., P. Rubin, P.D. Woolf et al. Hyperprolactinemia and hypothyroidism following
cytotoxic therapy for central nervous system malignancies. J Clin Oncol 5(11): 1841-1851(1987).
Constine, L.S., P.D. Woolf, D. Cann et al. Hypothalamic-pituitary dysfunction after radiation
for brain tumors. N Engl J Med 328(2): 87-94 (1993).
Constine, L.S., N. Tarbell, M.M. Hudson et al. Subsequent malignancies in children treated for
Hodgkin's disease: associations with gender and radiation dose. Int J Radiat Oncol Biol Phys
72(1): 24-33 (2008).
Coplan, J., E.M. Post, R.A. Richman et al. Hearing loss after therapy with radiation. Am J Dis
Child 135(11): 1066-1067 (1981).
Corazziari, E., S. Cucchiara, A. Staiano et al. Gastrointestinal transit time, frequency ofdefecation, and anorectal manometry in healthy and constipated children. J Pediatr 106(3):379-382 (1985).
Cristy, M. and K.F. Eckerman. Specific absorbed fractions of energy at various ages frominternal photon sources. I. Methods. ORNL/TM-8381/ V 1: (1987).
Critchley, H.O., W.H. Wallace, S.M. Shalet et al. Abdominal irradiation in childhood; thepotential for pregnancy. Br J Obstet Gynaecol 99(5): 392-394 (1992).
Cuddihy, R.G. Thyroidal iodine-131 uptake, turnover and blocking in adults and adolescents.
Health Phys. 12(8): 1021-1025 (1966).
Curran, W.J., C. Hecht-Leavitt, L. Schut et al. Magnetic resonance imaging of cranial radiation
lesions. Int J Radiat Oncol Biol Phys 13(7): 1093-1098 (1987).
Curtis, R.E., P.A. Rowlings, H.J. Deeg et al. Solid cancers after bone marrow transplantation.
N Engl J Med 336(13): 897-904 (1997).
Curwen, G.B., J.F. Winther, E.J. Tawn et al. G2 chromosomal radiosensitivity in Danish
survivors of childhood and adolescent cancer and their offspring. Br J Cancer 93(9): 10381045 (2005).
Curwen, G.B., K.K. Cadwell, J.F. Winther et al. The heritability of G2 chromosomal
radiosensitivity and its association with cancer in Danish cancer survivors and their offspring.
Int J Radiat Biol 86(11): 986-995 (2010).
Curwen, G.B., S. Murphy, E.J. Tawn et al. A study of DNA damage recognition and repair
gene polymorphisms in relation to cancer predisposition and G2 chromosomal radiosensitivity.
Environ Mol Mutagen 52(1): 72-76 (2011).
Cutuli, B., C. Borel, F. Dhermain et al. Breast cancer occurred after treatment for Hodgkin's
disease: analysis of 133 cases. Radiother Oncol 59(3): 247-255 (2001).
Cvancarova, M., S.O. Samuelsen, H. Magelssen et al. Reproduction rates after cancer
treatment: experience from the Norwegian radium hospital. J Clin Oncol 27(3): 334-343(2009).
Dahllof, G., M. Barr, P. Bolme et al. Disturbances in dental development after total body
irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 65(1): 41-44(1988).
Dahllof, G. Oral and dental late effects after pediatric stem cell transplantation. Biol Blood
Marrow Transplant 14(1 Suppl 1): 81-83 (2008).
Damber, L., L.G. Larsson, L. Johansson et al. A cohort study with regard to the risk ofhaematological malignancies in patients treated with x-rays for benign lesions in the locomotor
system. I. Epidemiological analyses. Acta Oncol 34(6): 713-719 (1995).
Damber, L., L. Johansson, R. Johansson et al. Thyroid cancer after X-ray treatment of benign
disorders of the cervical spine in adults. Acta Oncol 41(1): 25-28 (2002).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D16
D17
D18
D19
D20
D21
D22
D23
D24
D25
D26
D27
D28

229

Darby, S., D. Hill, A. Auvinen et al. Radon in homes and risk of lung cancer: collaborative
analysis of individual data from 13 European case-control studies. BMJ 330(7485): 223(2005).
Darby, S.C., R. Doll, S.K. Gill et al. Long term mortality after a single treatment course with
X-rays in patients treated for ankylosing spondylitis. Br J Cancer 55(2): 179-190 (1987).
Darby, S.C., G.M. Kendall, T.P. Fell et al. A summary of mortality and incidence of cancer inmen from the United Kingdom who participated in the United Kingdom's atmospheric nuclear
weapon tests and experimental programmes. BMJ (Clin Res Ed) 296(6618): 332-338 (1988).
Darby, S.C., G. Reeves, T. Key et al. Mortality in a cohort of women given X-ray therapy for
metropathia haemorrhagica. Int J Cancer 56(6): 793-801 (1994).
Darby, S.C., D.J. Cutter, M. Boerma et al. Radiation-related heart disease: current knowledge
and future prospects. Int J Radiat Oncol Biol Phys 76(3): 656-665 (2010).
Dardynskaia, I., P.B. Imrey, A. Okeanov et al. Breast cancer trends in two oblasts of Belarus
and the Chernobyl accident. Int J Occup Environ Health 12(4): 415-422 (2006).
Darzy, K.H. and S.M. Shalet. Hypopituitarism following radiotherapy. Pituitary 12(1): 40-50(2009).
Das, B. and C.V. Karuppasamy. Spontaneous frequency of micronuclei among the newborns
from high level natural radiation areas of Kerala in the southwest coast of India. Int J Radiat
Biol 85(3): 272-280 (2009).
Das, B., D. Saini and M. Seshadri. No evidence of telomere length attrition in newborns fromhigh level natural background radiation areas in Kerala coast, south west India. Int J Radiat
Biol 88(9): 642-647 (2012).
Davis, F.G., J.D. Boice, Jr., J.L. Kelsey et al. Cancer mortality after multiple fluoroscopic
examinations of the chest. J Natl Cancer Inst 78(4): 645-652 (1987).
Davis, F.G., J.D. Boice, Jr., Z. Hrubec et al. Cancer mortality in a radiation-exposed cohort of
Massachusetts tuberculosis patients. Cancer Res 49(21): 6130-6136 (1989).
Davis, S., K.J. Kopecky and T.E. Hamilton. Hanford thyroid disease study final report. CDC
Contract Number 200-89-0716. Fred Hutchinson Cancer Center, 2002.
Davis, S., K.J. Kopecky, T.E. Hamilton et al. Thyroid neoplasia, autoimmune thyroiditis, andhypothyroidism in persons exposed to iodine 131 from the hanford nuclear site. J Am Med
Assoc 292(21): 2600-2613 (2004).
Davis, S., V. Stepanenko, N. Rivkind et al. Risk of thyroid cancer in the Bryansk Oblast of theRussian Federation after the Chernobyl Power Station accident. Radiat Res 162(3): 241-248(2004).
Davis, S., R. Day, K. Kopecky et al. Childhood leukaemia in Belarus, Russia, and Ukraine
following the Chernobyl power station accident: results from an international collaborative
population-based case-control study. Int J Epidemiol 35(2): 386-396 (2006).
Dawson, L.A. and R.K. Ten Haken. Partial volume tolerance of the liver to radiation. Semin
Radiat Oncol 15(4): 279-283 (2005).
Dawson, L.A., B.D. Kavanagh, A.C. Paulino et al. Radiation-associated kidney injury. Int J
Radiat Oncol Biol Phys 76(3 Suppl): S108-S115 (2010).
Dawson, W.B. Growth impairment following radiotherapy in childhood. Clin Radiol 19(3):241-256 (1968).
Day, R., M.B. Gorin and A.W. Eller. Prevalence of lens changes in Ukrainian children
residing around Chernobyl. Health Phys 68(5): 632-642 (1995).
De Bruin, M.L., L.D. Dorresteijn, M.B. van't Veer et al. Increased risk of stroke and transientischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 101(13): 928937 (2009).
De Jong, S.A., J.G. Demeter, H. Jarosz et al. Thyroid carcinoma and hyperparathyroidism afterradiation therapy for adolescent acne vulgaris. Surgery 110(4): 691-695 (1991).
de Vathaire, F., P. Fragu, P. Francois et al. Long-term effects on the thyroid of irradiation forskin angiomas in childhood. Radiat Res 133(3): 381-386 (1993).
de Vathaire, F., M. Schlumberger, M.J. Delisle et al. Leukaemias and cancers following
iodine-131 administration for thyroid cancer. Br J Cancer 75(5): 734-739 (1997).
de Vathaire, F., C. Hardiman, A. Shamsaldin et al. Thyroid carcinomas after irradiation for a
first cancer during childhood. Arch Intern Med 159(22): 2713-2719 (1999).

230

D29
D30
D31
D32
D33
D34
D35
D36
D37
D38
D39
D40
D41
D42
D43
D44
D45
D46
D47
D48
D49
D50
E1

UNSCEAR 2013 REPORTde Vathaire, F., C. El-Fayech, F.F. Ben Ayed et al. Radiation dose to the pancreas and risk of
diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol
13(10): 1002-1010 (2012).
Deak, P.D., Y. Smal and W.A. Kalender. Multisection CT protocols: sex- and age-specificconversion factors used to determine effective dose from dose-length product. Radiology
257(1): 158-166 (2010).
Deeg, H.J. Acute and delayed toxicities of total body irradiation. Seattle Marrow Transplant
Team. Int J Radiat Oncol Biol Phys 9(12): 1933-1939 (1983).
DeGroot, L. and E. Paloyan. Thyroid carcinoma and radiation. A Chicago endemic. J Am Med
Assoc 225(5): 487-491 (1973).
DeGroot, L.J., M. Reilly, K. Pinnameneni et al. Retrospective and prospective study ofradiation-induced thyroid disease. Am J Med 74(5): 852-862 (1983).
Denys, D., S.C. Kaste, L.E. Kun et al. The effects of radiation on craniofacial skeletal growth:a quantitative study. Int J Pediatr Otorhinolaryngol 45(1): 7-13 (1998).
Dershaw, D.D., J. Yahalom and J.A. Petrek. Breast carcinoma in women previously treated for
Hodgkin disease: mammographic evaluation. Radiology 184(2): 421-423 (1992).
Devney, R.B., C.A. Sklar, M.E. Nesbit, Jr. et al. Serial thyroid function measurements inchildren with Hodgkin disease. J Pediatr 105(2): 223-227 (1984).
Dias, A. Effects on the hearing of patients treated by irradiation in the head and neck area. J
Laryngol Otol 80(3): 276-287 (1966).
Didcock, E., H.A. Davies, M. Didi et al. Pubertal growth in young adult survivors ofchildhood leukemia. J Clin Oncol 13(10): 2503-2507 (1995).
Didi, M., E. Didcock, H.A. Davies et al. High incidence of obesity in young adults after
treatment of acute lymphoblastic leukemia in childhood. J Pediatr 127(1): 63-67 (1995).
DIN. Clinical dosimetry - Part 3: Diagnostic radiology. Standard DIN 6809-3:2012-09.
Deutsches Institut für Normung, Berlin, 2012. (German).
Domenicucci, M., M. Artico, F. Nucci et al. Meningioma following high-dose radiation
therapy. Case report and review of the literature. Clin Neurol Neurosurg 92(4): 349-352(1990).
Donaldson, S.S., S. Jundt, C. Ricour et al. Radiation enteritis in children. A retrospective
review, clinicopathologic correlation, and dietary management. Cancer 35(4): 1167-1178(1975).
Dores, G.M., C. Metayer, R.E. Curtis et al. Second malignant neoplasms among long-term
survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol
20(16): 3484-3494 (2002).
Dores, G.M., W.F. Anderson, L.E. Beane Freeman et al. Risk of breast cancer according toclinicopathologic features among long-term survivors of Hodgkin's lymphoma treated withradiotherapy. Br J Cancer 103(7): 1081-1084 (2010).
dos Santos Silva, I., F. Malveiro, M.E. Jones et al. Mortality after radiological investigation
with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal. Radiat Res
159(4): 521-534 (2003).
Dottorini, M.E., G. Lomuscio, L. Mazzucchelli et al. Assessment of female fertility andcarcinogenesis after iodine-131 therapy for differentiated thyroid carcinoma. J Nucl Med
36(1): 21-27 (1995).
Drexler, G., H. Eckerl and M. Zankl. On the influence of the exposure model on organ doses.
Radiat Prot Dosim 28(3): 181-188 (1989).
Duffner, P.K. and M.E. Cohen. The long-term effects of central nervous system therapy onchildren with brain tumors. Neurol Clin 9(2): 479-495 (1991).
Duffy, B.J., Jr. and P.J. Fitzgerald. Thyroid cancer in childhood and adolescence; a report on
28 cases. Cancer 3(6): 1018-1032 (1950).
Dunning, D.E., Jr. and G. Schwarz. Variability of human thyroid characteristics and estimatesof dose from ingested 131I. Health Phys 40(5): 661-675 (1981).
Eames, G.M., J. Crosson, J. Steinberger et al. Cardiovascular function in children followingbone marrow transplant: a cross-sectional study. Bone Marrow Transplant 19(1): 61-66(1997).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

E2
E3
E4
E5
E6
E7
E8
E9
E10
E11
E12
E13
E14
E15
F1
F2
F3
F4
F5
F6
F7
F8
F9

231

Eberlein, U., J.H. Bröer, C. Vandevoorde et al. Biokinetics and dosimetry of commonly usedradiopharmaceuticals in diagnostic nuclear medicine - a review. Eur J Nucl Med Mol Imaging
38(12): 2269-2281 (2011).
EC. Molecular, cellular, biological characterization of childhood thyroid cancer. EUR 16538.
European Commission, Luxembourg, 1996.
EC. European guidelines on quality criteria for diagnostic radiographic images in paediatrics.
EUR 16261. European Commission, Luxembourg, 1996.
EC. European guidance on estimating population doses from medical X-ray procedures.
Radiation Protection 154. European Commission, Luxembourg, 2008.
Eckerman, K.F. and J.C. Ryman. External exposure to radionuclides in air, water, and soil.
Federal Guidance Technical Report 12. U.S. Environmental Protection Agency, Washington,
DC, 1993.
Edeiken, B.S., H.I. Libshitz and M.A. Cohen. Slipped proximal humeral epiphysis: acomplication of radiotherapy to the shoulder in children. Skeletal Radiol 9(2): 123-125 (1982).
Edmonds, C.J. and T. Smith. The long-term hazards of the treatment of thyroid cancer withradioiodine. Br J Radiol 59(697): 45-51 (1986).
Edwards, M.K., J.G. Terry, J.F. Montebello et al. Gliomas in children following radiation
therapy for lymphoblastic leukemia. Acta Radiol 369(Suppl): 651-653 (1986).
Eidemuller, M., E. Holmberg, P. Jacob et al. Breast cancer risk among Swedish hemangioma
patients and possible consequences of radiation-induced genomic instability. Mutat Res 669(12): 48-55 (2009).
Ellenberg, L., Q. Liu, G. Gioia et al. Neurocognitive status in long-term survivors of childhood
CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology
23(6): 705-717 (2009).
Ellis, M.J., C.R. Parikh, J.K. Inrig et al. Chronic kidney disease after hematopoietic celltransplantation: a systematic review. Am J Transplant 8(11): 2378-2390 (2008).
Estilo, C.L., J.M. Huryn, D.H. Kraus et al. Effects of therapy on dentofacial development inlong-term survivors of head and neck rhabdomyosarcoma: the memorial sloan-kettering cancer
center experience. J Pediatr Hematol Oncol 25(3): 215-222 (2003).
Evans, A.E., P. Norkool, I. Evans et al. Late effects of treatment for Wilms' tumor. A reportfrom the National Wilms' Tumor Study Group. Cancer 67(2): 331-336 (1991).
Eve, I.S. A review of the physiology of the gastrointestinal tract in relation to radiation doses
from radioactive materials. Health Phys. 12(2): 131-161 (1966).
Fahnehjelm, K.T., A.L. Tornquist, M. Olsson et al. Visual outcome and cataract development
after allogeneic stem-cell transplantation in children. Acta Ophthalmol Scand 85(7): 724-733(2007).
Fajardo, L.F., J.R. Stewart and K.E. Cohn. Morphology of radiation-induced heart disease.
Arch Pathol 86(5): 512-519 (1968).
Fajardo, L.F., J.R. Eltringham and J.R. Steward. Combined cardiotoxicity of adriamycin andx-radiation. Lab Invest 34(1): 86-96 (1976).
Fajardo, L.F. Pathology of Radiation Injury. p. in: Book Pathology of Radiation Injury.
Masson Publishing, New York, 1982.
Fajardo, L.F., M. Berthrong and R.E. Anderson. Radiation Pathology. p. in: Book Radiation
Pathology. Oxford University Press, New York, 2001.
Faraci, M., F. Bagnasco, P. Corti et al. Osteochondroma after hematopoietic stem celltransplantation in childhood. An Italian study on behalf of the AIEOP-HSCT group. Biol
Blood Marrow Transplant 15(10): 1271-1276 (2009).
Ferry, C., G. Gemayel, V. Rocha et al. Long-term outcomes after allogeneic stem celltransplantation for children with hematological malignancies. Bone Marrow Transplant 40(3):219-224 (2007).
Flentje, M., A. Weirich, R. Potter et al. Hepatotoxicity in irradiated nephroblastoma patientsduring postoperative treatment according to SIOP9/GPOH. Radiother Oncol 31(3): 222-228(1994).
Fletcher, B.D. Effects of pediatric cancer therapy on the musculoskeletal system. Pediatr
Radiol 27(8): 623-636 (1997).

232

F10
F11
F12
F13
F14
F15
F16
F17
F18
F19
F20
F21

F22
F23
F24
F25
F26
F27
F28
F29
G1
G2
G3

UNSCEAR 2013 REPORT

Flint-Richter, P. and S. Sadetzki. Genetic predisposition for the development of radiationassociated meningioma: an epidemiological study. Lancet Oncol 8(5): 403-410 (2007).
Fontana, M., C. Stanton, A. Pompili et al. Late multifocal gliomas in adolescents previously
treated for acute lymphoblastic leukemia. Cancer 60(7): 1510-1518 (1987).
Franceschi, S., A. Fassina, R. Talamini et al. Risk factors for thyroid cancer in northern Italy.
Int J Epidemiol 18(3): 578-584 (1989).
Franceschi, S., R. Talamini, A. Fassina et al. Diet and epithelial cancer of the thyroid gland.
Tumori 76(4): 331-338 (1990).
Freeman, J.E., P.G. Johnston and J.M. Voke. Somnolence after prophylactic cranial irradiationin children with acute lymphoblastic leukaemia. BMJ 4(5891): 523-525 (1973).
Freitas, J.E., D.P. Swanson, M.D. Gross et al. Iodine-131: optimal therapy for hyperthyroidism
in children and adolescents? J Nucl Med 20(8): 847-850 (1979).
Friedman, D.L. and L.S. Constine. Late effects of cancer treatment. p. 353-339 in: Pediatric
Radiation Oncology (E. C. Halperin et al., eds.). Lippincott Williams and Wilkins,
Philadelphia, 2010.
Friedman, D.L., J. Whitton, W. Leisenring et al. Subsequent neoplasms in 5-year survivors ofchildhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102(14): 10831095 (2010).
Fritsch, P., K. Moutairou, G. Lataillade et al. Localization of plutonium retention in the small
intestine of the neonatal rat, guinea pig, baboon and macaca after Pu-citrate ingestion. Int J
Radiat Biol 54(4): 537-543 (1988).
Fritsch, P., K. Moutairou and J.D. Harrison. Mechanisms of intestinal absorption of ingested
plutonium in neonatal mammals. Radiat Prot Dosim 41(2-4): 77-82 (1992).
Fromm, M., P. Littman, R.B. Raney et al. Late effects after treatment of twenty children with
soft tissue sarcomas of the head and neck. Experience at a single institution with a review ofthe literature. Cancer 57(10): 2070-2076 (1986).
Fryer, C.J., R.J. Hutchinson, M. Krailo et al. Efficacy and toxicity of 12 courses of ABVD
chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease inchildren: a report from the Children's Cancer Study Group. J Clin Oncol 8(12): 1971-1980(1990).
Fujiwara, S., R.L. Carter, M. Akiyama et al. Autoantibodies and immunoglobulins among
atomic bomb survivors. Radiat Res 137(1): 89-95 (1994).
Fujiwara, S., R. Sposto, M. Shiraki et al. Levels of parathyroid hormone and calcitonin inserum among atomic bomb survivors. Radiat Res 137(1): 96-103 (1994).
Furmanchuk, A.W., N. Roussak and C. Ruchti. Occult thyroid carcinomas in the region of
Minsk, Belarus. An autopsy study of 215 patients. Histopathology 23(4): 319-325 (1993).
Furst, C.J., M. Lundell, L.E. Holm et al. Cancer incidence after radiotherapy for skinhemangioma: a retrospective cohort study in Sweden. J Natl Cancer Inst 80(17): 1387-1392(1988).
Furst, C.J., M. Lundell, S.O. Ahlback et al. Breast hypoplasia following irradiation of thefemale breast in infancy and early childhood. Acta Oncol 28(4): 519-523 (1989).
Furst, C.J., M. Lundell and L.E. Holm. Tumors after radiotherapy for skin hemangioma inchildhood. A case-control study. Acta Oncol 29(5): 557-562 (1990).
Furukawa, K., D.L. Preston, S. Lonn et al. Radiation and smoking effects on lung cancer
incidence among atomic bomb survivors. Radiat Res 174(1): 72-82 (2010).
Furukawa, K., D. Preston, S. Funamoto et al. Long-term trend of thyroid cancer risk among
Japanese atomic-bomb survivors: 60 years after exposure. Int J Cancer 132(5): 1222-1226(2013).
Gabriele, P., R. Orecchia, M. Magnano et al. Vestibular apparatus disorders after externalradiation therapy for head and neck cancers. Radiother Oncol 25(1): 25-30 (1992).
Galanski, M., H.D. Nagel and G. Stamm. Paediatric CT exposure practice in the Federal
Republic of Germany - Results of a nation-wide survey in 2005/2006. Medizinische
Hochschule Hannover, Hannover, 2006.
Galizkaya, N. Evaluation of the immune system of children in zone of heightening radiation.
Zdravookhr Beloruss 6: 33-35 (1990). (Russian).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

G4
G5
G6
G7
G8
G9
G10
G11
G12
G13
G14
G15
G16
G17
G18
G19
G20
G21
G22
G23
G24
G25
G26

233

Gapanovich, V.N., R.F. Iaroshevich, L.P. Shuvaeva et al. Childhood leukemia in Belarus
before and after the Chernobyl accident: continued follow-up. Radiat Environ Biophys 40(4):259-267 (2001).
Garmey, E.G., Q. Liu, C.A. Sklar et al. Longitudinal changes in obesity and body mass index
among adult survivors of childhood acute lymphoblastic leukemia: a report from theChildhood Cancer Survivor Study. J Clin Oncol 26(28): 4639-4645 (2008).
Gelfand, M.J., M.T. Parisi and S.T. Treves. Pediatric radiopharmaceutical administered doses:
2010 North American consensus guidelines. J Nucl Med 52(2): 318-322 (2011).
Gerstner, H.B., R.B. Lewis and E.O. Richey. Early effects of high intensity x-radiation on
skeletal muscle. J Gen Physiol 37(4): 445-459 (1954).
Getaz, E.P., K. Shimaoka and U. Rao. Anaplastic carcinoma of the thyroid following external
irradiation. Cancer 43(6): 2248-2253 (1979).
Gevorgyan, A., G.C. La Scala, P.C. Neligan et al. Radiation-induced craniofacial bone growth
disturbances. J Craniofac Surg 18(5): 1001-1007 (2007).
Gilbert, E.S., D.L. Cragle and L.D. Wiggs. Updated analyses of combined mortality data forworkers at the Hanford Site, Oak Ridge National Laboratory, and Rocky Flats Weapons Plant.
Radiat Res 136(3): 408-421 (1993).
Gilbert, E.S., R. Tarone, A. Bouville et al. Thyroid cancer rates and 131I doses from Nevada
atmospheric nuclear bomb tests. J Natl Cancer Inst 90(21): 1654-1660 (1998).
Gilbert, E.S., M. Stovall, M. Gospodarowicz et al. Lung cancer after treatment for Hodgkin's
disease: focus on radiation effects. Radiat Res 159(2): 161-173 (2003).
Glanzmann, C. Subsequent malignancies in patients treated with 131-iodine for thyroid cancer.
Strahlenther Onkol 168(6): 337-343 (1992).
Glatstein, E., S. McHardy-Young, N. Brast et al. Alterations in serum thyrotropin (TSH) andthyroid function following radiotherapy in patients with malignant lymphoma. J Clin
Endocrinol Metab 32(6): 833-841 (1971).
Gleeson, H.K., K. Darzy and S.M. Shalet. Late endocrine, metabolic and skeletal sequelae
following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab 16(2): 335348 (2002).
Glicksman, A.S., F.C. Chu, H.N. Bane et al. Quantitative and qualitative evaluation of skinerythema. II. Clinical study in patients on a standardized irradiation schedule. Radiology 75:
411-415 (1960).
Goellner, M.H., E.E. Ziegler and S.J. Fomon. Urination during the first three years of life.
Nephron 28(4): 174-178 (1981).
Gogtay, N., J.N. Giedd, L. Lusk et al. Dynamic mapping of human cortical development
during childhood through early adulthood. Proc Natl Acad Sci U S A 101(21): 8174-8179(2004).
Goldsby, R., Y. Chen, S. Raber et al. Survivors of childhood cancer have increased risk ofgastrointestinal complications later in life. Gastroenterology 140(5): 1464-1471 e1461 (2011).
Goodman, J.E., M.A. Nascarella and P.A. Valberg. Ionizing radiation: a risk factor formesothelioma. Cancer Causes Control 20(8): 1237-1254 (2009).
Goolden, A.W., J.R. Mallard and H.E. Farran. Radiation sialitis following radioiodine therapy.
Br J Radiol 30(352): 210-212 (1957).
Gordon, K.B., D.H. Char and R.H. Sagerman. Late effects of radiation on the eye and ocularadnexa. Int J Radiat Oncol Biol Phys 31(5): 1123-1139 (1995).
Gosch, D., K. Gosch and T. Kahn. Conversion coefficients for estimation of effective dose topatients from dose area product during fluoroscopy x-ray examinations. Rofo 179(10): 10351042 (2007). (German).
Gottlober, P., G. Krahn and R.U. Peter. Cutaneous radiation syndrome: clinical features,
diagnosis and therapy. Hautarzt 51(8): 567-574 (2000). (German).
Graham, S., M.L. Levin, A.M. Lilienfeld et al. Preconception, intrauterine, and postnatal
irradiation as related to leukemia. Natl Cancer Inst Monogr 19: 347-371 (1966).
Grant, E.J., K. Ozasa, D.L. Preston et al. Effects of radiation and lifestyle factors on risks ofurothelial carcinoma in the Life Span Study of atomic bomb survivors. Radiat Res 178(1): 8698 (2012).

234

G27
G28
G29
G30
G31
G32
G33
G34
G35
G36
G37
G38
G39
G40
G41
G42
G43
H1
H2
H3
H4

UNSCEAR 2013 REPORTGreen, D.M., M.L. Brecher, D. Yakar et al. Thyroid function in pediatric patients after neckirradiation for Hodgkin disease. Med Pediatr Oncol 8(2): 127-136 (1980).
Green, D.M., Y.A. Grigoriev, B. Nan et al. Congestive heart failure after treatment for Wilms'
tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19(7): 1926-1234(2001).
Green, D.M., E.M. Peabody, B. Nan et al. Pregnancy outcome after treatment for Wilms
tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 20(10): 2506-2513(2002).
Green, D.M., T. Kawashima, M. Stovall et al. Fertility of female survivors of childhood
cancer: a report from the childhood cancer survivor study. J Clin Oncol 27(16): 2677-2685(2009).
Green, D.M., C.A. Sklar, J.D. Boice, Jr. et al. Ovarian failure and reproductive outcomes afterchildhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol
27(14): 2374-2381 (2009).
Green, D.M., T. Kawashima, M. Stovall et al. Fertility of male survivors of childhood cancer:
a report from the Childhood Cancer Survivor Study. J Clin Oncol 28(2): 332-339 (2010).
Green, D.M., J.M. Lange, E.M. Peabody et al. Pregnancy outcome after treatment for Wilms
tumor: a report from the national Wilms tumor long-term follow-up study. J Clin Oncol
28(17): 2824-2830 (2010).
Gregl, A. and J.W. Weiss. Hypoplasia of the breast after roentgen irradiation of hemangiomas
in infancy. Fortschr Geb Rontgenstr Nuklearmed 96: 272-277 (1962). (German).
Grewal, S., T. Merchant, R. Reymond et al. Auditory late effects of childhood cancer therapy:
a report from the Children's Oncology Group. Pediatrics 125(4): e938-e950 (2010).
Grosche, B., D. Lackland, L. Mohr et al. Leukaemia in the vicinity of two tritium-releasing
nuclear facilities: a comparison of the Kruemmel Site, Germany, and the Savannah River Site,
South Carolina, USA. J Radiol Prot 19(3): 243-252 (1999).
Grunwald, H.W. and F. Rosner. Acute myeloid leukemia following treatment of Hodgkin's
disease: a review. Cancer 50(4): 676-683 (1982).
Gunz, F.W. and H. Atkinson. Medical radiations and leukaemia: A retrospective survey. BMJ
1: 389-393 (1964).
Gurney, J.G., N.S. Kadan-Lottick, R.J. Packer et al. Endocrine and cardiovascular late effects
among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer
97(3): 663-673 (2003).
Gurney, J.G., K.K. Ness, M. Stovall et al. Final height and body mass index among adultsurvivors of childhood brain cancer: childhood cancer survivor study. J Clin Endocrinol Metab
88(10): 4731-4739 (2003).
Gurney, J.G., K.K. Ness, J. Rosenthal et al. Visual, auditory, sensory, and motor impairments
in long-term survivors of hematopoietic stem cell transplantation performed in childhood:
results from the Bone Marrow Transplant Survivor study. Cancer 106(6): 1402-1408 (2006).
Gurney, J.G., K.K. Ness, S.D. Sibley et al. Metabolic syndrome and growth hormone
deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 107(6): 13031312 (2006).
Gusev, I.A., A.K. Guskova and F.A. Mettler Jr. Medical Management of Radiation Accidents.
Second edition. p. in: Book Medical Management of Radiation Accidents. Second edition.
CRC Press, New York, 2001.
Haddy, N., A. Mousannif, M. Tukenova et al. Relationship between the brain radiation dose
for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality.
Brain 134(Pt 5): 1362-1372 (2011).
Hagendoorn, J., M.E. Schipper, A. Cloin et al. A patient with tracheoesophageal fistula andesophageal cancer after radiotherapy. Nat Rev Gastroenterol Hepatol 7(12): 702-706 (2010).
Hahn, E.W., S.M. Feingold and L. Nisce. Aspermia and recovery of spermatogenesis in cancer
patients following incidental gonadal irradiation during treatment: a progress report. Radiology
119(1): 223-225 (1976).
Hahn, K., P. Schnell-Inderst, B. Grosche et al. Thyroid cancer after diagnostic administrationof iodine-131 in childhood. Radiat Res 156(1): 61-70 (2001).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

H5
H6
H7
H8
H9
H10
H11
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H13
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H16
H17
H18
H19
H20
H21
H22
H23
H24
H25
H26
H27

235

Hall, P., L.E. Holm, G. Lundell et al. Cancer risks in thyroid cancer patients. Br J Cancer
64(1): 159-163 (1991).
Hall, P., G. Berg, G. Bjelkengren et al. Cancer mortality after iodine-131 therapy for
hyperthyroidism. Int J Cancer 50(6): 886-890 (1992).
Hall, P., A. Mattsson and J.D. Boice, Jr. Thyroid cancer after diagnostic administration ofiodine-131. Radiat Res 145(1): 86-92 (1996).
Hall, P., F. Granath, M. Lundell et al. Lenticular opacities in individuals exposed to ionizing
radiation in infancy. Radiat Res 152(2): 190-195 (1999).
Hall, P., H.O. Adami, D. Trichopoulos et al. Effect of low doses of ionising radiation in
infancy on cognitive function in adulthood: Swedish population based cohort study. BMJ
328(7430): 19 (2004).
Hallquist, A., L. Hardell and P.O. Lofroth. External radiotherapy prior to thyroid cancer: acase-control study. Int J Radiat Oncol Biol Phys 27(5): 1085-1089 (1993).
Halonen, P., J. Mattila, T. Ruuska et al. Liver histology after current intensified therapy forchildhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are themain findings. Med Pediatr Oncol 40(3): 148-154 (2003).
Hamatani, K., H. Eguchi, R. Ito et al. RET/PTC rearrangements preferentially occurred inpapillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. Cancer
Res 68(17): 7176-7182 (2008).
Hamatani, K., M. Mukai, K. Takahashi et al. Rearranged anaplastic lymphoma kinase (ALK)gene in adult-onset papillary thyroid cancer amongst atomic bomb survivors. Thyroid 22(11):1153-1159 (2012).
Hamilton, P.M., R.P. Chiacchierini and R.G. Kaczmarek. A follow-up study of persons who
had iodine-131 and other diagnostic procedures during childhood and adolescence. FDA 898276. U.S. Department of Health and Human Services Publication, National Technical
Information Service, Springfield, 1989.
Hamilton, T.E., G. van Belle and J.P. LoGerfo. Thyroid neoplasia in Marshall Islanders
exposed to nuclear fallout. J Am Med Assoc 258(5): 629-635 (1987).
Hamilton, T.E., M.L. Ritchey, G.M. Haase et al. The management of synchronous bilateralWilms tumor: a report from the National Wilms Tumor Study Group. Ann Surg 253(5): 10041010 (2011).
Hamre, M.R., L.L. Robison, M.E. Nesbit et al. Effects of radiation on ovarian function in
long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens
Cancer Study Group. J Clin Oncol 5(11): 1759-1765 (1987).
Hancock, S.L., R.S. Cox and I.R. McDougall. Thyroid diseases after treatment of Hodgkin's
disease. N Engl J Med 325(9): 599-605 (1991).
Hancock, S.L., S.S. Donaldson and R.T. Hoppe. Cardiac disease following treatment of
Hodgkin's disease in children and adolescents. J Clin Oncol 11(7): 1208-1215 (1993).
Hancock, S.L., M.A. Tucker and R.T. Hoppe. Breast cancer after treatment of Hodgkin's
disease. J Natl Cancer Inst 85(1): 25-31 (1993).
Hancock, S.L., M.A. Tucker and R.T. Hoppe. Factors affecting late mortality from heartdisease after treatment of Hodgkin's disease. J Am Med Assoc 270(16): 1949-1955 (1993).
Hancock, S.L., I.R. McDougall and L.S. Constine. Thyroid abnormalities after therapeutic
external radiation. Int J Radiat Oncol Biol Phys 31(5): 1165-1170 (1995).
Hanford, J.M., E.H. Quimby and V.K. Frantz. Cancer arising many years after radiation
therapy. Incidence after irradiation of benign lesions in the neck. J Am Med Assoc 181(5):404-410 (1962).
Harley, N., R. Albert, R. Shore et al. Follow-up study of patients treated by x-ray epilation fortinea capitis. Estimation of the dose to the thyroid and pituitary glands and other structures of
the head and neck. Phys Med Biol 21(4): 631-642 (1976).
Harley, N. Comparing radon daughter dose: environmental versus underground exposure.
Radiat Prot Dosim 7(1-4): 371-375 (1984).
Hart, D., D.G. Jones and B.F. Wall. Coefficients for estimating effective doses from paediatric
x-ray examinations. NRPB-R279. National Radiological Protection Board, Chilton, 1996.
Hart, D., M.C. Hillier and B.F. Wall. Doses to patients from medical x-ray examinations in the
UK - 2000 review. NRPB-W14. National Radiological Protection Board, Chilton, 2002.

236

H28
H29
H30
H31
H32
H33
H34
H35
H36
H37
H38
H39
H40
H41
H42
H43
H44
H45
H46
H47
H48
H49
H50

UNSCEAR 2013 REPORT

Hatch, M. and M. Susser. Background gamma radiation and childhood cancers within ten
miles of a US nuclear plant. Int J Epidemiol 19(3): 546-552 (1990).
Hatch, M.C., S. Wallenstein, J. Beyea et al. Cancer rates after the Three Mile Island nuclear
accident and proximity of residence to the plant. Am J Public Health 81(6): 719-724 (1991).
Haupt, R., T.R. Fears, L.L. Robison et al. Educational attainment in long-term survivors ofchildhood acute lymphoblastic leukemia. J Am Med Assoc 272(18): 1427-1432 (1994).
Hawkins, M.M., G.J. Draper and J.E. Kingston. Incidence of second primary tumours amongchildhood cancer survivors. Br J Cancer 56(3): 339-347 (1987).
Hawkins, M.M. and R.A. Smith. Pregnancy outcomes in childhood cancer survivors: probableeffects of abdominal irradiation. Int J Cancer 43(3): 399-402 (1989).
Hawkins, M.M., L.M. Wilson, M.A. Stovall et al. Epipodophyllotoxins, alkylating agents, andradiation and risk of secondary leukaemia after childhood cancer. BMJ 304(6832): 951-958(1992).
Hawkins, M.M., L.M. Wilson, H.S. Burton et al. Radiotherapy, alkylating agents, and risk ofbone cancer after childhood cancer. J Natl Cancer Inst 88(5): 270-278 (1996).
Hayashi, T., S. Fujiwara, Y. Morishita et al. HLA haplotype is associated with diabetes among
atomic bomb survivors. Hum Immunol 64(9): 910-916 (2003).
Hayek, A., E.M. Chapman and J.D. Crawford. Long-term results of treatment of thyrotoxicosisin children and adolescents with radioactive iodine. N Engl J Med 283(18): 949-953 (1970).
Heidenreich, W.F., J. Kenigsberg, P. Jacob et al. Time trends of thyroid cancer incidence inBelarus after the Chernobyl accident. Radiat Res 151(5): 617-625 (1999).
Hempelmann, L.H., W.J. Hall, M. Phillips et al. Neoplasms in persons treated with x-rays ininfancy: fourth survey in 20 years. J Natl Cancer Inst 55(3): 519-530 (1975).
Henderson, T.O., A. Amsterdam, S. Bhatia et al. Systematic review: surveillance for breast
cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer.
Ann Intern Med 152(7): 444-455; W144-454 (2010).
Henderson, T.O., K.C. Oeffinger, J. Whitton et al. Secondary gastrointestinal cancer inchildhood cancer survivors: a cohort study. Ann Intern Med 156(11): 757-766, W-260 (2012).
Henderson, T.O., P. Rajaraman, M. Stovall et al. Risk factors associated with secondary
sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Int
J Radiat Oncol Biol Phys 84(1): 224-230 (2012).
Herter, L.D., E. Golendziner, J.A. Flores et al. Ovarian and uterine sonography in healthy girls
between 1 and 13 years old: correlation of findings with age and pubertal status. AJR Am J
Roentgenol 178(6): 1531-1536 (2002).
Hess, J., G.A. Thomas, H. Braselmann et al. Gain of chromosome band 7q11 in papillary
thyroid carcinomas of young patients is associated with exposure to low-dose irradiation. Proc
Natl Acad Sci U S A 108(23): 9595-9600 (2011).
Heyn, R., A. Ragab, R.B. Raney, Jr. et al. Late effects of therapy in orbital rhabdomyosarcoma
in children. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 57(9): 1738-1743(1986).
Higginson, J., C.S. Muir and N. Munoz. Human Cancer: Epidemiology and Environmental
Causes. p. in: Book Human Cancer: Epidemiology and Environmental Causes. Cambridge
University Press, Cambridge, UK, 1992.
Hildreth, N.G., R.E. Shore and L.H. Hempelmann. Risk of breast cancer among women
receiving radiation treatment in infancy for thymic enlargement. Lancet 2(8344): 273 (1983).
Hildreth, N.G., R.E. Shore, L.H. Hempelmann et al. Risk of extrathyroid tumors following
radiation treatment in infancy for thymic enlargement. Radiat Res 102(3): 378-391 (1985).
Hildreth, N.G., R.E. Shore and P.M. Dvoretsky. The risk of breast cancer after irradiation of
the thymus in infancy. N Engl J Med 321(19): 1281-1284 (1989).
Hill, D.A., E. Gilbert, G.M. Dores et al. Breast cancer risk following radiotherapy for Hodgkin
lymphoma: modification by other risk factors. Blood 106(10): 3358-3365 (2005).
Hillebrandt, S., C. Streffer, E.P. Demidchik et al. Polymorphisms in the p53 gene in thyroid
tumours and blood samples of children from areas in Belarus. Mutat Res 381(2): 201-207(1997).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

H51
H52
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H54
H55
H56
H57
H58
H59
H60
H61

H62
H63
H64
H65
H66
H67

H68
H69
H70
H71

237

Hjalmars, U., M. Kulldorff and G. Gustafsson. Risk of acute childhood leukaemia in Sweden
after the Chernobyl reactor accident. Swedish Child Leukaemia Group. BMJ 309(6948): 154157 (1994).
Hodgson, D.C., E.S. Gilbert, G.M. Dores et al. Long-term solid cancer risk among 5-year
survivors of Hodgkin's lymphoma. J Clin Oncol 25(12): 1489-1497 (2007).
Hoffman, D.A., W.M. McConahey, E.L. Diamond et al. Mortality in women treated for
hyperthyroidism. Am J Epidemiol 115(2): 243-254 (1982).
Hoffmeister, P.A., S.R. Hingorani, B.E. Storer et al. Hypertension in long-term survivors ofpediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant 16(4): 515-524(2010).
Hogarty, A.N., A. Leahey, H. Zhao et al. Longitudinal evaluation of cardiopulmonary
performance during exercise after bone marrow transplantation in children. J Pediatr 136(3):311-317 (2000).
Hogeboom, C.J., S.C. Grosser, K.A. Guthrie et al. Stature loss following treatment for Wilms
tumor. Med Pediatr Oncol 36(2): 295-304 (2001).
Holm, L.E., K.E. Wiklund, G.E. Lundell et al. Thyroid cancer after diagnostic doses of iodine131: a retrospective cohort study. J Natl Cancer Inst 80(14): 1132-1138 (1988).
Holm, L.E., K.E. Wiklund, G.E. Lundell et al. Cancer risk in population examined withdiagnostic doses of 131I. J Natl Cancer Inst 81(4): 302-306 (1989).
Holm, L.E., P. Hall, K. Wiklund et al. Cancer risk after iodine-131 therapy for
hyperthyroidism. J Natl Cancer Inst 83(15): 1072-1077 (1991).
Holmberg, E., L.E. Holm, M. Lundell et al. Excess breast cancer risk and the role of parity,
age at first childbirth and exposure to radiation in infancy. Br J Cancer 85(3): 362-366 (2001).
Holtta, P., S. Alaluusua, U.M. Saarinen-Pihkala et al. Long-term adverse effects on dentitionin children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous
stem cell transplantation with or without total body irradiation. Bone Marrow Transplant29(2): 121-127 (2002).
Holtta, P., S. Alaluusua, U.M. Saarinen-Pihkala et al. Agenesis and microdontia of permanent
teeth as late adverse effects after stem cell transplantation in young children. Cancer 103(1):181-190 (2005).
Holtta, P., L. Hovi, U.M. Saarinen-Pihkala et al. Disturbed root development of permanent
teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer
103(7): 1484-1493 (2005).
Homolka, P. and J.H. Billinger. Erhebung von diagnostischen Referenzwerten für pädiatrische
Röntgenuntersuchungen in Österreich. Medizinische Universität Wien, Zentrum fürBiomedizinische Technik und Physik, Wien, 2008. (German).
Howard, B.A. and B.A. Gusterson. Human breast development. J Mammary Gland Biol
Neoplasia 5(2): 119-137 (2000).
Howe, G.R., J.D. Burch, A.M. Chiarelli et al. An exploratory case-control study of brain
tumors in children. Cancer Res 49(15): 4349-4352 (1989).
Howe, G.R. and J. McLaughlin. Breast cancer mortality between 1950 and 1987 after
exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy
cohort study and a comparison with breast cancer mortality in the atomic bomb survivors
study. Radiat Res 145(6): 694-707 (1996).
Hrubec, Z., J.D. Boice, Jr., R.R. Monson et al. Breast cancer after multiple chest fluoroscopies:
second follow-up of Massachusetts women with tuberculosis. Cancer Res 49(1): 229-234(1989).
Hsieh, W.A., I.F. Lin, W.P. Chang et al. Lens opacities in young individuals long after
exposure to protracted low-dose-rate gamma radiation in 60Co-contaminated buildings in
Taiwan. Radiat Res 173(2): 197-204 (2010).
Hsu, W.L., D.L. Preston, M. Soda et al. The incidence of leukemia, lymphoma and multiple
myeloma among atomic bomb survivors: 1950-2001. Radiat Res 179(3): 361-382 (2013).
Hua, C., J.K. Bass, R. Khan et al. Hearing loss after radiotherapy for pediatric brain tumors:effect of cochlear dose. Int J Radiat Oncol Biol Phys 72(3): 892-899 (2008).

238

H72
H73
H74
H75
H76
H77
I1
I2
I3
I4
I5
I6
I7
I8
I9
I10
I11
I12
I13
I14
I15
I16

UNSCEAR 2013 REPORT

Hudson, M.M., C. Greenwald, E. Thompson et al. Efficacy and toxicity of multiagent
chemotherapy and low-dose involved-field radiotherapy in children and adolescents with
Hodgkin's disease. J Clin Oncol 11(1): 100-108 (1993).
Hudson, M.M., C.A. Poquette, J. Lee et al. Increased mortality after successful treatment for
Hodgkin's disease. J Clin Oncol 16(11): 3592-3600 (1998).
Hudson, M.M., K.K. Ness, J.G. Gurney et al. Clinical ascertainment of health outcomesamong adults treated for childhood cancer. J Am Med Assoc 309(22): 2371-2381 (2013).
Huma, Z., F. Boulad, P. Black et al. Growth in children after bone marrow transplantation for
acute leukemia. Blood 86(2): 819-824 (1995).
Hunger, S.P., M.P. Link and S.S. Donaldson. ABVD/MOPP and low-dose involved-fieldradiotherapy in pediatric Hodgkin's disease: the Stanford experience. J Clin Oncol 12(10):2160-2166 (1994).
Huvos, A.G. and H.Q. Woodard. Postradiation sarcomas of bone. Health Phys 55(4): 631-636(1988).
IAEA. The radiological accident in Goiânia. STI/PUB/815. International Atomic Energy
Agency, Vienna, 1988.
IAEA. The International Chernobyl Project: Technical Report. International Atomic Energy
Agency, Vienna, 1991.
IAEA. Accidental overexposure of radiotherapy patients in San Jose, Costa Rica.
STI/PUB/1027. International Atomic Energy Agency, Vienna, 1998.
IAEA. Assessment of doses to the public from ingested radionuclides. Safety Reports SeriesNo. 14. STI/PUB/1067. International Atomic Energy Agency, Vienna, 1999.
IARC. Cancer: causes, occurrence and control. IARC Publication No. 100. (L. Tomatis, ed.).
International Agency for Research on Cancer, Lyon, 1990.
ICRP. Report on the task group on reference man. ICRP Publication 23. International
Commission on Radiological Protection, Pergamon Press, Oxford, 1975.
ICRP. Recommendations of the International Commission on Radiological Protection. ICRP
Publication 26. Annals of the ICRP 1(3). International Commission on RadiologicalProtection, Pergamon Press, Oxford, 1977.
ICRP. Limits for intakes of radionuclides by workers. ICRP Publication 30 (Part 1). Annals of
the ICRP 2(3-4). International Commission on Radiological Protection, Pergamon Press,
Oxford, 1979.
ICRP. Radiation dose to patients from radiopharmaceuticals. ICRP Publication 53. Annals of
the ICRP 18(1-4). International Commission on Radiological Protection, Pergamon Press,
Oxford, 1987.
ICRP. Age-dependent doses to members of the public from intake of radionuclides: Part 1.
ICRP Publication 56. Annals of the ICRP 20(2). International Commission on RadiologicalProtection, Pergamon Press, Oxford, 1990.
ICRP. 1990 Recommendations of the International Commission on Radiological Protection.
ICRP Publication 60. Annals of the ICRP 21(1-3). International Commission on RadiologicalProtection, Pergamon Press, Oxford, 1991.
ICRP. The biological basis for dose limitation in the skin. ICRP Publication 59. Annals of the
ICRP 22(2). International Commission on Radiological Protection, Pergamon Press, Oxford,
1992.
ICRP. Age-dependent doses to members of the public from intake of radionuclides: Part 2.
Ingestion dose coefficients. ICRP Publication 67. Annals of the ICRP 23(3-4). International
Commission on Radiological Protection, Pergamon Press, Oxford, 1993.
ICRP. Human respiratory tract model for radiological protection. ICRP Publication 66. Annalsof the ICRP 24(1-3). International Commission on Radiological Protection, Pergamon Press,
Oxford, 1994.
ICRP. Basic anatomical and physiological data for use in radiological protection: the skeleton.
ICRP Publication 70. Annals of the ICRP 25(2). International Commission on RadiologicalProtection, Pergamon Press, Oxford, 1995.
ICRP. Age-dependent doses to members of the public from intake of radionuclides: Part 4.
Inhalation dose coefficients. ICRP Publication 71. Annals of the ICRP 25(3-4). International
Commission on Radiological Protection, Pergamon Press, Oxford, 1995.

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I17
I18
I19
I20
I21
I22
I23
I24
I25
I26
I27
I28
I29

I30
I31
I32
I33
I34
I35
I36

239

ICRP. Age-dependent doses to members of the public from intake of radionuclides: Part 3.
Ingestion dose coefficients. ICRP Publication 69. Annals of the ICRP 25(1). International
Commission on Radiological Protection, Pergamon Press, Oxford, 1995.
ICRP. Radiological protection and safety in medicine. ICRP Publication 73. Annals of the
ICRP 26(2). International Commission on Radiological Protection, Pergamon Press, Oxford,
1996.
ICRP. Conversion coefficients for use in radiological protection against external radiation.
ICRP Publication 74. Annals of the ICRP 26(3-4). International Commission on RadiologicalProtection, Pergamon Press, Oxford, 1996.
ICRP. Radiation dose to patients from radiopharmaceuticals. Addendum 2 to ICRP
Publication 53. ICRP Publication 80. Annals of the ICRP 28(3). International Commission on
Radiological Protection, Pergamon Press, Oxford, 1998.
ICRP. Risk estimation for multifactorial diseases. ICRP Publication 83. Annals of the ICRP
29(3-4). International Commission on Radiological Protection, Pergamon Press, Oxford, 1999.
ICRP. Basic anatomical and physiological data for use in radiological protection: reference
values. ICRP Publication 89. Annals of the ICRP 32(3-4). International Commission on
Radiological Protection, Pergamon Press, Oxford, 2002.
ICRP. Biological effects after prenatal irradiation (embryo and fetus). ICRP Publication 90.
Annals of the ICRP 33(1-2). International Commission on Radiological Protection, Pergamon
Press, 2003.
ICRP. Human alimentary tract model for radiological protection. ICRP Publication 100.
Annals of the ICRP 36(1-2). International Commission on Radiological Protection, Elsevier
Ltd., 2006.
ICRP. The 2007 Recommendations of the International Commission on RadiologicalProtection. ICRP Publication 103. Annals of the ICRP 37(2-4). International Commission on
Radiological Protection, Elsevier Ltd., 2007.
ICRP. Nuclear decay data for dosimetric calculations. ICRP Publication 107. Annals of the
ICRP 38(3). International Commission on Radiological Protection, Elsevier Ltd., 2008.
ICRP. Radiation dose to patients from radiopharmaceuticals. Addendum 3 to ICRP
Publication 53. ICRP Publication 106. Annals of the ICRP 38(1-2). International Commission
on Radiological Protection, Elsevier Ltd., 2008.
ICRP. Adult reference computational phantoms. ICRP Publication 110. Annals of the ICRP
39(2). International Commission on Radiological Protection, Elsevier Ltd., 2009.
ICRP. ICRP statement on tissue reactions / Early and late effects of radiation in normal tissues
and organs – Threshold doses for tissue reactions in a radiation protection context. ICRP
Publication 118. Annals of the ICRP 41(1-2). International Commission on RadiologicalProtection, Elsevier Ltd., 2012.
ICRP. Compendium of dose cefficients based on ICRP Publication 60. ICRP Publication 119.
Annals of the ICRP 41(Suppl. 1). International Commission on Radiological Protection,
Elsevier Ltd., 2012.
IEC. International Standard. Medical electrical equipment - Part 2-43: Particular requirements
for the basic safety and essential performance of X-ray equipment for interventional
procedures. IEC 60601-2-43. International Electrotechnical Commission, Geneva, 2000.
Iknayan, H.F. Carcinoma associated with irradiation of the immature breast. Radiology 114(2):431-433 (1975).
Il'in, L.A., G.V. Arkhangel'skaya, Y.O. Konstantinov et al. Radioaktivnyi Iod Probleme
Radiatsionnoi Bezopasnosti. p. in: Book Radioaktivnyi Iod Probleme Radiatsionnoi
Bezopasnosti. Atomizdat, Moscow, 1972. (Russian).
Imaizumi, M., T. Usa, T. Tominaga et al. Radiation dose-response relationships for thyroid
nodules and autoimmune thyroid diseases in Hiroshima and Nagasaki atomic bomb survivors
55-58 years after radiation exposure. J Am Med Assoc 295(9): 1011-1022 (2006).
Inati, A., S.E. Sallan, J.R. Cassady et al. Efficacy and morbidity of central nervous system"prophylaxis" in childhood acute lymphoblastic leukemia: eight years' experience with cranial
irradiation and intrathecal methotrexate. Blood 61(2): 297-303 (1983).
Infante-Rivard, C. Diagnostic x rays, DNA repair genes and childhood acute lymphoblastic
leukemia. Health Phys 85(1): 60-64 (2003).

240

I37
I38
I39
I40
I41
I42
I43
I44
I45
I46
I47
I48
I49
J1
J2
J3
J4
J5
J6
J7
J8
J9
J10

UNSCEAR 2013 REPORT

Inoue, S., Y. Shibata and H. Ifirayu. Thyroid diseases among A-bomb survivor in Nagasaki.
RERF TR/12-92. Radiation Effects Research Foundation, Hiroshima, 1992.
Inskip, P.D., R.R. Monson, J.K. Wagoner et al. Cancer mortality following radium treatment
for uterine bleeding. Radiat Res 123(3): 331-344 (1990).
Inskip, P.D., A. Ekbom, M.R. Galanti et al. Medical diagnostic x rays and thyroid cancer. J
Natl Cancer Inst 87(21): 1613-1621 (1995).
Inskip, P.D., L.L. Robison, M. Stovall et al. Radiation dose and breast cancer risk in thechildhood cancer survivor study. J Clin Oncol 27(24): 3901-3907 (2009).
Ito, C., M. Kato, T. Yamamoto et al. Study of stomach cancer in atomic bomb survivors.
Report 1. Histological findings and prognosis. J Radiat Res 30(2): 164-175 (1989).
Ito, M., S. Yamashita, K. Ashizawa et al. Childhood thyroid diseases around Chernobyl
evaluated by ultrasound examination and fine needle aspiration cytology. Thyroid 5(5): 365368 (1995).
Ivanov, V.K., A.F. Tsyb, E.V. Nilova et al. Cancer risks in the Kaluga oblast of the RussianFederation 10 years after the Chernobyl accident. Radiat Environ Biophys 36(3): 161-167(1997).
Ivanov, V.K., A.I. Gorsky, A.F. Tsyb et al. Dynamics of thyroid cancer incidence in Russia
following the Chernobyl accident. J Radiol Prot 19(4): 305-318 (1999).
Ivanov, V.K., A.I. Gorskii, A.F. Tsyb et al. Incidence of post-Chernobyl leukemia and thyroid
cancer in children and adolescents in the Briansk region: evaluation of radiation risks. Vopr
Onkol 49(4): 445-449 (2003). (Russian).
Ivanov, V.K., S.Y. Chekin, V.S. Parshin et al. Non-cancer thyroid diseases among children in
the Kaluga and Bryansk regions of the Russian Federation exposed to radiation following theChernobyl accident. Health Phys 88(1): 16-22 (2005).
Iwanaga, M., W.L. Hsu, M. Soda et al. Risk of myelodysplastic syndromes in people exposed
to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors. J Clin
Oncol 29(4): 428-434 (2011).
Izumi, S., K. Koyama, M. Soda et al. Cancer incidence in children and young adults did notincrease relative to parental exposure to atomic bombs. Br J Cancer 89(9): 1709-1713 (2003).
Izumi, S., A. Suyama and K. Koyama. Radiation-related mortality among offspring of atomic
bomb survivors: a half-century of follow-up. Int J Cancer 107(2): 292-297 (2003).
Jablon, S. and H. Kato. Studies of the mortality of A-bomb survivors. 5. Radiation dose andmortality, 1950-1970. Radiat Res 50(3): 649-698 (1972).
Jablon, S., Z. Hrubec and J.D. Boice, Jr. Cancer in populations living near nuclear facilities.
NIH Publication No. 90-874. National Institutes of Health, Bethesda, MD, 1990.
Jacob, P., G. Goulko, W.F. Heidenreich et al. Thyroid cancer risk to children calculated.
Nature 392(6671): 31-32 (1998).
Jacob, P., Y. Kenigsberg, I. Zvonova et al. Childhood exposure due to the Chernobyl accident
and thyroid cancer risk in contaminated areas of Belarus and Russia. Br J Cancer 80(9): 14611469 (1999).
Jacob, P., T.I. Bogdanova, E. Buglova et al. Thyroid cancer risk in areas of Ukraine andBelarus affected by the Chernobyl accident. Radiat Res 165(1): 1-8 (2006).
Jacobs, A.J., W.M. Maniscalco, A.B. Parkhurst et al. In vivo and in vitro demonstration of
reduced myelin synthesis following early postnatal exposure to ionizing radiation in the rat.
Radiat Res 105(1): 97-104 (1986).
Jacobs, F., H. Thierens, A. Piepsz et al. Optimised tracer-dependent dosage cards to obtainweight-independent effective doses. Eur J Nucl Med Mol Imaging 32(5): 581-588 (2005).
Jaffe, N., H.L. Ried, M. Cohen et al. Radiation induced osteochondroma in long-term
survivors of childhood cancer. Int J Radiat Oncol Biol Phys 9(5): 665-670 (1983).
Jaikrishan, G., K.R. Sudheer, V.J. Andrews et al. Study of stillbirth and major congenital
anomaly among newborns in the high-level natural radiation areas of Kerala, India. J
Community Genet 4(1): 21-31 (2013).
Jakacki, R.I., J.W. Goldwein, R.L. Larsen et al. Cardiac dysfunction following spinal
irradiation during childhood. J Clin Oncol 11(6): 1033-1038 (1993).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

J11
J12
J13
J14
J15
J16
J17
K1
K2
K3
K4
K5
K6
K7
K8
K9
K10
K11
K12
K13
K14
K15
K16

241

Janiszewski, P.M., K.C. Oeffinger, T.S. Church et al. Abdominal obesity, liver fat, and muscle
composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab
92(10): 3816-3821 (2007).
Janjan, N.A. and D.L. Zellmer. Calculated risk of breast cancer following mantle irradiation
determined by measured dose. Cancer Detect Prev 16(5-6): 273-282 (1992).
Janower, M.L. and O.S. Miettinen. Neoplasms after childhood irradiation of the thymus gland.
J Am Med Assoc 215(5): 753-756 (1971).
Jensen, S.B., A.M. Pedersen, A. Vissink et al. A systematic review of salivary gland
hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on
quality of life. Support Care Cancer 18(8): 1039-1060 (2010).
Johnson, D.W. and W.A. Goetz. Patient exposure trends in medical and dental radiography.
Health Phys 50(1): 107-116 (1986).
Johnson, F.L. and F.M. Balis. Hepatopathy following irradiation and chemotherapy for Wilms'
tumor. Am J Pediatr Hematol Oncol 4(2): 217-221 (1982).
Jones, D.P., S.L. Spunt, D. Green et al. Renal late effects in patients treated for cancer inchildhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 51(6): 724-731(2008).
Kaatsch, P., C. Spix, R. Schulze-Rath et al. Leukaemia in young children living in the vicinityof German nuclear power plants. Int J Cancer 122(4): 721-726 (2008).
Kadan-Lottick, N.S., L.K. Zeltzer, Q. Liu et al. Neurocognitive functioning in adult survivorsof childhood non-central nervous system cancers. J Natl Cancer Inst 102(12): 881-893 (2010).
Kaefer, M., D. Zurakowski, S.B. Bauer et al. Estimating normal bladder capacity in children. J
Urol 158(6): 2261-2264 (1997).
Kal, H.B. and M.L. Van Kempen-Harteveld. Induction of severe cataract and late renal
dysfunction following total body irradiation: dose-effect relationships. Anticancer Res 29(8):3305-3309 (2009).
Kaldor, J.M., N.E. Day, E.A. Clarke et al. Leukemia following Hodgkin's disease. N Engl J
Med 322(1): 7-13 (1990).
Kaldor, J.M., N.E. Day, J. Bell et al. Lung cancer following Hodgkin's disease: a case-control
study. Int J Cancer 52(5): 677-681 (1992).
Kaletsch, U., P. Kaatsch, R. Meinert et al. Childhood cancer and residential radon exposure results of a population-based case-control study in Lower Saxony (Germany). Radiat Environ
Biophys 38(3): 211-215 (1999).
Kaplan, E.B., R.A. Wodell, R.W. Wilmott et al. Late effects of bone marrow transplantation
on pulmonary function in children. Bone Marrow Transplant 14(4): 613-621 (1994).
Kaplan, M.M., M.B. Garnick, R. Gelber et al. Risk factors for thyroid abnormalities after neckirradiation for childhood cancer. Am J Med 74(2): 272-280 (1983).
Karagas, M.R., H.H. Nelson, M.S. Zens et al. Squamous cell and basal cell carcinoma of theskin in relation to radiation therapy and potential modification of risk by sun exposure.
Epidemiology 18(6): 776-784 (2007).
Karlsson, P., E. Holmberg, L.M. Lundberg et al. Intracranial tumors after radium treatment forskin hemangioma during infancy--a cohort and case-control study. Radiat Res 148(2): 161-167(1997).
Karlsson, P., E. Holmberg, M. Lundell et al. Intracranial tumors after exposure to ionizing
radiation during infancy: a pooled analysis of two Swedish cohorts of 28,008 infants with skinhemangioma. Radiat Res 150(3): 357-364 (1998).
Karsila-Tenovuo, S., K. Jahnukainen, T. Peltomaki et al. Disturbances in craniofacial
morphology in children treated for solid tumors. Oral Oncol 37(7): 586-592 (2001).
Kasatkina, E.P., D.E. Shilin, A.L. Rosenbloom et al. Effects of low level radiation from the
Chernobyl accident in a population with iodine deficiency. Eur J Pediatr 156(12): 916-920(1997).
Kaste, S.C., G. Chen, J. Fontanesi et al. Orbital development in long-term survivors of
retinoblastoma. J Clin Oncol 15(3): 1183-1189 (1997).
Kaste, S.C., K.P. Hopkins, D. Jones et al. Dental abnormalities in children treated for acutelymphoblastic leukemia. Leukemia 11(6): 792-796 (1997).

242

K17
K18
K19
K20
K21
K22
K23
K24
K25
K26
K27
K28
K29
K30
K31
K32
K33
K34
K35
K36
K37
K38
K39
K40

UNSCEAR 2013 REPORT

Kaste, S.C., K.P. Hopkins, L.C. Bowman et al. Dental abnormalities in children treated forneuroblastoma. Med Pediatr Oncol 30(1): 22-27 (1998).
Kaste, S.C., P. Goodman, W. Leisenring et al. Impact of radiation and chemotherapy on risk ofdental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115(24):5817-5827 (2009).
Katzman, H., T. Waugh and W. Berdon. Skeletal changes following irradiation of childhood
tumors. J Bone Joint Surg Am 51(5): 825-842 (1969).
Kay, H.E., P.J. Knapton, J.P. O'Sullivan et al. Encephalopathy in acute leukaemia associatedwith methotrexate therapy. Arch Dis Child 47(253): 344-354 (1972).
Kazakov, V.S., E.P. Demidchik and L.N. Astakhova. Thyroid cancer after Chernobyl. Nature359(6390): 21 (1992).
Kazlauskaite, R., A.T. Evans, C.V. Villabona et al. Corticotropin tests for hypothalamicpituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 93(11): 4245-4253(2008).
Kendall, G.M. and T.J. Smith. Doses from radon and its decay products to children. J Radiol
Prot 25(3): 241-256 (2005).
Kendall, G.M., M.P. Little, R. Wakeford et al. A record-based case-control study of natural
background radiation and the incidence of childhood leukaemia and other cancers in GreatBritain during 1980-2006. Leukemia 27(1): 3-9 (2013).
Kenney, L.B., Y. Yasui, P.D. Inskip et al. Breast cancer after childhood cancer: a report fromthe Childhood Cancer Survivor Study. Ann Intern Med 141(8): 590-597 (2004).
Kenney, L.B., L.E. Cohen, M. Shnorhavorian et al. Male reproductive health after childhood,adolescent, and young adult cancers: a report from the Children's Oncology Group. J Clin
Oncol 30(27): 3408-3416 (2012).
Kerber, R.A., J.E. Till, S.L. Simon et al. A cohort study of thyroid disease in relation to fallout
from nuclear weapons testing. J Am Med Assoc 270(17): 2076-2082 (1993).
Keus, R.B., E.J. Rutgers, G.H. Ho et al. Limb-sparing therapy of extremity soft tissue
sarcomas: treatment outcome and long-term functional results. Eur J Cancer 30A(10): 14591463 (1994).
Khursheed, A., M.C. Hillier, P.C. Shrimpton et al. Influence of patient age on normalized
effective doses calculated for CT examinations. Br J Radiol 75(898): 819-830 (2002).
Kiehna, E.N., R.K. Mulhern, C. Li et al. Changes in attentional performance of children andyoung adults with localized primary brain tumors after conformal radiation therapy. J Clin
Oncol 24(33): 5283-5290 (2006).
Kim, T.H., C.R. Freeman and J.H. Webster. The significance of unilateral radiation
nephropathy. Int J Radiat Oncol Biol Phys 6(11): 1567-1571 (1980).
Kingma, A., R.I. Van Dommelen, E.L. Mooyaart et al. No major cognitive impairment inyoung children with acute lymphoblastic leukemia using chemotherapy only: a prospective
longitudinal study. J Pediatr Hematol Oncol 24(2): 106-114 (2002).
Kingston, J.E., M.M. Hawkins, G.J. Draper et al. Patterns of multiple primary tumours inpatients treated for cancer during childhood. Br J Cancer 56(3): 331-338 (1987).
Kinsella, T.J., G. Trivette, J. Rowland et al. Long-term follow-up of testicular function
following radiation therapy for early-stage Hodgkin's disease. J Clin Oncol 7(6): 718-724(1989).
Kishikawa, M., K. Koyama, M. Iseki et al. Histologic characteristics of skin cancer in
Hiroshima and Nagasaki: background incidence and radiation effects. Int J Cancer 117(3):363-369 (2005).
Kizer, K.W. Nasopharyngeal radium treatment of veterans. Mil Med 161(3): A3 (1996).
Kline, L.B., J.Y. Kim and R. Ceballos. Radiation optic neuropathy. Ophthalmology 92(8):1118-1126 (1985).
Kline, R.W., M.T. Gillin and L.E. Kun. Cranial irradiation in acute leukemia: dose estimate in
the lens. Int J Radiat Oncol Biol Phys 5(1): 117-121 (1979).
Koike, K., A. Yabuhara, F.C. Yang et al. Frequent natural killer cell abnormality in children in
an area highly contaminated by the Chernobyl accident. Int J Hematol 61(3): 139-145 (1995).
Koike, S., N. Aida, M. Hata et al. Asymptomatic radiation-induced telangiectasia in children
after cranial irradiation: frequency, latency, and dose relation. Radiology 230(1): 93-99 (2004).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

K41
K42
K43
K44
K45
K46
K47
K48
K49
K50
K51
K52
K53
K54
K55
K56
L1
L2
L3
L4
L5
L6
L7

243

Kolar, J., V. Bek and R. Vrabec. Hypoplasia of the growing breast after contact-x-ray therapy
for cutaneous angiomas. Arch Dermatol 96(4): 427-430 (1967).
Kolonel, L.N., J.H. Hankin, L.R. Wilkens et al. An epidemiologic study of thyroid cancer in
Hawaii. Cancer Causes Control 1(3): 223-234 (1990).
Komorowski, R.A., G.A. Hanson and J.C. Garancis. Anaplastic thyroid carcinoma following
low-dose irradiation. Am J Clin Pathol 70(2): 303-307 (1978).
Kopecky, K.J., S. Davis, T.E. Hamilton et al. Estimation of thyroid radiation doses for the
hanford thyroid disease study: results and implications for statistical power of theepidemiological analyses. Health Phys 87(1): 15-32 (2004).
Korcok, M. Taste loss persists after head/neck irradiation. J Am Med Assoc 247(4): 422(1982).
Koshurnikova, N.A., L.Y. Kaigorodova, E.I. Rabinovich et al. Thyroid cancer incidence due totechnogenic exposure in childhood. Health Phys 103(1): 24-27 (2012).
Kossenko, M.M., L.A. Nikolayenko and S.B. Yepifanova. Chronic radiation sickness among
Techa riverside residents. AFRRI Contract Report 98-1. Armed Forces Radiobiology ResearchInstitute, Bethesda, 1998.
Kramer, R., A. Cavalcanti, V.F. Cassola et al. CALDose_X online: Web-based, real time
Monte Carlo calculations for patient dosimetry in X-ray diagnosis. CALDose. 2012.
Kramer, S., M. Southard and C. Mansfield. Radiation effects and tolerance of the central
nervous system. Front Radiat Ther Oncol 6: 332-345 (1972).
Kreisel, D., A.S. Krupnick and C.B. Huddleston. Outcomes and late complications after
pulmonary resections in the pediatric population. Semin Thorac Cardiovasc Surg 16(3): 215219 (2004).
Kreisman, H. and N. Wolkove. Pulmonary toxicity of antineoplastic therapy. Semin Oncol
19(5): 508-520 (1992).
Krestinina, L., D.L. Preston, F.G. Davis et al. Leukemia incidence among people exposed tochronic radiation from the contaminated Techa River, 1953-2005. Radiat Environ Biophys
49(2): 195-201 (2010).
Krewski, D., J.H. Lubin, J.M. Zielinski et al. Residential radon and risk of lung cancer: a
combined analysis of 7 North American case-control studies. Epidemiology 16(2): 137-145(2005).
Kun, L.E. and B.M. Camitta. Hepatopathy following irradiation and adriamycin. Cancer 42(1):81-84 (1978).
Kusunoki, Y., M. Akiyama, S. Kyoizumi et al. Age-related alteration in the composition of
immunocompetent blood cells in atomic bomb survivors. Int J Radiat Biol Relat Stud Phys
Chem Med 53(1): 189-198 (1988).
Kusunoki, Y., T. Hayashi, M. Hakoda et al. Long-term effects of A-bomb radiation on the
immune system: beyond a half century. RERF Update 15(1): 7-18. Radiation Effects Research
Foundation, Hiroshima, 2004.
Land, C.E., Y. Shimosato, G. Saccomanno et al. Radiation-associated lung cancer: acomparison of the histology of lung cancers in uranium miners and survivors of the atomic
bombings of Hiroshima and Nagasaki. Radiat Res 134(2): 234-243 (1993).
Land, C.E., M. Tokunaga, S. Tokuoka et al. Early-onset breast cancer in A-bomb survivors.
Lancet 342(8865): 237 (1993).
Land, C.E., N. Hayakawa, S.G. Machado et al. A case-control interview study of breast cancer
among Japanese A-bomb survivors. II. Interactions with radiation dose. Cancer Causes
Control 5(2): 167-176 (1994).
Land, C.E., T. Saku, Y. Hayashi et al. Incidence of salivary gland tumors among atomic bomb
survivors, 1950-1987. Evaluation of radiation-related risk. Radiat Res 146(1): 28-36 (1996).
Land, C.E., M. Tokunaga, K. Koyama et al. Incidence of female breast cancer among atomic
bomb survivors, Hiroshima and Nagasaki, 1950-1990. Radiat Res 160(6): 707-717 (2003).
Land, C.E., Z. Zhumadilov, B.I. Gusev et al. Ultrasound-detected thyroid nodule prevalence
and radiation dose from fallout. Radiat Res 169(4): 373-383 (2008).
Larsen, P.R., R.A. Conard, K.D. Knudsen et al. Thyroid hypofunction after exposure to fallout
from a hydrogen bomb explosion. J Am Med Assoc 247(11): 1571-1575 (1982).

244

L8
L9
L10
L11

L12
L13
L14
L15
L16
L17
L18
L19
L20
L21
L22
L23
L24
L25
L26
L27
L28
L29
L30

UNSCEAR 2013 REPORT

Laskin, W.B., T.A. Silverman and F.M. Enzinger. Postradiation soft tissue sarcomas. An
analysis of 53 cases. Cancer 62(11): 2330-2340 (1988).
Lassmann, M., L. Biassoni, M. Monsieurs et al. The new EANM paediatric dosage card. Eur J
Nucl Med Mol Imaging 34(5): 796-798 (2007).
Lassmann, M., L. Biassoni, M. Monsieurs et al. The new EANM paediatric dosage card:
additional notes with respect to F-18. Eur J Nucl Med Mol Imaging 35(9): 1666-1668 (2008).
Laughton, S.J., T.E. Merchant, C.A. Sklar et al. Endocrine outcomes for children withembryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiationand high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26(7):1112-1118 (2008).
Laurier, D. and D. Bard. Epidemiologic studies of leukemia among persons under 25 years ofage living near nuclear sites. Epidemiol Rev 21(2): 188-206 (1999).
Laurier, D., C. Rommens, C. Drombry-Ringeard et al. Assessment of the risk of radiationinduced leukaemia in the vicinity of nuclear installations: the Nord-Cotentin radio-ecologicalstudy. Rev Epidemiol Sante Publique 48(Suppl 2): 2S24-36 (2000). (French).
Laurier, D., B. Grosche and P. Hall. Risk of childhood leukaemia in the vicinity of nuclear
installations--findings and recent controversies. Acta Oncol 41(1): 14-24 (2002).
Laurier, D., D. Hemon and J. Clavel. Childhood leukaemia incidence below the age of 5 years
near French nuclear power plants. J Radiol Prot 28(3): 401-403 (2008).
Law, G.R., E.V. Kane, E. Roman et al. Residential radon exposure and adult acute leukaemia.
Lancet 355(9218): 1888 (2000).
Leach, W. Irradiation of the ear. J Laryngol Otol 79(10): 870-880 (1965).
Leggett, R.W. Predicting the retention of Cs in individuals. Health Phys 50(6): 747-759(1986).
Leggett, R.W. A generic age-specific biokinetic model for calcium-like elements. Radiat Prot
Dosim 41(2-4): 183-198 (1992).
Leiper, A.D. Non-endocrine late complications of bone marrow transplantation in childhood:part II. Br J Haematol 118(1): 23-43 (2002).
Lessard, E.T., R.P. Miltenberger, R.A. Conard et al. Thyroid absorbed dose for people at
Rongelap, Utirik, and Sifo on March 1, 1954. BNL-51882. U.S. Department of Energy, 1985.
Leung, W., G. Neale, F. Behm et al. Deficient innate immunity, thymopoiesis, and gene
expression response to radiation in survivors of childhood acute lymphoblastic leukemia.
Cancer Epidemiol 34(3): 303-308 (2010).
Levine, L.A. and J.P. Richie. Urological complications of cyclophosphamide. J Urol 141(5):1063-1069 (1989).
Lichter, M.D., M.R. Karagas, L.A. Mott et al. Therapeutic ionizing radiation and the incidenceof basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study
Group. Arch Dermatol 136(8): 1007-1011 (2000).
Lima, J., V. Trovisco, P. Soares et al. BRAF mutations are not a major event in postChernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 89(9): 4267-4271 (2004).
Lindberg, S., P. Karlsson, B. Arvidsson et al. Cancer incidence after radiotherapy for skinhaemangioma during infancy. Acta Oncol 34(6): 735-740 (1995).
Little, M.P., M.W. Charles, J.W. Hopewell et al. Assessment of skin doses. Doc NRPB 8(3):1-43 (1997).
Little, M.P., F. de Vathaire, A. Shamsaldin et al. Risks of brain tumour following treatment forcancer in childhood: modification by genetic factors, radiotherapy and chemotherapy. Int J
Cancer 78(3): 269-275 (1998).
Little, M.P. Comparison of the risks of cancer incidence and mortality following radiation
therapy for benign and malignant disease with the cancer risks observed in the Japanese Abomb survivors. Int J Radiat Biol 77(4): 431-464 (2001).
Little, M.P. and J.D. Boice, Jr. Analysis of breast cancer in the Massachusetts TB fluoroscopy
cohort and in the Japanese A-bomb survivors, taking account of dosimetric error and curvaturein the A-bomb dose response: absence of evidence of reduction of risk following fractionatedirradiation. Int J Low Radiat 1(1): 88-101 (2003).

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L31
L32
L33
L34
L35
L36
L37
L38
L39
L40
L41
L42
L43
L44
M1
M2
M3
M4
M5
M6

M7
M8

245

Little, M.P., D.T. Goodhead, B.A. Bridges et al. Evidence relevant to untargeted andtransgenerational effects in the offspring of irradiated parents. Mutat Res 753(1): 50-67(2013).
Liu, Y., M.E. Scheurer, R. El-Zein et al. Association and interactions between DNA repair
gene polymorphisms and adult glioma. Cancer Epidemiol Biomarkers Prev 18(1): 204-214(2009).
Lowell, D.M., R.G. Martineau and S.B. Luria. Carcinoma of the male breast following
radiation. Report of a case occurring 35 years after radiation therapy of unilateral prepubertal
gynecomastia. Cancer 22(3): 585-586 (1968).
Lubin, J.H., Y.L. Qiao, P.R. Taylor et al. Quantitative evaluation of the radon and lung cancer
association in a case control study of Chinese tin miners. Cancer Res 50(1): 174-180 (1990).
Lubin, J.H., J.D. Boice, Jr., C. Edling et al. Lung cancer in radon-exposed miners andestimation of risk from indoor exposure. J Natl Cancer Inst 87(11): 817-827 (1995).
Lubin, J.H., M.S. Linet, J.D. Boice, Jr. et al. Case-control study of childhood acutelymphoblastic leukemia and residential radon exposure. J Natl Cancer Inst 90(4): 294-300(1998).
Lubin, J.H., D.W. Schafer, E. Ron et al. A reanalysis of thyroid neoplasms in the Israeli tinea
capitis study accounting for dose uncertainties. Radiat Res 161(3): 359-368 (2004).
Lund, E. and M.R. Galanti. Incidence of thyroid cancer in Scandinavia following fallout fromatomic bomb testing: an analysis of birth cohorts. Cancer Causes Control 10(3): 181-187(1999).
Lundell, M. Estimates of absorbed dose in different organs in children treated with radium forskin hemangiomas. Radiat Res 140(3): 327-333 (1994).
Lundell, M., T. Hakulinen and L.E. Holm. Thyroid cancer after radiotherapy for skinhemangioma in infancy. Radiat Res 140(3): 334-339 (1994).
Lundell, M. and L.E. Holm. Risk of solid tumors after irradiation in infancy. Acta Oncol
34(6): 727-734 (1995).
Lundell, M. and L.E. Holm. Mortality from leukemia after irradiation in infancy for skinhemangioma. Radiat Res 145(5): 595-601 (1996).
Luxton, R.W. and P.B. Kunkler. Radiation nephritis. Acta Radiol Ther Phys Biol 66: 169-178(1964).
Lyon, J.L., S.C. Alder, M.B. Stone et al. Thyroid disease associated with exposure to the
Nevada nuclear weapons test site radiation: a reevaluation based on corrected dosimetry andexamination data. Epidemiology 17(6): 604-614 (2006).
Mabuchi, K. and S. Kusumi. Leukemia. p. 40-44 in: Effects of A-bomb Radiation on the
Human Body (I. Shigematsu, ed.). Harwood Academic Publishers, Tokyo, Japan, 1995.
Machado, S.G., C.E. Land and F.W. McKay. Cancer mortality and radioactive fallout insouthwestern Utah. Am J Epidemiol 125(1): 44-61 (1987).
Mackenzie, I. Breast cancer following multiple fluoroscopies. Br J Cancer 19: 1-8 (1965).
Magelssen, H., K.K. Melve, R. Skjaerven et al. Parenthood probability and pregnancy
outcome in patients with a cancer diagnosis during adolescence and young adulthood. Hum
Reprod 23(1): 178-186 (2008).
Maguire, A., A.W. Craft, R.G. Evans et al. The long-term effects of treatment on the dental
condition of children surviving malignant disease. Cancer 60(10): 2570-2575 (1987).
Marina, N.M., C.A. Greenwald, D.L. Fairclough et al. Serial pulmonary function studies inchildren treated for newly diagnosed Hodgkin's disease with mantle radiotherapy plus cycles
of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin,
bleomycin, vinblastine, and dacarbazine. Cancer 75(7): 1706-1711 (1995).
Marras, T.K., C.K. Chan, J.H. Lipton et al. Long-term pulmonary function abnormalities andsurvival after allogeneic marrow transplantation. Bone Marrow Transplant 33(5): 509-517(2004).
Martinez-Tello, F.J., R. Martinez-Cabruja, J. Fernandez-Martin et al. Occult carcinoma of the
thyroid. A systematic autopsy study from Spain of two series performed with two different
methods. Cancer 71(12): 4022-4029 (1993).

246

M9
M10
M11
M12
M13
M14
M15
M16
M17
M18
M19
M20
M21
M22
M23
M24
M25
M26
M27
M28
M29

UNSCEAR 2013 REPORT

Mathews, J.D., A.V. Forsythe, Z. Brady et al. Cancer risk in 680,000 people exposed tocomputed tomography scans in childhood or adolescence: data linkage study of 11 million
Australians. BMJ 346: f2360 (2013).
Mauch, P., L. Constine, J. Greenberger et al. Hematopoietic stem cell compartment: acute andlate effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 31(5): 13191339 (1995).
Maxon, H.R., E.L. Saenger, S.R. Thomas et al. Clinically important radiation-associatedthyroid disease. A controlled study. J Am Med Assoc 244(16): 1802-1805 (1980).
Mayer, E.I., R.E. Dopfer, T. Klingebiel et al. Longitudinal gonadal function after bone marrowtransplantation for acute lymphoblastic leukemia during childhood. Pediatr Transplant 3(1):38-44 (1999).
Mays, C.W. Skeletal effects following 224Ra injections into humans. Health Phys 35(1): 8390 (1978).
Mazzaferri, E.L. Thyroid cancer and Graves' disease. J Clin Endocrinol Metab 70(4): 826-829(1990).
McDonald, S., P. Rubin and P. Maasilta. Response of normal lung to irradiation. Tolerance
doses/tolerance volumes in pulmonary radiation syndromes. Front Radiat Ther Oncol 23: 255276; discussion 299-301 (1989).
McDonald, S., P. Rubin, T.L. Phillips et al. Injury to the lung from cancer therapy: clinicalsyndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys
31(5): 1187-1203 (1995).
McDougall, J.A., R. Sakata, H. Sugiyama et al. Timing of menarche and first birth in relation
to risk of breast cancer in A-bomb survivors. Cancer Epidemiol Biomarkers Prev 19(7): 17461754 (2010).
McGeoghegan, D. and K. Binks. The mortality and cancer morbidity experience of workers at
the Springfields uranium production facility, 1946-95. J Radiol Prot 20(2): 111-137 (2000).
McHaney, V.A., G. Thibadoux, F.A. Hayes et al. Hearing loss in children receiving cisplatinchemotherapy. J Pediatr 102(2): 314-317 (1983).
McLaughlin, J.R., E.A. Clarke, E.D. Nishri et al. Childhood leukemia in the vicinity ofCanadian nuclear facilities. Cancer Causes Control 4(1): 51-58 (1993).
McTiernan, A.M., N.S. Weiss and J.R. Daling. Incidence of thyroid cancer in women in
relation to previous exposure to radiation therapy and history of thyroid disease. J Natl Cancer
Inst 73(3): 575-581 (1984).
Meacham, L.R., J.G. Gurney, A.C. Mertens et al. Body mass index in long-term adultsurvivors of childhood cancer: a report of the Childhood Cancer Survivor Study. Cancer
103(8): 1730-1739 (2005).
Meadows, A.T., G.J. D'Angio, V. Mike et al. Patterns of second malignant neoplasms inchildren. Cancer 40(4 Suppl): 1903-1911 (1977).
Meadows, A.T., J. Gordon, D.J. Massari et al. Declines in IQ scores and cognitive
dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation.
Lancet 2(8254): 1015-1018 (1981).
Meinert, R., U. Kaletsch, P. Kaatsch et al. Associations between childhood cancer and ionizing
radiation: results of a population-based case-control study in Germany. Cancer Epidemiol
Biomarkers Prev 8(9): 793-799 (1999).
Merchant, T.E., O. Goloubeva, D.L. Pritchard et al. Radiation dose-volume effects on growth
hormone secretion. Int J Radiat Oncol Biol Phys 52(5): 1264-1270 (2002).
Merchant, T.E., L. Nguyen, D. Nguyen et al. Differential attenuation of clavicle growth after
asymmetric mantle radiotherapy. Int J Radiat Oncol Biol Phys 59(2): 556-561 (2004).
Merchant, T.E., C.H. Hua, H. Shukla et al. Proton versus photon radiotherapy for common
pediatric brain tumors: comparison of models of dose characteristics and their relationship to
cognitive function. Pediatr Blood Cancer 51(1): 110-117 (2008).
Merchant, T.E., H.M. Conklin, S. Wu et al. Late effects of conformal radiation therapy forpediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, andhearing deficits. J Clin Oncol 27(22): 3691-3697 (2009).

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M33
M34
M35
M36
M37
M38

M39
M40
M41
M42
M43
M44
M45
M46
M47
M48
M49
M50
M51

247

Merchant, T.E., S.R. Rose, C. Bosley et al. Growth hormone secretion after conformal
radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol 29(36): 47764780 (2011).
Mertens, A.C., Y. Yasui, Y. Liu et al. Pulmonary complications in survivors of childhood andadolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 95(11): 24312441 (2002).
Metayer, C., C.F. Lynch, E.A. Clarke et al. Second cancers among long-term survivors of
Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol 18(12): 2435-2443(2000).
Mettler, F.A. and J.C. Nenot. Accidental radiation injury from industrial radiography sources.
p. 241-258 in: Medical Management of Radiation Accidents (I. A. Gusev et al., eds.). CRC
Press, New York, 2001.
Mettler, F.A., Jr., M.R. Williamson, H.D. Royal et al. Thyroid nodules in the population living
around Chernobyl. J Am Med Assoc 268(5): 616-619 (1992).
Mettler, F.A., Jr. and A.C. Upton. Medical Effects of Ionizing Radiation. p. 517 in: Book
Medical Effects of Ionizing Radiation. Saunders Elsevier, Philadelphia, 2008.
Metzger, M.L., L.R. Meacham, B. Patterson et al. Female reproductive health after childhood,adolescent, and young adult cancers: guidelines for the assessment and management of female
reproductive complications. J Clin Oncol 31(9): 1239-1247 (2013).
Mike, V., A.T. Meadows and G.J. D'Angio. Incidence of second malignant neoplasms inchildren: results of an international study. Lancet 2(8311): 1326-1331 (1982).
Mikryukova, L.D., E.V. Ostroumova, V.F. Ekgardt et al. Ophthalmic disorders amongresidents exposed of the Techa riverside villages (Incidence of visual disturbances amongresidents of the Techa riverside villages). IRPA 11. International Congress of the International
Radiation Protection Association, Madrid, 2004.
Miller, A.B., G.R. Howe, G.J. Sherman et al. Mortality from breast cancer after irradiation
during fluoroscopic examinations in patients being treated for tuberculosis. N Engl J Med
321(19): 1285-1289 (1989).
Miller, T.L., S.R. Lipsitz, G. Lopez-Mitnik et al. Characteristics and determinants of adiposityin pediatric cancer survivors. Cancer Epidemiol Biomarkers Prev 19(8): 2013-2022 (2010).
Minamoto, A., H. Taniguchi, N. Yoshitani et al. Cataract in atomic bomb survivors. Int J
Radiat Biol 80(5): 339-345 (2004).
Mitus, A., M. Tefft and F.X. Fellers. Long-term follow-up of renal functions of 108 children
who underwent nephrectomy for malignant disease. Pediatrics 44(6): 912-921 (1969).
Mizuno, T., S. Tokuoka, M. Kishikawa et al. Molecular basis of basal cell carcinogenesis in
the atomic-bomb survivor population: p53 and PTCH gene alterations. Carcinogenesis 27(11):2286-2294 (2006).
Modan, B., D. Baidatz, H. Mart et al. Radiation-induced head and neck tumours. Lancet
1(7852): 277-279 (1974).
Modan, B., E. Ron and A. Werner. Thyroid cancer following scalp irradiation. Radiology
123(3): 741-744 (1977).
Modan, B., E. Alfandary, D. Shapiro et al. Factors affecting the development of skin cancer
after scalp irradiation. Radiat Res 135(1): 125-128 (1993).
Momani, M.S., E. Shore-Freedman, B.J. Collins et al. Familial concordance of thyroid andother head and neck tumors in an irradiated cohort: analysis of contributing factors. J Clin
Endocrinol Metab 89(5): 2185-2191 (2004).
Moretti, J.A. Sensori-neural hearing loss following radiotherapy to the nasopharynx.
Laryngoscope 86(4): 598-602 (1976).
Mori, T., C. Kido, K. Fukutomi et al. Summary of entire Japanese thorotrast follow-up study:
updated 1998. Radiat Res 152(6 Suppl): S84-87 (1999).
Morimoto, I., Y. Yoshimoto, K. Sato et al. Serum TSH, thyroglobulin, and thyroidal disorders
in atomic bomb survivors exposed in youth: 30-year follow-up study. RERF TR/20-85.
Radiation Effects Research Foundation, Hiroshima, 1985.
Morimoto, I., Y. Yoshimoto, K. Sato et al. Serum TSH, thyroglobulin, and thyroidal disorders
in atomic bomb survivors exposed in youth: 30-year follow-up study. J Nucl Med 28(7): 11151122 (1987).

248

M52
M53
M54
M55
M56
M57
M58
M59
M60
M61
M62
N1
N2
N3
N4
N5
N6
N7
N8
N9
N10
N11

UNSCEAR 2013 REPORT

Morrison, F.S., F. Critz, W.T. Tatum et al. Hodgkin's disease of the esophagus: successfultreatment of a rare complication. Cancer 31(5): 1244-1246 (1973).
Motosue, M.S., L. Zhu, K. Srivastava et al. Pulmonary function after whole lung irradiation inpediatric patients with solid malignancies. Cancer 118(5): 1450-1456 (2012).
Mueller, B.A., E.J. Chow, A. Kamineni et al. Pregnancy outcomes in female childhood andadolescent cancer survivors: a linked cancer-birth registry analysis. Arch Pediatr Adolesc Med
163(10): 879-886 (2009).
Mueller, S., H.J. Fullerton, K. Stratton et al. Radiation, atherosclerotic risk factors, and strokerisk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J
Radiat Oncol Biol Phys 86(4): 649-655 (2013).
Mulder, R.L., L.C. Kremer, H.M. van Santen et al. Prevalence and risk factors of radiationinduced growth hormone deficiency in childhood cancer survivors: a systematic review.
Cancer Treat Rev 35(7): 616-632 (2009).
Mulhern, R.K., J.L. Kepner, P.R. Thomas et al. Neuropsychologic functioning of survivors ofchildhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal
irradiation: a Pediatric Oncology Group study. J Clin Oncol 16(5): 1723-1728 (1998).
Mulrooney, D.A., M.W. Yeazel, T. Kawashima et al. Cardiac outcomes in a cohort of adultsurvivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer
Survivor Study cohort. BMJ 339: b4606 (2009).
Mushkacheva, G., E. Rabinovich, V. Privalov et al. Thyroid abnormalities associated withprotracted childhood exposure to 131I from atmospheric emissions from the Mayak weapons
facility in Russia. Radiat Res 166(5): 715-722 (2006).
Muth, H. and B. Glöbel. Age dependent concentration of 226Ra in human bone and sometransfer factors from diet to human tissues. Health Phys 44(Suppl 1): 113-121 (1983).
Myrden, J. and J. Quinlan. Breast carcinoma following multiple flouroscopies withpneumothorax treatment for pulmonary tuberculosis. Ann R Coll Physicians Surg Canada 7:
45 (1974).
Myrden, J.A. and J.E. Hiltz. Breast cancer following multiple fluoroscopies during artificial
pneumothorax treatment of pulmonary tuberculosis. Can Med Assoc J 100(22): 1032-1034(1969).
Nagataki, S. Delayed effects of atomic bomb radiation on the thyroid. p. 1-10 in: Radiationand the Thyroid (S. Nagataki, ed.). Excerpta Medica, Amsterdam, 1989.
Nagataki, S. Radiation and the Thyroid. Proceedings of the 27th Annual Meeting of theJapanese Nuclear Medicine Society, Nagasaki, Japan, October 1987. Excerpta Medica,
Amsterdam, 1989.
Nagel, H.D. Radiation exposure in computed tomography: fundamentals, influencing
parameters, dose assessment, optimisation, scanner data, terminology. 4th Revised andupdated edition. CTB Publications, Hamburg, 2002.
Nair, R.R., B. Rajan, S. Akiba et al. Background radiation and cancer incidence in Kerala,
India-Karanagappally cohort study. Health Phys 96(1): 55-66 (2009).
Nakashima, E. Relationship of five anthropometric measurements at age 18 to radiation doseamong atomic bomb survivors exposed in utero. Radiat Res 138(1): 121-126 (1994).
Nakashima, E., K. Neriishi and A. Minamoto. A reanalysis of atomic-bomb cataract data,
2000-2002: a threshold analysis. Health Phys 90(2): 154-160 (2006).
Nakatsuka, H., Y. Shimizu, T. Yamamoto et al. Colorectal cancer incidence among atomic
bomb survivors, 1950-80. J Radiat Res (Tokyo) 33(4): 342-361 (1992).
Nandagopal, R., C. Laverdiere, D. Mulrooney et al. Endocrine late effects of childhood cancer
therapy: a report from the Children's Oncology Group. Horm Res 69(2): 65-74 (2008).
Narayan, P., P.H. Lange and E.E. Fraley. Ejaculation and fertility after extended
retroperitoneal lymph node dissection for testicular cancer. J Urol 127(4): 685-688 (1982).
Nathan, P.C., V. Jovcevska, K.K. Ness et al. The prevalence of overweight and obesity inpediatric survivors of cancer. J Pediatr 149(4): 518-525 (2006).
Nathan, P.C., S.K. Patel, K. Dilley et al. Guidelines for identification of, advocacy for, andintervention in neurocognitive problems in survivors of childhood cancer: a report from theChildren's Oncology Group. Arch Pediatr Adolesc Med 161(8): 798-806 (2007).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

N12
N13
N14
N15
N16
N17
N18
N19
N20
N21
N22
N23
N24
N25
N26
N27
N28
N29
N30
N31
N32
N33
N34

249

NCEP. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III) final report. Circulation 106(25): 3143-3421 (2002).
NCI. SEER Cancer Statistics Review, 1975-2007. Based on November 2009 SEER datasubmission. Retrieved from (http://seer.cancer.gov/csr/1975_2007/). Last accessed on (3 Oct.
2011).
NCI. Late effects of treatment for childhood cancer. Retrieved from(http://cancer.gov/cancertopics/pdq/treatment/lateeffects/HealthProfessional). Last accessed on(11 Nov 2011).
NCRP. Protection of the thyroid gland in the event of releases of radioiodine. NCRP Report
No. 55. National Council on Radiation Protection and Measurements, Bethesda, 1977.
NCRP. Evaluation of occupational and environmental exposures to radon and radon daughtersin the United States. NCRP Report No. 78. National Council on Radiation Protection andMeasurements, Bethesda, 1984.
NCRP. Induction of thyroid cancer by ionizing radiation. NCRP Report No. 80. National
Council on Radiation Protection and Measurements, Bethesda, 1985.
NCRP. Risk to the thyroid from ionizing radiation. NCRP Report No. 159. National Council
on Radiation Protection and Measurements, Bethesda, 2008.
NCRP. Second primary cancers and cardiovascular disease after radiation therapy. NCRP
Report No. 170. National Council on Radiation Protection and Measurements, Bethesda, 2011.
NCRP. Preconception and prenatal radiation exposure: Health effects and protective guidance.
NCRP Report No. 174. National Council on Radiation Protection and Measurements, 2013.
Neglia, J.P., A.T. Meadows, L.L. Robison et al. Second neoplasms after acute lymphoblastic
leukemia in childhood. N Engl J Med 325(19): 1330-1336 (1991).
Neglia, J.P., L.L. Robison, M. Stovall et al. New primary neoplasms of the central nervous
system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J
Natl Cancer Inst 98(21): 1528-1537 (2006).
Nelson, D.F., K.V. Reddy, R.E. O'Mara et al. Thyroid abnormalities following neck irradiationfor Hodgkin's disease. Cancer 42(6): 2553-2562 (1978).
Nenadov Beck, M., V. Meresse, O. Hartmann et al. Long-term pulmonary sequelae after
autologous bone marrow transplantation in children without total body irradiation. Bone
Marrow Transplant 16(6): 771-775 (1995).
Neriishi, K., E. Nakashima, A. Minamoto et al. Postoperative cataract cases among atomic
bomb survivors: radiation dose response and threshold. Radiat Res 168(4): 404-408 (2007).
Neriishi, K., E. Nakashima, M. Akahoshi et al. Radiation dose and cataract surgery incidence
in atomic bomb survivors, 1986-2005. Radiology 265(1): 167-174 (2012).
Nesbit, M.E., L.L. Robison and H.N. Sather. Evaluation of long-term survivors of childhood
acute lymphoblastic leukemia (ALL). Abstract. Proc Am Assoc Cancer Res 23: 107 (1982).
Neuhauser, E.B., M.H. Wittenborg, C.Z. Berman et al. Irradiation effects of roentgen therapy
on the growing spine. Radiology 59(5): 637-650 (1952).
Neville, K.A., R.J. Cohn, K.S. Steinbeck et al. Hyperinsulinemia, impaired glucose tolerance,and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin
Endocrinol Metab 91(11): 4401-4407 (2006).
Newton, W.A., Jr., A.T. Meadows, H. Shimada et al. Bone sarcomas as second malignant
neoplasms following childhood cancer. Cancer 67(1): 193-201 (1991).
Nijman, J.M., S. Jager, P.W. Boer et al. The treatment of ejaculation disorders after
retroperitoneal lymph node dissection. Cancer 50(12): 2967-2971 (1982).
Nikiforov, Y.E., M.N. Nikiforova, D.R. Gnepp et al. Prevalence of mutations of ras and p53 inbenign and malignant thyroid tumors from children exposed to radiation after the Chernobyl
nuclear accident. Oncogene 13(4): 687-693 (1996).
Noshchenko, A.G., K.B. Moysich, A. Bondar et al. Patterns of acute leukaemia occurrence
among children in the Chernobyl region. Int J Epidemiol 30(1): 125-129 (2001).
Noshchenko, A.G., P.V. Zamostyan, O.Y. Bondar et al. Radiation-induced leukemia risk
among those aged 0-20 at the time of the Chernobyl accident: a case-control study in the
Ukraine. Int J Cancer 99(4): 609-618 (2002).

250

N35
N36
N37
N38
N39
N40
N41
N42

N43
N44
N45

N46
N47
O1
O2
O3
O4
O5
O6
O7

UNSCEAR 2013 REPORT

Noshchenko, A.G., O.Y. Bondar and V.D. Drozdova. Radiation-induced leukemia amongchildren aged 0-5 years at the time of the Chernobyl accident. Int J Cancer 127(2): 412-426(2010).
Notter, G., R. Walstam and L. Wikholm. Radiation induced cataracts after radium therapy inchildren. A preliminary report. Acta Radiol Diagn (Stockh) 254(Suppl): 87-89 (1966).
NRC. The effects on populations of exposure to low levels of ionizing radiation: 1980
(Committee on the Biological Effects of Ionizing Radiations, BEIR III). National ResearchCouncil, National Academy Press, Washington, D.C., 1980.
NRC. Health effects of exposure to low levels of ionizing radiation (Committee on the
Biological Effects of Ionizing Radiations, BEIR V). National Research Council, National
Academy Press, Washington, D.C., 1990.
NRC. Comparative dosimetry of radon in mines and homes (Panel on Dosimetric Assumptions
Affecting the Application of Radon Risk Estimates). National Research Council, National
Academy Press, Washington, D.C., 1991.
NRC. Risk assessment of radon in drinking water (Committee on Risk Assessment ofExposure to Radon in Drinking Water). National Research Council, National Academy Press,
Washington, D.C., 1999.
NRC. Health effects of exposure to radon (Committee on Health Risks of Exposure to Radon,
BEIR VI). National Research Council, National Academy Press, Washington, D.C., 1999.
NRC. Assessment of the scientific information for the radiation exposure screening andeducation program (Committee to Assess the Scientific Information for the Radiation
Exposure Screening and Education Program). National Research Council, National Academies
Press, Washington, D.C., 2005.
NRC. Health risks from exposure to low levels of ionizing radiation (Committee to Assess
Health Risks from Exposure to Low Levels of Ionizing Radiation, BEIR VII - Phase 2).
National Research Council, National Academy Press, Washington D.C., 2006.
NRPB. Reference doses and patient size in paediatric radiology. NRPB- R318. National
Radiological Protection Board, Didcot, 2000.
Nygaard, R., S. Garwicz, T. Haldorsen et al. Second malignant neoplasms in patients treatedfor childhood leukemia. A population-based cohort study from the Nordic countries. The
Nordic Society of Pediatric Oncology and Hematology (NOPHO). Acta Paediatr Scand
80(12): 1220-1228 (1991).
Nysom, K., K. Holm, B. Hesse et al. Lung function after allogeneic bone marrowtransplantation for leukaemia or lymphoma. Arch Dis Child 74(5): 432-436 (1996).
Nysom, K., K. Holm, K.F. Michaelsen et al. Degree of fatness after allogeneic BMT forchildhood leukaemia or lymphoma. Bone Marrow Transplant 27(8): 817-820 (2001).
O'Brien, M.M., S.S. Donaldson, R.R. Balise et al. Second malignant neoplasms in survivors ofpediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin
Oncol 28(7): 1232-1239 (2010).
O'Sullivan, E.A., M.S. Duggal and C.C. Bailey. Changes in the oral health of children during
treatment for acute lymphoblastic leukaemia. Int J Paediatr Dent 4(1): 31-34 (1994).
Oberfield, S.E., D. Chin, N. Uli et al. Endocrine late effects of childhood cancers. J Pediatr
131(1 Pt 2): S37-S41 (1997).
Oberlin, O., A. Rey, J. Anderson et al. Treatment of orbital rhabdomyosarcoma: survival andlate effects of treatment--results of an international workshop. J Clin Oncol 19(1): 197-204(2001).
Ochs, J., R. Mulhern, D. Fairclough et al. Comparison of neuropsychologic functioning andclinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranialradiation or parenteral methotrexate: a prospective study. J Clin Oncol 9(1): 145-151 (1991).
OECD. Gastrointestinal absorption of selected radionuclides. A report by an NEA Expert
Group. Organisation for Economic Co-operation and Development, Nuclear Energy Agency,
Paris, 1988.
Oeffinger, K.C., G.R. Buchanan, D.A. Eshelman et al. Cardiovascular risk factors in young
adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 23(7):424-430 (2001).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

O8
O9
O10
O11
O12
O13
O14
O15
O16
O17
O18
O19
O20
O21
O22
O23
O24
O25
P1
P2
P3
P4

251

Oeffinger, K.C., A.C. Mertens, C.A. Sklar et al. Obesity in adult survivors of childhood acutelymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol
21(7): 1359-1365 (2003).
Oeffinger, K.C., A.C. Mertens, C.A. Sklar et al. Chronic health conditions in adult survivors ofchildhood cancer. N Engl J Med 355(15): 1572-1582 (2006).
Oeffinger, K.C. Are survivors of acute lymphoblastic leukemia (ALL) at increased risk ofcardiovascular disease? Pediatr Blood Cancer 50(2 Suppl): 462-468 (2008).
Oeffinger, K.C., B. Adams-Huet, R.G. Victor et al. Insulin resistance and risk factors for
cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J
Clin Oncol 27(22): 3698-3704 (2009).
Ogilvy-Stuart, A.L., D.J. Clark, W.H. Wallace et al. Endocrine deficit after fractionated total
body irradiation. Arch Dis Child 67(9): 1107-1110 (1992).
Oliveira, A.R., C.E. Brandao-Mello, N.J. Valverde et al. Localized lesions induced by 137Cs
during the Goiania accident. Health Phys 60(1): 25-29 (1991).
Omran, A.R., R.E. Shore, R.A. Markoff et al. Follow-up study of patients treated by X-ray
epilation for tinea capitis: psychiatric and psychometric evaluation. Am J Public Health 68(6):561-567 (1978).
Orine, S., R. Chambers and R. Johnson. Post-radiation carcinoma of male breast bilaterally. J
Am Med Assoc 201: 707 (1967).
Orzan, F., A. Brusca, F. Gaita et al. Associated cardiac lesions in patients with radiationinduced complete heart block. Int J Cardiol 39(2): 151-156 (1993).
Osechinsky, I. and A. Martirosov Haematological diseases in the Belarus Republic after the
Chernobyl accident. International Conference on Health Consequences of the Chernobyl andother Radiological Accidents. World Health Organization, Geneva, 1995.
Ostroumova, E., D.L. Preston, E. Ron et al. Breast cancer incidence following low-dose rateenvironmental exposure: Techa River Cohort, 1956-2004. Br J Cancer 99(11): 1940-1945(2008).
Ostroumova, E., A. Rozhko, M. Hatch et al. Measures of thyroid function among Belarusianchildren and adolescents exposed to iodine-131 from the accident at the chernobyl nuclear
plant. Environ Health Perspect 121(7): 865-871 (2013).
Otake, M. and W.J. Schull. Radiation-related posterior lenticular opacities in Hiroshima andNagasaki atomic bomb survivors based on the DS86 dosimetry system. Radiat Res 121(1): 313 (1990).
Otake, M., S.C. Finch, K. Choshi et al. Radiation-related ophthalmological changes and aging
among Hiroshima and Nagasaki A-bomb survivors: a reanalysis. Radiat Res 131(3): 315-324(1992).
Otake, M., Y. Fujikoshi, W.J. Schull et al. A longitudinal study of growth and development of
stature among prenatally exposed atomic bomb survivors. Radiat Res 134(1): 94-101 (1993).
Otake, M. and W.J. Schull. Radiation-related brain damage and growth retardation among theprenatally exposed atomic bomb survivors. Int J Radiat Biol 74(2): 159-171 (1998).
Oudin, C., M.C. Simeoni, N. Sirvent et al. Prevalence and risk factors of the metabolic
syndrome in adult survivors of childhood leukemia. Blood 117(17): 4442-4448 (2011).
Ozasa, K., Y. Shimizu, A. Suyama et al. Studies of the mortality of atomic bomb survivors,
Report 14, 1950-2003: An overview of cancer and noncancer diseases. Radiat Res 177(3):229-243 (2012).
Pacini, F., T. Vorontsova, E. Molinaro et al. Prevalence of thyroid autoantibodies in children
and adolescents from Belarus exposed to the Chernobyl radioactive fallout. Lancet 352(9130):763-766 (1998).
Packer, R.J., A.T. Meadows, L.B. Rorke et al. Long-term sequelae of cancer treatment on thecentral nervous system in childhood. Med Pediatr Oncol 15(5): 241-253 (1987).
Packer, R.J., J. Goldwein, H.S. Nicholson et al. Treatment of children with medulloblastomas
with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's
Cancer Group Study. J Clin Oncol 17(7): 2127-2136 (1999).
Padovani, L., N. Andre, L.S. Constine et al. Neurocognitive function after radiotherapy for
paediatric brain tumours. Nat Rev Neurol 8(10): 578-588 (2012).

252

P5
P6
P7
P8
P9
P10
P11
P12
P13
P14
P15
P16
P17
P18
P19
P20
P21
P22
P23
P24
P25
P26
P27

UNSCEAR 2013 REPORT

Palmer, S.L., O. Goloubeva, W.E. Reddick et al. Patterns of intellectual development among
survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol 19(8): 2302-2308(2001).
Paloyan, E., A.M. Lawrence, M.H. Brooks et al. Total thyroidectomy and parathyroid
autotransplantation for radiation-associated thyroid cancer. Surgery 80(1): 70-76 (1976).
Pan, C.C., B.D. Kavanagh, L.A. Dawson et al. Radiation-associated liver injury. Int J Radiat
Oncol Biol Phys 76(3 Suppl): S94-S100 (2010).
Parker, L.N., J.L. Belsky, T. Yamamoto et al. Thyroid carcinoma after exposure to atomic
radiation. A continuing survey of a fixed population, Hiroshima and Nagasaki, 1958-1971.
Ann Intern Med 80(5): 600-604 (1974).
Parker, R.G. Tolerance of mature bone and cartilage in clinical radiation therapy. p. 312-331
in: Frontiers of Radiation Therapy and Oncology (J. M. Vaeth, ed.). Karger, Basel andUniversity Park Press, Baltimore, 1972.
Parkin, D.M., E. Cardis, E. Masuyer et al. Childhood leukaemia following the Chernobyl
accident: the European Childhood Leukaemia-Lymphoma Incidence Study (ECLIS). Eur J
Cancer 29A(1): 87-95 (1992).
Parkin, D.M., D. Clayton, R.J. Black et al. Childhood leukaemia in Europe after Chernobyl: 5
year follow-up. Br J Cancer 73(8): 1006-1012 (1996).
Parsons, J.T., F.J. Bova, W.M. Mendenhall et al. Response of the normal eye to high doseradiotherapy. Oncology (Williston Park) 10(6): 837-847; discussion 847-848, 851-852 (1996).
Patterson, B.C., L. Truxillo, K. Wasilewski-Masker et al. Adrenal function testing in pediatriccancer survivors. Pediatr Blood Cancer 53(7): 1302-1307 (2009).
Paulino, A.C. Role of radiation therapy in parameningeal rhabdomyosarcoma. Cancer Invest
17(3): 223-230 (1999).
Paulino, A.C., J.H. Simon, W. Zhen et al. Long-term effects in children treated withradiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 48(5): 14891495 (2000).
Paulino, A.C., B.C. Wen, C.K. Brown et al. Late effects in children treated with radiation
therapy for Wilms' tumor. Int J Radiat Oncol Biol Phys 46(5): 1239-1246 (2000).
Paulino, A.C. Hypothyroidism in children with medulloblastoma: a comparison of 3600 and2340 cGy craniospinal radiotherapy. Int J Radiat Oncol Biol Phys 53(3): 543-547 (2002).
Paulino, A.C. Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol
Biol Phys 60(1): 265-274 (2004).
Paulino, A.C., L.S. Constine, P. Rubin et al. Normal tissue development, homeostasis,senescence, and the sensitivity to radiation injury across the age spectrum. Semin Radiat Oncol
20(1): 12-20 (2010).
Paulino, A.C., M. Lobo, B.S. Teh et al. Ototoxicity after intensity-modulated radiation therapy
and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol
Phys 78(5): 1445-1450 (2010).
Pawel, D., D. Preston, D. Pierce et al. Improved estimates of cancer site-specific risks for Abomb survivors. Radiat Res 169(1): 87-98 (2008).
Pearce, M.S., J.A. Salotti, M.P. Little et al. Radiation exposure from CT scans in childhoodand subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet
380(9840): 499-505 (2012).
Pedrick, T.J. and R.T. Hoppe. Recovery of spermatogenesis following pelvic irradiation for
Hodgkin's disease. Int J Radiat Oncol Biol Phys 12(1): 117-121 (1986).
Perkel, V.S., M.H. Gail, J. Lubin et al. Radiation-induced thyroid neoplasms: evidence forfamilial susceptibility factors. J Clin Endocrinol Metab 66(6): 1316-1322 (1988).
Perkins, J.L., Y. Liu, P.A. Mitby et al. Nonmelanoma skin cancer in survivors of childhood
and adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol 23(16):3733-3741 (2005).
Peter, R.U. Cutaneous radiation syndrome in multi-organ failure. Br J Radiol 27(Suppl): 180184 (2005).
Petoussi-Henss, N., H. Schlattl, M. Zankl et al. Organ doses from environmental exposurescalculated using voxel phantoms of adults and children. Phys Med Biol 57(18): 5679-5713(2012).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

P28
P29
P30
P31
P32
P33
P34
P35
P36
P37
P38
P39
P40
P41
P42
P43
P44
P45
P46
P47
P48
P49
P50
P51

253

Petoussi, N., P. Jacob, M. Zankl et al. Organ doses for foetuses, babies, children and adults
from environmental gamma rays. Radiat Prot Dosim 37(1): 31-41 (1991).
Peylan-Ramu, N., D.G. Poplack, C.L. Blei et al. Computer assisted tomography inmethotrexate encephalopathy. J Comput Assist Tomogr 1(2): 216-221 (1977).
Peylan-Ramu, N., A. Bin-Nun, M. Skleir-Levy et al. Orbital growth retardation in
retinoblastoma survivors: work in progress. Med Pediatr Oncol 37(5): 465-470 (2001).
Phipps, S., S.N. Rai, W.H. Leung et al. Cognitive and academic consequences of stem-celltransplantation in children. J Clin Oncol 26(12): 2027-2033 (2008).
Piepsz, A., K. Hahn, I. Roca et al. A radiopharmaceuticals schedule for imaging in paediatrics.
Paediatric Task Group European Association Nuclear Medicine. Eur J Nucl Med 17(3-4): 127129 (1990).
Pierce, D.A., Y. Shimizu, D.L. Preston et al. Studies of the mortality of atomic bomb
survivors. Report 12, Part I. Cancer: 1950-1990. Radiat Res 146(1): 1-27 (1996).
Pietila, S., A. Makipernaa, H. Sievanen et al. Obesity and metabolic changes are common inyoung childhood brain tumor survivors. Pediatr Blood Cancer 52(7): 853-859 (2009).
Pifer, J.W., L.H. Hempelmann, H.J. Dodge et al. Neoplasms in the Ann Arbor series ofthymus-irradiated children; a second survey. Am J Roentgenol Radium Ther Nucl Med 103(1):13-18 (1968).
Pirker-Fruhauf, U.M., J. Friesenbichler, E.C. Urban et al. Osteoporosis in children and young
adults: a late effect after chemotherapy for bone sarcoma. Clin Orthop Relat Res 470(10):2874-2885 (2012).
Polliack, A. Late therapy-induced cardiac and pulmonary complications in cured patients with
Hodgkin's disease treated with conventional combination chemo-radiotherapy. Leuk
Lymphoma 15(Suppl 1): 7-10 (1995).
Posner, M.R., E. Reinherz, H. Lane et al. Circulating lymphocyte populations in Hodgkin's
disease after mantle and paraaortic irradiation. Blood 61(4): 705-708 (1983).
Potter, J.D., M.L. Slattery, R.M. Bostick et al. Colon cancer: a review of the epidemiology.
Epidemiol Rev 15(2): 499-545 (1993).
Pottern, L.M., M.M. Kaplan, P.R. Larsen et al. Thyroid nodularity after childhood irradiation
for lymphoid hyperplasia: a comparison of questionnaire and clinical findings. J Clin
Epidemiol 43(5): 449-460 (1990).
Preissig, S.H., G.L. Bohmfalk, G.W. Reichel et al. Anaplastic astrocytoma following radiation
for a glomus jugular tumor. Cancer 43(6): 2243-2247 (1979).
Preston-Martin, S., A. Paganini-Hill, B.E. Henderson et al. Case-control study of intracranial
meningiomas in women in Los Angeles County, California. J Natl Cancer Inst 65(1): 67-73(1980).
Preston-Martin, S., B.E. Henderson and L. Bernstein. Medical and dental x rays as risk factors
for recently diagnosed tumors of the head. Natl Cancer Inst Monogr 69: 175-179 (1985).
Preston-Martin, S., L. Bernstein, M.C. Pike et al. Thyroid cancer among young women related
to prior thyroid disease and pregnancy history. Br J Cancer 55(2): 191-195 (1987).
Preston-Martin, S., W. Mack and B.E. Henderson. Risk factors for gliomas and meningiomas
in males in Los Angeles County. Cancer Res 49(21): 6137-6143 (1989).
Preston-Martin, S. and S.C. White. Brain and salivary gland tumors related to prior dental
radiography: implications for current practice. J Am Dent Assoc 120(2): 151-158 (1990).
Preston, D.L., S. Kusumi, M. Tomonaga et al. Cancer incidence in atomic bomb survivors.
Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res 137(2 Suppl):
S68-97 (1994).
Preston, D.L., A. Mattsson, E. Holmberg et al. Radiation effects on breast cancer risk: a pooled
analysis of eight cohorts. Radiat Res 158(2): 220-235 (2002).
Preston, D.L., E. Ron, S. Yonehara et al. Tumors of the nervous system and pituitary glandassociated with atomic bomb radiation exposure. J Natl Cancer Inst 94(20): 1555-1563 (2002).
Preston, D.L., Y. Shimizu, D.A. Pierce et al. Studies of mortality of atomic bomb survivors.
Report 13: Solid cancer and noncancer disease mortality: 1950-1997. Radiat Res 160(4): 381407 (2003).
Preston, D.L., D.A. Pierce, Y. Shimizu et al. Effect of recent changes in atomic bomb survivor
dosimetry on cancer mortality risk estimates. Radiat Res 162(4): 377-389 (2004).

254

P52
P53
P54
P55
P56
P57
P58
P59
P60
P61
P62
Q1
R1
R2
R3
R4
R5
R6
R7
R8

R9
R10

UNSCEAR 2013 REPORT

Preston, D.L., E. Ron, S. Tokuoka et al. Solid cancer incidence in atomic bomb survivors:
1958-1998. Radiat Res 168(1): 1-64 (2007).
Price, D.B., G.C. Hotson and J.P. Loh. Pontine calcification following radiotherapy: CT
demonstration. J Comput Assist Tomogr 12(1): 45-46 (1988).
Prindull, G., W. Weigel, E. Jentsch et al. Aseptic osteonecrosis in children treated for acutelymphoblastic leukemia and aplastic anemia. Eur J Pediatr 139(1): 48-51 (1982).
Prisyazhiuk, A., O.A. Pjatak, V.A. Buzanov et al. Cancer in the Ukraine, post-Chernobyl.
Lancet 338(8778): 1334-1335 (1991).
Prisyazhniuk, A., V. Gristchenko, V. Zakordonets et al. The time trends of cancer incidence inthe most contaminated regions of the Ukraine before and after the Chernobyl accident. Radiat
Environ Biophys 34(1): 3-6 (1995).
Pritchard, J., M.R. Sandland, F.B. Breatnach et al. The effects of radiation therapy for
Hodgkin's disease in a child with ataxia telangiectasia: a clinical, biological and pathologic
study. Cancer 50(5): 877-886 (1982).
Probert, J.C. and B.R. Parker. The effects of radiation therapy on bone growth. Radiology
114(1): 155-162 (1975).
Proctor, S.J., J. Kernaham and P. Taylor. Depression as component of post-cranial irradiation
somnolence syndrome. Lancet 1(8231): 1215-1216 (1981).
Prysyazhnyuk, A., V. Gristchenko, Z. Fedorenko et al. Twenty years after the Chernobyl
accident: solid cancer incidence in various groups of the Ukrainian population. Radiat Environ
Biophys 46(1): 43-51 (2007).
Pryzant, R.M., M.L. Meistrich, G. Wilson et al. Long-term reduction in sperm count after
chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. J Clin Oncol
11(2): 239-247 (1993).
Pukkala, E., A. Kesminiene, S. Poliakov et al. Breast cancer in Belarus and Ukraine after the
Chernobyl accident. Int J Cancer 119(3): 651-658 (2006).
Qvist, C.F. and B. Zachau-Christiansen. Radiation cataract following fractionated radium
therapy in childhood. Acta Radiol 51(3): 207-216 (1959).
Raaijmakers, E. and A.M. Engelen. Is sensorineural hearing loss a possible side effect ofnasopharyngeal and parotid irradiation? A systematic review of the literature. Radiother Oncol
65(1): 1-7 (2002).
Raaschou-Nielsen, O., C.E. Andersen, H.P. Andersen et al. Domestic radon and childhood
cancer in Denmark. Epidemiology 19(4): 536-543 (2008).
Rajaraman, P., J. Simpson, G. Neta et al. Early life exposure to diagnostic radiation andultrasound scans and risk of childhood cancer: case-control study. BMJ 342: d472 (2011).
Rallison, M.L., B.M. Dobyns, F.R. Keating et al. Thyroid disease in children. A survey ofsubjects potentially exposed to fallout radiation. Am J Med 56(4): 457-463 (1974).
Rallison, M.L., B.M. Dobyns, A.W. Meikle et al. Natural history of thyroid abnormalities:
prevalence, incidence, and regression of thyroid diseases in adolescents and young adults. Am
J Med 91(4): 363-370 (1991).
Ramachandran, E.N., C.V. Karuppasamy, V.D. Cheriyan et al. Cytogenetic studies on
newborns from high and normal level natural radiation areas of Kerala in southwest coast ofIndia. Int J Radiat Biol 89(4): 259-267 (2013).
Raney, B., Jr., R. Heyn, D.M. Hays et al. Sequelae of treatment in 109 patients followed for 5
to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup
Rhabdomyosarcoma Study Committee. Cancer 71(7): 2387-2394 (1993).
Raney, R.B., L. Asmar, R. Vassilopoulou-Sellin et al. Late complications of therapy in 213
children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive
report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of theChildren's Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol 33(4): 362371 (1999).
Raney, R.B., J.R. Anderson, J. Kollath et al. Late effects of therapy in 94 patients withlocalized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma
Study (IRS)-III, 1984-1991. Med Pediatr Oncol 34(6): 413-420 (2000).
Raventos, A. and T. Winship. The latent interval for thyroid cancer following irradiation.
Radiology 83: 501-508 (1964).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

R11
R12
R13
R14
R15
R16
R17
R18
R19
R20
R21
R22
R23
R24
R25
R26
R27
R28
R29
R30
R31
R32
R33

255

Razzouk, B.I., S.R. Rose, S. Hongeng et al. Obesity in survivors of childhood acutelymphoblastic leukemia and lymphoma. J Clin Oncol 25(10): 1183-1189 (2007).
Recklitis, C., T. O'Leary and L. Diller. Utility of routine psychological screening in thechildhood cancer survivor clinic. J Clin Oncol 21(5): 787-792 (2003).
Reddick, W.E., H.A. White, J.O. Glass et al. Developmental model relating white mattervolume to neurocognitive deficits in pediatric brain tumor survivors. Cancer 97(10): 25122519 (2003).
Reddick, W.E., Z.Y. Shan, J.O. Glass et al. Smaller white-matter volumes are associated withlarger deficits in attention and learning among long-term survivors of acute lymphoblastic
leukemia. Cancer 106(4): 941-949 (2006).
Refetoff, S., J. Harrison, B.T. Karanfilski et al. Continuing occurrence of thyroid carcinoma
after irradiation to the neck in infancy and childhood. N Engl J Med 292(4): 171-175 (1975).
Reimers, T.S., S. Ehrenfels, E.L. Mortensen et al. Cognitive deficits in long-term survivors ofchildhood brain tumors: Identification of predictive factors. Med Pediatr Oncol 40(1): 26-34(2003).
Reulen, R.C., M.P. Zeegers, W.H. Wallace et al. Pregnancy outcomes among adult survivorsof childhood cancer in the British Childhood Cancer Survivor Study. Cancer Epidemiol
Biomarkers Prev 18(8): 2239-2247 (2009).
Reulen, R.C., D.L. Winter, C. Frobisher et al. Long-term cause-specific mortality among
survivors of childhood cancer. J Am Med Assoc 304(2): 172-179 (2010).
Reulen, R.C., C. Frobisher, D.L. Winter et al. Long-term risks of subsequent primary
neoplasms among survivors of childhood cancer. J Am Med Assoc 305(22): 2311-2319(2011).
Richardson, D., H. Sugiyama, N. Nishi et al. Ionizing radiation and leukemia mortality among
Japanese Atomic Bomb Survivors, 1950-2000. Radiat Res 172(3): 368-382 (2009).
Richardson, D.B. and S. Wing. Lung cancer mortality among workers at a nuclear materials
fabrication plant. Am J Ind Med 49(2): 102-111 (2006).
Rider, W.D. Radiation damage to the brain--a new syndrome. J Can Assoc Radiol 14: 67-69(1963).
Ris, M.D., R. Packer, J. Goldwein et al. Intellectual outcome after reduced-dose radiation
therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J
Clin Oncol 19(15): 3470-3476 (2001).
Ritchey, M., F. Ferrer, P. Shearer et al. Late effects on the urinary bladder in patients treatedfor cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer
52(4): 439-446 (2009).
Ritchey, M.L., D.M. Green, P.R. Thomas et al. Renal failure in Wilms' tumor patients: a reportfrom the National Wilms' Tumor Study Group. Med Pediatr Oncol 26(2): 75-80 (1996).
Riva, D., C. Giorgi, F. Nichelli et al. Intrathecal methotrexate affects cognitive function inchildren with medulloblastoma. Neurology 59(1): 48-53 (2002).
Robbins, J., J.E. Rall and R.A. Conard. Late effects of radioactive iodine in fallout. Combinedclinical staff conference at the National Institutes of Health. Ann Intern Med 66(6): 1214-1242(1967).
Robbins, J. Thyroid Suppression Therapy for Prevention of Thyroid Tumors After Radiation
Exposure. p. in: Book Thyroid Suppression Therapy for Prevention of Thyroid Tumors After
Radiation Exposure. Academic Press, New York, 1977.
Robbins, J. and W.H. Adams. Radiation effects in the Marshall Islands. p. 11-24 in: Radiationand the Thyroid (S. Nagataki, ed.). Excerpta Medica, Amsterdam, 1989.
Robbins, J., M.J. Merino, J.D. Boice, Jr. et al. Thyroid cancer: a lethal endocrine neoplasm.
Ann Intern Med 115(2): 133-147 (1991).
Robinson, K.E., J.F. Kuttesch, J.E. Champion et al. A quantitative meta-analysis ofneurocognitive sequelae in survivors of pediatric brain tumors. Pediatr Blood Cancer 55(3):525-531 (2010).
Ron, E. and B. Modan. Thyroid. p. in: Book Thyroid. W.B. Saunders, Philadelphia, 1982.
Ron, E. and B. Modan. Leukemia, Thyroid Cancer and CNS Tumors Following Childhood
Scalp Irradiation: Israel Tinea Study. p. in: Book Leukemia, Thyroid Cancer and CNS Tumors
Following Childhood Scalp Irradiation: Israel Tinea Study. Raven Press, New York, 1982.

256

R34
R35
R36
R37
R38
R39
R40
R41
R42
R43
R44

R45
R46
R47
R48
R49

R50
R51
R52
R53
R54
R55
R56

UNSCEAR 2013 REPORT

Ron, E., B. Modan, S. Floro et al. Mental function following scalp irradiation duringchildhood. Am J Epidemiol 116(1): 149-160 (1982).
Ron, E. and B. Modan. Thyroid and other neoplasms following childhood scalp irradiation. p.
139-151 in: Radiation Carcinogenesis: Epidemiology and Biological Significance (J. D. BoiceJr. et al., eds.). Raven Press, New York, 1984.
Ron, E., R.A. Kleinerman, J.D. Boice, Jr. et al. A population-based case-control study ofthyroid cancer. J Natl Cancer Inst 79(1): 1-12 (1987).
Ron, E., B. Modan and J.D. Boice, Jr. Mortality after radiotherapy for ringworm of the scalp.
Am J Epidemiol 127(4): 713-725 (1988).
Ron, E., B. Modan, J.D. Boice, Jr. et al. Tumors of the brain and nervous system afterradiotherapy in childhood. N Engl J Med 319(16): 1033-1039 (1988).
Ron, E., B. Modan, D. Preston et al. Thyroid neoplasia following low-dose radiation inchildhood. Radiat Res 120(3): 516-531 (1989).
Ron, E., B. Modan, D. Preston et al. Radiation-induced skin carcinomas of the head and neck.
Radiat Res 125(3): 318-325 (1991).
Ron, E., J. Lubin and A.B. Schneider. Thyroid cancer incidence. Nature 360(6400): 113(1992).
Ron, E., D.L. Preston, K. Mabuchi et al. Cancer incidence in atomic bomb survivors. Part IV:
Comparison of cancer incidence and mortality. Radiat Res 137(2 Suppl): S98-112 (1994).
Ron, E., J.H. Lubin, R.E. Shore et al. Thyroid cancer after exposure to external radiation: apooled analysis of seven studies. Radiat Res 141(3): 259-277 (1995).
Ron, E. Cancer risk following radioactive iodine-131 exposures in medicine. p. 65-77 in:
Implications of New Data on Radiation Cancer Risk (NCRP Proceedings, Annual meeting,1996) (J. D. Boice Jr., ed.). National Council on Radiation Protection and Measurements,
Bethesda, MD, 1997.
Ron, E., M.M. Doody, D.V. Becker et al. Cancer mortality following treatment for adulthyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group. J Am Med
Assoc 280(4): 347-355 (1998).
Ron, E., T. Ikeda, D.L. Preston et al. Male breast cancer incidence among atomic bomb
survivors. J Natl Cancer Inst 97(8): 603-605 (2005).
Ronckers, C.M., C.E. Land, R.B. Hayes et al. Late health effects of childhood nasopharyngeal
radium irradiation: nonmelanoma skin cancers, benign tumors, and hormonal disorders.
Pediatr Res 52(6): 850-858 (2002).
Ronckers, C.M., F.E. Van Leeuwen, R.B. Hayes et al. Cancer incidence after nasopharyngeal
radium irradiation. Epidemiology 13(5): 552-560 (2002).
Ronckers, C.M., P.G. Verduijn, C.E. Land et al. [No convincing evidence for a causal
relationship between childhood nasopharyngeal radium irradiation and head-neck tumors or
hormone-related disorders later in life; a retrospective cohort study]. Ned Tijdschr Geneeskd
148(36): 1775-1780 (2004). (Dutch).
Ronckers, C.M., M.M. Doody, J.E. Lonstein et al. Multiple diagnostic X-rays for spine
deformities and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 17(3): 605-613(2008).
Rose, S.R., R.H. Lustig, P. Pitukcheewanont et al. Diagnosis of hidden central hypothyroidismin survivors of childhood cancer. J Clin Endocrinol Metab 84(12): 4472-4479 (1999).
Rose, S.R. Cranial irradiation and central hypothyroidism. Trends Endocrinol Metab 12(3):97-104 (2001).
Rose, S.R., R.K. Danish, N.S. Kearney et al. ACTH deficiency in childhood cancer survivors.
Pediatr Blood Cancer 45(6): 808-813 (2005).
Rosenberg, S.A. and H.S. Kaplan. The evolution and summary results of the Stanford
randomized clinical trials of the management of Hodgkin's disease: 1962-1984. Int J Radiat
Oncol Biol Phys 11(1): 5-22 (1985).
Rosner, F., R.W. Carey and M.H. Zarrabi. Breast cancer and acute leukemia: report of 24
cases and review of the literature. Am J Hematol 4(2): 151-172 (1978).
Rubin, P. and G. Casarett. Chapter 3. Skin and adnexa. p. 62-119 in: Clinical Radiation
Pathology. Saunders, Philadelphia, 1966.

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

R57
R58
R59
R60
R61
R62
R63
R64
R65
R66
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S2
S3
S4
S5
S6
S7
S8
S9
S10
S11
S12
S13
S14

257

Rubin, P. and G.W. Casarett. Clinical Radiation Pathology. p. in: Book Clinical Radiation
Pathology. Saunders, Philadelphia, 1966.
Rubin, P. and G.W. Casarett. A direction for clinical radiation pathology. The tolerance dose.
p. 1-16 in: Frontiers of Radiation Therapy and Oncology (J. M. Vaeth, ed.). Karger, Basel andUniversity Park Press, Baltimore, 1972.
Rubin, P., P. Van Houtte and L. Constine. Radiation sensitivity and organ tolerances inpediatric oncology: a new hypothesis. Front Radiat Ther Oncol 16: 62-82 (1981).
Rubin, P. The Franz Buschke lecture: late effects of chemotherapy and radiation therapy: a
new hypothesis. Int J Radiat Oncol Biol Phys 10(1): 5-34 (1984).
Rubin, P., L.S. Constine, L.F. Fajardo et al. RTOG Late Effects Working Group. Overview.
Late Effects of Normal Tissues (LENT) scoring system. Int J Radiat Oncol Biol Phys 31(5):1041-1042 (1995).
Rubino, C., F. de Vathaire, M.E. Dottorini et al. Second primary malignancies in thyroid
cancer patients. Br J Cancer 89(9): 1638-1644 (2003).
Rubino, C., E. Adjadj, F. Doyon et al. Radiation exposure and familial aggregation of cancers
as risk factors for colorectal cancer after radioiodine treatment for thyroid carcinoma. Int J
Radiat Oncol Biol Phys 62(4): 1084-1089 (2005).
Rubinstein, L.J., M.M. Herman, T.F. Long et al. Disseminated necrotizing
leukoencephalopathy: a complication of treated central nervous system leukemia andlymphoma. Cancer 35(2): 291-305 (1975).
Ryan, P., M.W. Lee, B. North et al. Risk factors for tumors of the brain and meninges: resultsfrom the Adelaide Adult Brain Tumor Study. Int J Cancer 51(1): 20-27 (1992).
Ryberg, M., M. Lundell, B. Nilsson et al. Malignant disease after radiation treatment of benign
gynaecological disorders. A study of a cohort of metropathia patients. Acta Oncol 29(5): 563567 (1990).
Sadamori, N., M. Mine and M. Hori. Skin cancer among atom bomb survivors. Lancet
1(8649): 1267 (1989).
Sadamori, N., M. Mine, M. Hori et al. Incidence of skin cancer among Nagasaki atomic bomb
survivors (preliminary report). J Radiat Res 31(3): 280-287 (1990).
Sadamori, N., M. Mine and T. Honda. Incidence of skin cancer among Nagasaki atomic bomb
survivors. J Radiat Res 32(Suppl 2): 217-225 (1991).
Sadamori, N., M. Otake and T. Honda. Study of skin cancer incidence in Nagasaki atomic
bomb survivors, 1958-1985. Radiation Effects Research Foundation, Hiroshima, 1991.
Sadetzki, S., A. Chetrit, L. Freedman et al. Long-term follow-up for brain tumor development
after childhood exposure to ionizing radiation for tinea capitis. Radiat Res 163(4): 424-432(2005).
Sadetzki, S., P. Flint-Richter, S. Starinsky et al. Genotyping of patients with sporadic andradiation-associated meningiomas. Cancer Epidemiol Biomarkers Prev 14(4): 969-976 (2005).
Sadetzki, S., A. Chetrit, A. Lubina et al. Risk of thyroid cancer after childhood exposure toionizing radiation for tinea capitis. J Clin Endocrinol Metab 91(12): 4798-4804 (2006).
Saenger, E.L., F.N. Silverman, T.D. Sterling et al. Neoplasia following therapeutic irradiation
for benign conditions in childhood. Radiology 74(6): 889-904 (1960).
Sagerman, R.H., J.R. Cassady, P. Tretter et al. Radiation induced neoplasia following externalbeam therapy for children with retinoblastoma. Am J Roentgenol Radium Ther Nucl Med
105(3): 529-535 (1969).
Saku, T., Y. Hayashi, O. Takahara et al. Salivary gland tumors among atomic bomb survivors,
1950-1987. Cancer 79(8): 1465-1475 (1997).
Salvati, M., M. Artico, R. Caruso et al. A report on radiation-induced gliomas. Cancer 67(2):392-397 (1991).
Samartzis, D., N. Nishi, M. Hayashi et al. Exposure to ionizing radiation and development ofbone sarcoma: new insights based on atomic-bomb survivors of Hiroshima and Nagasaki. J
Bone Joint Surg Am 93(11): 1008-1015 (2011).
Samartzis, D., N. Nishi, J. Cologne et al. Ionizing radiation exposure and the development ofsoft-tissue sarcomas in atomic-bomb survivors. J Bone Joint Surg Am 95(3): 222-229 (2013).
Sampson, R.J., C.R. Key, C.R. Buncher et al. Thyroid carcinoma in Hiroshima and Nagasaki.
I. Prevalence of thyroid carcinoma at autopsy. J Am Med Assoc 209(1): 65-70 (1969).

258

S15
S16
S17
S18
S19
S20
S21

S22
S23
S24
S25
S26
S27

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S29
S30
S31
S32
S33
S34
S35
S36

UNSCEAR 2013 REPORT

Sanders, J.E., C.D. Buckner, J.M. Leonard et al. Late effects on gonadal function of
cyclophosphamide, total-body irradiation, and marrow transplantation. Transplantation 36(3):252-255 (1983).
Sanders, J.E., C.D. Buckner, D. Amos et al. Ovarian function following marrowtransplantation for aplastic anemia or leukemia. J Clin Oncol 6(5): 813-818 (1988).
Sanders, J.E. The impact of marrow transplant preparative regimens on subsequent growth anddevelopment. The Seattle Marrow Transplant Team. Semin Hematol 28(3): 244-249 (1991).
Sanders, J.E., J. Hawley, W. Levy et al. Pregnancies following high-dose cyclophosphamide
with or without high-dose busulfan or total-body irradiation and bone marrow transplantation.
Blood 87(7): 3045-3052 (1996).
Sanders, J.E., P.A. Hoffmeister, A.E. Woolfrey et al. Thyroid function following
hematopoietic cell transplantation in children: 30 years' experience. Blood 113(2): 306-308(2009).
Sandler, D.P., G.W. Comstock and G.M. Matanoski. Neoplasms following childhood radium
irradiation of the nasopharynx. J Natl Cancer Inst 68(1): 3-8 (1982).
Sankila, R., S. Garwicz, J.H. Olsen et al. Risk of subsequent malignant neoplasms among
1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based
cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and theNordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14(5): 1442-1446 (1996).
Sankila, R., J.H. Olsen, H. Anderson et al. Risk of cancer among offspring of childhoodcancer survivors. Association of the Nordic Cancer Registries and the Nordic Society ofPaediatric Haematology and Oncology. N Engl J Med 338(19): 1339-1344 (1998).
Santoro, M., G.A. Thomas, G. Vecchio et al. Gene rearrangement and Chernobyl related
thyroid cancers. Br J Cancer 82(2): 315-322 (2000).
Satran, L., C. Sklar, L. Dehner et al. Thyroid neoplasm after high-dose radiotherapy. Am J
Pediatr Hematol Oncol 5(3): 307-309 (1983).
Saxena, K.M., E.M. Chapman and C.V. Pryles. Minimal dosage of iodide required to suppress
uptake of iodine-131 by normal thyroid. Science 138(3538): 430-431 (1962).
Schafer, D.W., J.H. Lubin, E. Ron et al. Thyroid cancer following scalp irradiation: areanalysis accounting for uncertainty in dosimetry. Biometrics 57(3): 689-697 (2001).
Schellong, G., M. Riepenhausen, C. Bruch et al. Late valvular and other cardiac diseases after
different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents:
report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD
studies. Pediatr Blood Cancer 55(6): 1145-1152 (2010).
Scherer, E., C. Streffer, K.-R. Trott et al. Radiopathology of Organs and Tissues. p. in: Book
Radiopathology of Organs and Tissues. Springer Berlin, 1991.
Schimke, R.N., J.T. Lowman and A.B. Cowan. Retinoblastoma and osteogenic sarcoma in
siblings. Cancer 34(6): 2077-2079 (1974).
Schlegel, P.N. and P.C. Walsh. Neuroanatomical approach to radical cystoprostatectomy withpreservation of sexual function. J Urol 138(6): 1402-1406 (1987).
Schneider, A.B., M.J. Favus, M.E. Stachura et al. Incidence, prevalence and characteristics ofradiation-induced thyroid tumors. Am J Med 64(2): 243-252 (1978).
Schneider, A.B., E. Shore-Freedman, U.Y. Ryo et al. Radiation-induced tumors of the headand neck following childhood irradiation. Prospective studies. Medicine (Baltimore) 64(1): 115 (1985).
Schneider, A.B., E. Ron, J. Lubin et al. Dose-response relationships for radiation-induced
thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the
thyroid. J Clin Endocrinol Metab 77(2): 362-369 (1993).
Schneider, A.B., J. Lubin, E. Ron et al. Salivary gland tumors after childhood radiation
treatment for benign conditions of the head and neck: dose-response relationships. Radiat Res
149(6): 625-630 (1998).
Schriock, E.A., M.J. Schell, M. Carter et al. Abnormal growth patterns and adult short staturein 115 long-term survivors of childhood leukemia. J Clin Oncol 9(3): 400-405 (1991).
Schubauer-Berigan, M.K., R.D. Daniels and L.E. Pinkerton. Radon exposure and mortality
among white and American Indian uranium miners: an update of the Colorado Plateau cohort.
Am J Epidemiol 169(6): 718-730 (2009).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

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S40
S41
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S45
S46
S47
S48
S49
S50
S51
S52
S53
S54
S55
S56
S57
S58

259

Schultheiss, T.E., L.E. Kun, K.K. Ang et al. Radiation response of the central nervous system.
Int J Radiat Oncol Biol Phys 31(5): 1093-1112 (1995).
Schultz-Hector, S. Heart. p. 347-368 in: Radiopathology of Organs and Tissues (E. Scherer etal., eds.). Springer Verlag, Berlin, 1991.
Schultz, K.A., K.K. Ness, J. Whitton et al. Behavioral and social outcomes in adolescentsurvivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol
25(24): 3649-3656 (2007).
Schultz, K.R., G.J. Green, D. Wensley et al. Obstructive lung disease in children after
allogeneic bone marrow transplantation. Blood 84(9): 3212-3220 (1994).
Schulz, R.J. and R.E. Albert. Follow-up study of patients treated by x-ray epilation for tinea
capitis. 3. Dose to organs of the head from the x-ray treatment of tinea capitis. Arch Environ
Health 17(6): 935-950 (1968).
Schumacher, R. and H. Allmendinger. Optimization of pulsed fluoroscopy in pediatricradiology using voiding cystourethrography as an example. MedicaMundi 52(2): 18-24(2008).
Schwartz, C.L., W.L. Hobbie, L.S. Constine et al. Survivors of Childhood Cancer: Assessment
and Management. p. in: Book Survivors of Childhood Cancer: Assessment and Management.
Mosby-Year Book Inc., St. Louis, Mosby, 1994.
Schwartz, C.L., W.L. Hobbie, L.S. Constine et al. Survivors of Childhood and Adolescent
Cancer. p. in: Book Survivors of Childhood and Adolescent Cancer. Springer, St.Louis,
Missouri, 2005.
Scott, J.E. Pubertal development in children treated for nephroblastoma. J Pediatr Surg 16(2):122-125 (1981).
Sgouros, G., K.S. Kolbert, A. Sheikh et al. Patient-specific dosimetry for 131I thyroid cancer
therapy using 124I PET and 3-dimensional-internal dosimetry (3D-ID) software. J Nucl Med
45(8): 1366-1372 (2004).
Shah, A.J., K. Epport, C. Azen et al. Progressive declines in neurocognitive function among
survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies. J
Pediatr Hematol Oncol 30(6): 411-418 (2008).
Shakhtarin, V.V., A.F. Tsyb, V.F. Stepanenko et al. Iodine deficiency, radiation dose, and therisk of thyroid cancer among children and adolescents in the Bryansk region of Russia
following the Chernobyl power station accident. Int J Epidemiol 32(4): 584-591 (2003).
Shalet, S.M., C.G. Beardwell, H.S. Jacobs et al. Testicular function following irradiation of thehuman prepubertal testis. Clin Endocrinol (Oxf) 9(6): 483-490 (1978).
Shalet, S.M., E.C. Crowne, M.A. Didi et al. Irradiation-induced growth failure. Baillieres Clin
Endocrinol Metab 6(3): 513-526 (1992).
Shalet, S.M. Endocrine sequelae of cancer therapy. Eur J Endocrinol 135(2): 135-143 (1996).
Shalitin, S., M. Phillip, J. Stein et al. Endocrine dysfunction and parameters of the metabolic
syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow
Transplant 37(12): 1109-1117 (2006).
Sharp, G.B., T. Mizuno, J.B. Cologne et al. Hepatocellular carcinoma among atomic bomb
survivors: significant interaction of radiation with hepatitis C virus infections. Int J Cancer
103(4): 531-537 (2003).
Sheline, G.E., W.M. Wara and V. Smith. Therapeutic irradiation and brain injury. Int J Radiat
Oncol Biol Phys 6(9): 1215-1228 (1980).
Shimizu, Y., H. Kato and W.J. Schull. Studies of the mortality of A-bomb survivors. 9.
Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86).
Radiat Res 121(2): 120-141 (1990).
Shimizu, Y., W.J. Schull and H. Kato. Cancer risk among atomic bomb survivors. The RERF
Life Span Study. Radiation Effects Research Foundation. J Am Med Assoc 264(5): 601-604(1990).
Shimizu, Y., K. Kodama, N. Nishi et al. Radiation exposure and circulatory disease risk:
Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003. BMJ 340: b5349 (2010).
Shirahige, Y., M. Ito, K. Ashizawa et al. Childhood thyroid cancer: comparison of Japan andBelarus. Endocr J 45(2): 203-209 (1998).

260

S59
S60
S61
S62
S63
S64
S65
S66
S67
S68
S69
S70
S71
S72
S73
S74
S75
S76
S77
S78
S79
S80
S81

UNSCEAR 2013 REPORT

Shore-Freedman, E., C. Abrahams, W. Recant et al. Neurilemomas and salivary gland tumorsof the head and neck following childhood irradiation. Cancer 51(12): 2159-2163 (1983).
Shore, R.E., R.E. Albert and B.S. Pasternack. Follow-up study of patients treated by X-ray
epilation for Tinea capitis; resurvey of post-treatment illness and mortality experience. Arch
Environ Health 31(1): 21-28 (1976).
Shore, R.E., E.D. Woodard, L.H. Hempelmann et al. Synergism between radiation and otherrisk factors for breast cancer. Prev Med 9(6): 815-822 (1980).
Shore, R.E., R.E. Albert, M. Reed et al. Skin cancer incidence among children irradiated for
ringworm of the scalp. Radiat Res 100(1): 192-204 (1984).
Shore, R.E., E. Woodard, N. Hildreth et al. Thyroid tumors following thymus irradiation. J
Natl Cancer Inst 74(6): 1177-1184 (1985).
Shore, R.E., N. Hildreth, E. Woodard et al. Breast cancer among women given X-ray therapy
for acute postpartum mastitis. J Natl Cancer Inst 77(3): 689-696 (1986).
Shore, R.E. Issues and epidemiological evidence regarding radiation-induced thyroid cancer.
Radiat Res 131(1): 98-111 (1992).
Shore, R.E., N. Hildreth, P. Dvoretsky et al. Thyroid cancer among persons given X-ray
treatment in infancy for an enlarged thymus gland. Am J Epidemiol 137(10): 1068-1080(1993).
Shore, R.E., N. Hildreth, P. Dvoretsky et al. Benign thyroid adenomas among persons Xirradiated in infancy for enlarged thymus glands. Radiat Res 134(2): 217-223 (1993).
Shore, R.E. and B.V. Worgul. Overview of the epidemiology of radiation cataracts. p. 183-189
in: Ocular Radiation Risk Assessment in Populations Exposed to Environmental Radiation
Contamination (A. K. Junk, eds.). Kluwer Academic Publishers, Netherlands, 1999.
Shore, R.E. and X. Xue. Comparative thyroid cancer risk of childhood and adult radiation
exposure and estimation of lifetime risk. p. 491-498 in: Radiation and Thyroid Cancer (G.
Thomas, eds.). World Scientific Publishing, Singapore, 1999.
Shore, R.E., M. Moseson, X. Xue et al. Skin cancer after X-ray treatment for scalp ringworm.
Radiat Res 157(4): 410-418 (2002).
Shore, R.E., M. Moseson, N. Harley et al. Tumors and other diseases following childhood xray treatment for ringworm of the scalp (Tinea capitis). Health Phys 85(4): 404-408 (2003).
Shore, R.E., K. Neriishi and E. Nakashima. Epidemiological studies of cataract risk at low tomoderate radiation doses: (not) seeing is believing. Radiat Res 174(6): 889-894 (2010).
Shrimpton, P.C., M.C. Hillier, M.A. Lewis et al. National survey of doses from CT in the UK:
2003. Br J Radiol 79(948): 968-980 (2006).
Shu, X.O., J.D. Potter, M.S. Linet et al. Diagnostic X-rays and ultrasound exposure and risk ofchildhood acute lymphoblastic leukemia by immunophenotype. Cancer Epidemiol Biomarkers
Prev 11(2): 177-185 (2002).
Signorello, L.B., S.S. Cohen, C. Bosetti et al. Female survivors of childhood cancer: preterm
birth and low birth weight among their children. J Natl Cancer Inst 98(20): 1453-1461 (2006).
Signorello, L.B., J.J. Mulvihill, D.M. Green et al. Stillbirth and neonatal death in relation toradiation exposure before conception: a retrospective cohort study. Lancet 376(9741): 624-630(2010).
Signorello, L.B., J.J. Mulvihill, D.M. Green et al. Congenital anomalies in the children ofcancer survivors: a report from the childhood cancer survivor study. J Clin Oncol 30(3): 239245 (2012).
Silber, J.H., J. Radcliffe, V. Peckham et al. Whole-brain irradiation and decline in intelligence:
the influence of dose and age on IQ score. J Clin Oncol 10(9): 1390-1396 (1992).
Silverman, C.L., P.R. Thomas, W.H. McAlister et al. Slipped femoral capital epiphyses in
irradiated children: dose, volume and age relationships. Int J Radiat Oncol Biol Phys 7(10):1357-1363 (1981).
Simon, S.L. Soil ingestion by humans: a review of history, data, and etiology with application
to risk assessment of radioactively contaminated soil. Health Phys 74(6): 647-672 (1998).
Simpson, C.L., L.H. Hempelmann and L.M. Fuller. Neoplasia in children treated with X-rays
in infancy for thymic enlargement. Radiology 64(6): 840-845 (1955).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

S82
S83
S84
S85
S86
S87
S88
S89
S90
S91
S92
S93
S94
S95
S96
S97
S98
S99
S100
S101
S102
S103

261

Sklar, C., A. Mertens, A. Walter et al. Final height after treatment for childhood acutelymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigraysof cranial irradiation. J Pediatr 123(1): 59-64 (1993).
Sklar, C., J. Whitton, A. Mertens et al. Abnormalities of the thyroid in survivors of Hodgkin's
disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85(9):3227-3232 (2000).
Sklar, C.A., L.L. Robison, M.E. Nesbit et al. Effects of radiation on testicular function in longterm survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer
Study Group. J Clin Oncol 8(12): 1981-1987 (1990).
Sklar, C.A. Growth and neuroendocrine dysfunction following therapy for childhood cancer.
Pediatr Clin North Am 44(2): 489-503 (1997).
Sklar, C.A. Overview of the effects of cancer therapies: the nature, scale and breadth of the
problem. Acta Paediatr 88(Suppl s433): 1-4 (1999).
Sklar, C.A., A.C. Mertens, P. Mitby et al. Premature menopause in survivors of childhood
cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 98(13): 890-896(2006).
Smith, G.R., P.R. Thomas, M. Ritchey et al. Long-term renal function in patients with
irradiated bilateral Wilms tumor. National Wilms' Tumor Study Group. Am J Clin Oncol
21(1): 58-63 (1998).
Smith, L.M., R.S. Cox and S.S. Donaldson. Second cancers in long-term survivors of Ewing's
sarcoma. Clin Orthop Relat Res (274): 275-281 (1992).
Smith, M.B., H. Xue, L. Strong et al. Forty-year experience with second malignancies after
treatment of childhood cancer: analysis of outcome following the development of the second
malignancy. J Pediatr Surg 28(10): 1342-1348; discussion 1348-1349 (1993).
Smith, P.G. and R. Doll. Late effects of x irradiation in patients treated for metropathia
haemorrhagica. Br J Radiol 49(579): 224-232 (1976).
Smith, R.E., Jr., A.R. Adler, P. Clark et al. Thyroid function after mantle irradiation in
Hodgkin's disease. J Am Med Assoc 245(1): 46-49 (1981).
Socie, G., R.E. Curtis, H.J. Deeg et al. New malignant diseases after allogeneic marrowtransplantation for childhood acute leukemia. J Clin Oncol 18(2): 348-357 (2000).
Socie, G., N. Salooja, A. Cohen et al. Nonmalignant late effects after allogeneic stem celltransplantation. Blood 101(9): 3373-3385 (2003).
Socolow, E.L., A. Hashizume, S. Neriishi et al. Thyroid carcinoma in man after exposure toionizing radiation. A summary of the findings in Hiroshima and Nagasaki. N Engl J Med 268:
406-410 (1963).
Sofer, T., J.R. Goldsmith, I. Nusselder et al. Geographical and temporal trends of childhood
leukemia in relation to the nuclear plant in the Negev, Israel, 1960-1985. Public Health Rev
19(1-4): 191-198 (1991).
Solans, R., J.A. Bosch, P. Galofre et al. Salivary and lacrimal gland dysfunction (sicca
syndrome) after radioiodine therapy. J Nucl Med 42(5): 738-743 (2001).
Sonis, A.L., N. Tarbell, R.W. Valachovic et al. Dentofacial development in long-term
survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities.
Cancer 66(12): 2645-2652 (1990).
Sonnabend, E., H. Spiess and C.W. Mays. Tooth breakage in patients injected with 224-Ra. p.
60-64 in: The Radiobiology of Radium and Thorotrast (W. Gossner, eds.). Urban &Schwarzenberg, Munich, 1986.
Speiser, B., P. Rubin and G. Casarett. Aspermia following lower truncal irradiation in
Hodgkin's disease. Cancer 32(3): 692-698 (1973).
Spiess, H. and C.W. Mays. Bone cancers induced by 224 Ra (Th X) in children and adults.
Health Phys 19(6): 713-729 (1970).
Spiess, H. and G. Mays. Protraction effect on bone-sarcoma induction of radium-224 inchildren and adults. p. 437-450 in: Radionuclide Carcinogenesis (C. L. Sanders, eds.). USAEC
Office of Information Services, Springfield, Virginia, 1973.
Spiess, H. and A. Gerspach. Soft-tissue effects following 224Ra injections into humans.
Health Phys 35(1): 61-81 (1978).

262

UNSCEAR 2013 REPORT

S104
S105
S106
S107
S108
S109
S110
S111
S112
S113
S114
S115
S116
S117
S118
S119
T1
T2
T3
T4
T5
T6

Spiess, H., C.W. Mays and E. Spiess-Paulus. Growth retardation in children injected with 224Ra. p. 45-50 in: The Radiobiology of Radium and Thorotrast (W. Gossner, eds.). Urban &Schwarzenberg, Munich, 1986.
Spitalnik, P.F. and F.H. Straus, 2nd. Patterns of human thyroid parenchymal reaction
following low-dose childhood irradiation. Cancer 41(3): 1098-1105 (1978).
Spycher, B.D., M. Feller, M. Zwahlen et al. Childhood cancer and nuclear power plants in
Switzerland: a census-based cohort study. Int J Epidemiol 40(5): 1247-1260 (2011).
Sridhar, K. and B. Ramamurthi. Intracranial meningioma subsequent to radiation for a
pituitary tumor: case report. Neurosurgery 25(4): 643-645 (1989).
SSK. Assessment of the epidemiological study on childhood cancer in the vicinity of nuclear
power plants (KiKK Study). Strahlenschutzkommission, Germany, 2008.
Stamm, G. and H.D. Nagel. [CT-expo--a novel program for dose evaluation in CT]. Rofo174(12): 1570-1576 (2002). (German).
Stather, J.W. and J.R. Greenhalgh. The metabolism of iodine in children and adults. NRPBR140. National Radiological Protection Board, Didcot, 1983.
Stefani, F.H., H. Spiess and C.W. Mays. Cataracts in patients injected with 224-Ra. p. 51-59
in: The Radiobiology of Radium and Thorotrast (W. Gossner, eds.). Urban & Schwarzenberg,
Munich, 1986.
Steinbuch, M., C.R. Weinberg, J.D. Buckley et al. Indoor residential radon exposure and riskof childhood acute myeloid leukaemia. Br J Cancer 81(5): 900-906 (1999).
Steiner, M., W. Burkart, B. Grosche et al. Trends in infant leukaemia in West Germany inrelation to in utero exposure due to Chernobyl accident. Radiat Environ Biophys 37(2): 87-93(1998).
Stevens, W., D.C. Thomas, J.L. Lyon et al. Leukemia in Utah and radioactive fallout from the
Nevada test site. A case-control study. J Am Med Assoc 264(5): 585-591 (1990).
Stewart, R.R., C.L. David, F. Eftekhari et al. Thyroid gland: US in patients with Hodgkindisease treated with radiation therapy in childhood. Radiology 172(1): 159-163 (1989).
Struelens, L., F. Vanhavere, H. Bosmans et al. Effective doses in angiography andinterventional radiology: calculation of conversion coefficients for angiography of the lower
limbs. Br J Radiol 78(926): 135-142 (2005).
Suchy, B., V. Waldmann, S. Klugbauer et al. Absence of RAS and p53 mutations in thyroid
carcinomas of children after Chernobyl in contrast to adult thyroid tumours. Br J Cancer 77(6):952-955 (1998).
Swerdlow, A.J., J.A. Barber, G.V. Hudson et al. Risk of second malignancy after Hodgkin's
disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol 18(3):498-509 (2000).
Sznajder, L., C. Abrahams, D.M. Parry et al. Multiple schwannomas and meningiomas
associated with irradiation in childhood. Arch Intern Med 156(16): 1873-1878 (1996).
Takahashi, T., S.L. Simon, K.R. Trott et al. A progress report of the Marshall Islands
nationwide thyroid study: an international cooperative scientific study. Tohoku J Exp Med
187(4): 363-375 (1999).
Takahashi, T., K. Trott and K. Fujimori. Thyroid Disease in the Marshall Islands. Findings
From 10 Years of Study. p. in: Book Thyroid Disease in the Marshall Islands. Findings From
10 Years of Study. Tohoku University Press, Sendai, Japan, 2001.
Tamaroff, M., D.R. Miller, M.L. Murphy et al. Immediate and long-term posttherapy
neuropsychologic performance in children with acute lymphoblastic leukemia treated without
central nervous system radiation. J Pediatr 101(4): 524-529 (1982).
Tao, Z., S. Akiba, Y. Zha et al. Cancer and non-cancer mortality among Inhabitants in the highbackground radiation area of Yangjiang, China (1979-1998). Health Phys 102(2): 173-181(2012).
Tapiovaara, M. and T. Siiskonen. PCXMC – A Monte Carlo program for calculating patient
doses in medical x-ray examinations. STUK-A231. Radiation and Nuclear Safety Authority,
Helsinki, 2008.
Tarbell, N.J., E.C. Guinan, L. Chin et al. Renal insufficiency after total body irradiation for
pediatric bone marrow transplantation. Radiother Oncol 18 (Suppl 1): 139-142 (1990).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

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T18
T19

T20

T21
T22
T23
T24
T25
T26
T27
T28

263

Tatsukawa, Y., E. Nakashima, M. Yamada et al. Cardiovascular disease risk among atomic
bomb survivors exposed in utero, 1978-2003. Radiat Res 170(3): 269-274 (2008).
Tawn, E.J., C.A. Whitehouse, J.F. Winther et al. Chromosome analysis in childhood cancer
survivors and their offspring--no evidence for radiotherapy-induced persistent genomic
instability. Mutat Res 583(2): 198-206 (2005).
Tawn, E.J., G.S. Rees, C. Leith et al. Germline minisatellite mutations in survivors ofchildhood and young adult cancer treated with radiation. Int J Radiat Biol 87(3): 330-340(2011).
Taylor, A.J., C. Frobisher, D.W. Ellison et al. Survival after second primary neoplasms of thebrain or spinal cord in survivors of childhood cancer: results from the British Childhood
Cancer Survivor Study. J Clin Oncol 27(34): 5781-5787 (2009).
Taylor, A.J., M.P. Little, D.L. Winter et al. Population-based risks of CNS tumors in survivorsof childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol 28(36): 52875293 (2010).
Taylor, D.M., P.H. Bligh and M.H. Duggan. The absorption of calcium, strontium, barium andradium from the gastrointestinal tract of the rat. Biochem J 83(1): 25-29 (1962).
Taylor, D.M. and M.C. Thorne. The potential for irradiation of the lens and cataract induction
by incorporated alpha-emitting radionuclides. Health Phys 54(2): 171-179 (1988).
Tefft, M. Radiation related toxicities in National Wilms' Tumor Study Number 1. Int J Radiat
Oncol Biol Phys 2(5-6): 455-463 (1977).
Teinturier, C., O. Hartmann, D. Valteau-Couanet et al. Ovarian function after autologous bonemarrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.
Bone Marrow Transplant 22(10): 989-994 (1998).
Thierry-Chef, I., S.L. Simon, C.E. Land et al. Radiation dose to the brain and subsequent riskof developing brain tumors in pediatric patients undergoing interventional neuroradiology
procedures. Radiat Res 170(5): 553-565 (2008).
Thierry-Chef, I., J. Dabin, E.G. Friberg et al. Assessing organ doses from paediatric CT scans-a novel approach for an epidemiology study (the EPI-CT study). Int J Environ Res Public
Health 10(2): 717-728 (2013).
Thomas, D.B., K. Rosenblatt, L.M. Jimenez et al. Ionizing radiation and breast cancer in men(United States). Cancer Causes Control 5(1): 9-14 (1994).
Thomas, G.A., H. Bunnell, H.A. Cook et al. High prevalence of RET/PTC rearrangements in
Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation
between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 84(11): 42324238 (1999).
Thomas, G.A., H. Bunnell and E.D. Williams. Association between morphological subtype of
post Chernobyl papillary carcinoma and rearrangement of the ret oncogene. p. 255-261 in:Radiation and Thyroid Cancer (G. A. Thomas, eds.). World Scientific Publishing, Singapore,
1999.
Thomas, P.R., K.D. Griffith, B.B. Fineberg et al. Late effects of treatment for Wilms' tumor.
Int J Radiat Oncol Biol Phys 9(5): 651-657 (1983).
Thomas, P.R., M. Tefft, G.J. D'Angio et al. Radiation associated toxicities in the second
national wilms' tumor study (NWTS-2). Int J Radiat Oncol Biol Phys 10(Suppl 2): 88 (1984).
Thompson, D.E., K. Mabuchi, E. Ron et al. Cancer incidence in atomic bomb survivors. Part
II: Solid tumors, 1958-1987. Radiat Res 137(2 Suppl): S17-S67 (1994).
Thompson, D.E., E. Ron and D.L. Preston. Cancer incidence in atomic bomb survivors. Part
II: Solid tumors, 1958-1987. RERF special report. Radiation Effects Research Foundation,
Hiroshima, 1994.
Thurlbeck, W.M. Postnatal human lung growth. Thorax 37(8): 564-571 (1982).
Tillotson, C., A. Rosenberg, M. Gebhardt et al. Postradiation multicentric osteosarcoma.
Cancer 62(1): 67-71 (1988).
Titov, L.P., G.D. Kharitonic, I.E. Gourmanchuk et al. Effects of radiation on the production of
immunoglobulins in children subsequent to the Chernobyl disaster. Allergy Proc 16(4): 185193 (1995).
Tokunaga, M., C.E. Land, T. Yamamoto et al. Breast cancer in Japanese A-bomb survivors.
Lancet 2(8304): 924 (1982).

264

T29
T30
T31
T32
T33
T34
T35
T36
T37
T38

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T40
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T42
T43
T44
T45

T46
T47
T48
T49
T50

UNSCEAR 2013 REPORT

Tokunaga, M., C.E. Land, T. Yamamoto et al. Incidence of female breast cancer among
atomic bomb survivors, Hiroshima and Nagasaki, 1950-1980. Radiat Res 112(2): 243-272(1987).
Tokunaga, M., C.E. Land, S. Tokuoka et al. Incidence of female breast cancer among atomic
bomb survivors, 1950-1985. Radiat Res 138(2): 209-223 (1994).
Torok, S., G. Borgulya, P. Lobmayer et al. Childhood leukaemia incidence in Hungary, 19732002. Interpolation model for analysing the possible effects of the Chernobyl accident. Eur J
Epidemiol 20(11): 899-906 (2005).
Travis, L.B., R.E. Curtis, J.D. Boice, Jr. et al. Second malignant neoplasms among long-term
survivors of ovarian cancer. Cancer Res 56(7): 1564-1570 (1996).
Travis, L.B., M. Gospodarowicz, R.E. Curtis et al. Lung cancer following chemotherapy andradiotherapy for Hodgkin's disease. J Natl Cancer Inst 94(3): 182-192 (2002).
Travis, L.B., M. Hauptmann, L.K. Gaul et al. Site-specific cancer incidence and mortality after
cerebral angiography with radioactive thorotrast. Radiat Res 160(6): 691-706 (2003).
Travis, L.B., D.A. Hill, G.M. Dores et al. Breast cancer following radiotherapy andchemotherapy among young women with Hodgkin disease. J Am Med Assoc 290(4): 465-475(2003).
Travis, L.B., S.D. Fossa, S.J. Schonfeld et al. Second cancers among 40,576 testicular cancer
patients: focus on long-term survivors. J Natl Cancer Inst 97(18): 1354-1365 (2005).
Tronko, M.D., T.I. Bogdanova, I.V. Komissarenko et al. Thyroid carcinoma in children andadolescents in Ukraine after the Chernobyl nuclear accident: statistical data andclinicomorphologic characteristics. Cancer 86(1): 149-156 (1999).
Tronko, M.D., A.V. Brenner, V.A. Olijnyk et al. Autoimmune thyroiditis and exposure toiodine 131 in the Ukrainian cohort study of thyroid cancer and other thyroid diseases after the
Chornobyl accident: results from the first screening cycle (1998-2000). J Clin Endocrinol
Metab 91(11): 4344-4351 (2006).
Tronko, M.D., G.R. Howe, T.I. Bogdanova et al. A cohort study of thyroid cancer and otherthyroid diseases after the chornobyl accident: thyroid cancer in Ukraine detected during firstscreening. J Natl Cancer Inst 98(13): 897-903 (2006).
Tronko, N., Y. Epstein, V. Oleinik et al. Thyroid gland in children after the Chernobyl
accident (yesterday and today). p. 31-46 in: Nagasaki Symposium on Chernobyl: Update andFuture (S. Nagataki, ed.). Elsevier Science B.V., Amsterdam, 1994.
Tronko, N.D., T.I. Bogdanova and O.V. Epstein. Thyroid cancer in children and adolescents of
Ukraine having been exposed as a result of the Chernobyl accident (15 years experience). Int J
Radiat Med 4: 222-232 (2002).
Trott, K.-R. and J. Kummermehr. Radiation effects in skin. p. 33-67 in: Radiopathology ofOrgans and Tissues (E. Scherer, eds.). Springer Verlag, Berlin, 1991.
Tryfonas, G., A. Violaki, G. Tsikopoulos et al. Late postoperative results in males treated fortesticular torsion during childhood. J Pediatr Surg 29(4): 553-556 (1994).
Tsuruda, J.S., K.E. Kortman, W.G. Bradley et al. Radiation effects on cerebral white matter:
MR evaluation. AJR Am J Roentgenol 149(1): 165-171 (1987).
Tsyb, A.F., E.M. Parshkov, V.K. Ivanov et al. Disease indices of thyroid and their dose
dependence in children and adolescents affected as a result of the Chernobyl accident. p. 9-19
in: Nagasaki Symposium on Chernobyl: Update and Future (S. Nagataki). Elsevier Science
B.V., Amsterdam, 1994.
Tucker, M.A., G.J. D'Angio, J.D. Boice, Jr. et al. Bone sarcomas linked to radiotherapy andchemotherapy in children. N Engl J Med 317(10): 588-593 (1987).
Tucker, M.A., A.T. Meadows, J.D. Boice, Jr. et al. Leukemia after therapy with alkylating
agents for childhood cancer. J Natl Cancer Inst 78(3): 459-464 (1987).
Tucker, M.A., C.N. Coleman, R.S. Cox et al. Risk of second cancers after treatment for
Hodgkin's disease. N Engl J Med 318(2): 76-81 (1988).
Tucker, M.A., P.H. Jones, J.D. Boice, Jr. et al. Therapeutic radiation at a young age is linked
to secondary thyroid cancer. The Late Effects Study Group. Cancer Res 51(11): 2885-2888(1991).
Tukenova, M., C. Guibout, O. Oberlin et al. Role of cancer treatment in long-term overall andcardiovascular mortality after childhood cancer. J Clin Oncol 28(8): 1308-1315 (2010).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

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U4

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U6

U7

U8

U9

U10

U11

U12

U13
U14

U15

265

Tukenova, M., I. Diallo, H. Anderson et al. Second malignant neoplasms in digestive organs
after childhood cancer: a cohort-nested case-control study. Int J Radiat Oncol Biol Phys 82(3):e383-390 (2012).
U.S.
EPA.
Exposure
Factors
Handbook.
Retrievedfrom(http://www.epa.gov/ncea/efh/pdfs/efh-chapter05.pdf). Last accessed on (2 May 2012).
UNSCEAR. Sources and Effects of Ionizing Radiation. UNSCEAR 1996 Report. United
Nations Scientific Committee on the Effects of Atomic Radiation, 1996 Report to the General
Assembly, with scientific annex. United Nations sales publication E.96.IX.3. United Nations,
New York, 1996.
Uderzo, C., D. Fraschini, A. Balduzzi et al. Long-term effects of bone marrow transplantation
on dental status in children with leukaemia. Bone Marrow Transplant 20(10): 865-869 (1997).
Uderzo, C., M. Pillon, P. Corti et al. Impact of cumulative anthracycline dose, preparative
regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5
years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on
behalf of the EBMT Pediatric Diseases and Late Effects Working Parties. Bone Marrow
Transplant 39(11): 667-675 (2007).
Underwood, G.B. and L.E. Gaul. Disfiguring sequelae from radium therapy; results oftreatment of a birthmark adjacent to the breast in a female infant. Arch Derm Syphilol 57(5):918 (1948).
UNSCEAR. Sources and Effects of Ionizing Radiation. UNSCEAR 1977 Report. United
Nations Scientific Committee on the Effects of Atomic Radiation, 1977 Report to the General
Assembly, with annexes. United Nations sales publication E.77.IX.1. United Nations, New
York, 1977.
UNSCEAR. Sources, Effects and Risks of Ionizing Radiation. UNSCEAR 1988 Report.
United Nations Scientific Committee on the Effects of Atomic Radiation, 1988 Report to theGeneral Assembly, with annexes. United Nations sales publication E.88.IX.7. United Nations,
New York, 1988.
UNSCEAR. Sources and Effects of Ionizing Radiation. UNSCEAR 1993 Report. United
Nations Scientific Committee on the Effects of Atomic Radiation, 1993 Report to the General
Assembly, with scientific annexes. United Nations sales publication E.94.IX.2. United
Nations, New York, 1993.
UNSCEAR. Sources and Effects of Ionizing Radiation. Volume I: Sources. UNSCEAR 2000
Report. United Nations Scientific Committee on the Effects of Atomic Radiation, 2000 Reportto the General Assembly, with scientific annexes. United Nations sales publication E.00.IX.3.
United Nations, New York, 2000.
UNSCEAR. Sources and Effects of Ionizing Radiation. Volume II: Effects. UNSCEAR 2000
Report. United Nations Scientific Committee on the Effects of Atomic Radiation, 2000 Reportto the General Assembly, with scientific annexes. United Nations sales publication E.00.IX.4.
United Nations, New York, 2000.
UNSCEAR. Hereditary Effects of Radiation. UNSCEAR 2001 Report. United Nations
Scientific Committee on the Effects of Atomic Radiation, 2001 Report to the General
Assembly, with scientific annex. United Nations sales publication E.01.IX.2. United Nations,
New York, 2001.
UNSCEAR. Effects of Ionizing Radiation. Volume I: Report to the General Assembly,
Scientific Annexes A and B. UNSCEAR 2006 Report. United Nations Scientific Committee
on the Effects of Atomic Radiation. United Nations sales publication E.08.IX.6. United
Nations, New York, 2008.
UNSCEAR. Effects of Ionizing Radiation. Volume II: Scientific Annexes C, D and E.
UNSCEAR 2006 Report. United Nations Scientific Committee on the Effects of Atomic
Radiation. United Nations sales publication E.09.IX.5. United Nations, New York, 2009.
UNSCEAR. Sources and Effects of Ionizing Radiation. Volume I: Sources. Report to theGeneral Assembly Scientific Annexes A and B. UNSCEAR 2008 Report. United Nations
Scientific Committee on the Effects of Atomic Radiation. United Nations sales publication
E.10.XI.3. United Nations, New York, 2010.
UNSCEAR. Sources and Effects of Ionizing Radiation. Volume II: Effects: Scientific Annexes
C, D and E. UNSCEAR 2008 Report. United Nations Scientific Committee on the Effects of

266

V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
W1
W2

UNSCEAR 2013 REPORT

Atomic Radiation. United Nations sales publication E.11.IX.3. United Nations, New York,2011.
van Daal, W.A., B.M. Goslings, J. Hermans et al. Thyroid gland carcinoma as a late sequel ofirradiation of the neck region. Ned Tijdschr Geneeskd 127(1): 12-15 (1983). (Dutch).
van der Pal, H.J., E.C. van Dalen, M. Hauptmann et al. Cardiac function in 5-year survivors ofchildhood cancer: a long-term follow-up study. Arch Intern Med 170(14): 1247-1255 (2010).
van der Pal, H.J., E.C. van Dalen, E. van Delden et al. High risk of symptomatic cardiac eventsin childhood cancer survivors. J Clin Oncol 30(13): 1429-1437 (2012).
van Kaick, G., H. Wesch, H. Luehrs et al. The German Thorotrast study - report on 20 years
follow-up. p. 98-103 in: Risks from Radium and Thorotrast (D.M. Taylor et al., eds.). British
Institute of Radiology, 1989.
van Kaick, G., A. Dalheimer, S. Hornik et al. The german thorotrast study: recent results andassessment of risks. Radiat Res 152(6 Suppl): S64-71 (1999).
van Leeuwen, F.E., R. Somers, B.G. Taal et al. Increased risk of lung cancer, non-Hodgkin's
lymphoma, and leukemia following Hodgkin's disease. J Clin Oncol 7(8): 1046-1058 (1989).
van Leeuwen, F.E., A.M. Stiggelbout, A.W. van den Belt-Dusebout et al. Second cancer risk
following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 11(3): 415-424(1993).
van Leeuwen, F.E., W.J. Klokman, M. Stovall et al. Roles of radiotherapy and smoking inlung cancer following Hodgkin's disease. J Natl Cancer Inst 87(20): 1530-1537 (1995).
van Leeuwen, F.E., W.J. Klokman, M.B. Veer et al. Long-term risk of second malignancy insurvivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol
18(3): 487-497 (2000).
van Leeuwen, F.E., W.J. Klokman, M. Stovall et al. Roles of radiation dose, chemotherapy,
and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95(13):971-980 (2003).
Van Why, S.K., A.L. Friedman, L.J. Wei et al. Renal insufficiency after bone marrowtransplantation in children. Bone Marrow Transplant 7(5): 383-388 (1991).
Vanel, D., C. Coffre, L. Zemoura et al. Chondrosarcoma in children subsequent to othermalignant tumours in different locations. Skeletal Radiol 11(2): 96-101 (1984).
Vasudevan, V., M.C. Cheung, R. Yang et al. Pediatric solid tumors and second malignancies:
characteristics and survival outcomes. J Surg Res 160(2): 184-189 (2010).
Vathaire, C.C., F.D. Vathaire, B.L. Vu et al. Childhood malignancies in French Polynesia
during the 1985-1995 period. Trop Med Int Health 9(9): 1005-1011 (2004).
Veiga, L.H., J.H. Lubin, H. Anderson et al. A pooled analysis of thyroid cancer incidence
following radiotherapy for childhood cancer. Radiat Res 178(4): 365-376 (2012).
Venkatramani, R., S. Kamath, K. Wong et al. Correlation of clinical and dosimetric factors
with adverse pulmonary outcomes in children after lung irradiation. Int J Radiat Oncol Biol
Phys 86(5): 942-948 (2013).
Vermiglio, F., M.G. Castagna, E. Volnova et al. Post-Chernobyl increased prevalence ofhumoral thyroid autoimmunity in children and adolescents from a moderately iodine-deficientarea in Russia. Thyroid 9(8): 781-786 (1999).
Vivanco, M., J.H. Dalle, C. Alberti et al. Malignant and benign thyroid nodules after total
body irradiation preceding hematopoietic cell transplantation during childhood. Eur J
Endocrinol 167(2): 225-233 (2012).
Vykhovanets, E.V., V.P. Chernyshov, I. Slukvin et al. 131I dose-dependent thyroid
autoimmune disorders in children living around Chernobyl. Clin Immunol Immunopathol
84(3): 251-259 (1997).
Waber, D.P., N.J. Tarbell, D. Fairclough et al. Cognitive sequelae of treatment in childhood
acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 13(10):2490-2496 (1995).
Waber, D.P., B.L. Shapiro, S.C. Carpentieri et al. Excellent therapeutic efficacy and minimallate neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk
acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer InstituteConsortium Protocol 87-01. Cancer 92(1): 15-22 (2001).

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W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
W25

267

Wagner, L.M., M.D. Neel, A.S. Pappo et al. Fractures in pediatric Ewing sarcoma. J Pediatr
Hematol Oncol 23(9): 568-571 (2001).
Wagoner, J.K. Leukemia and other malignancies following radiation therapy for gynecologicaldisorders. p. 153-159 in: Radiation Carcinogenesis: Epidemiology and Biological Significance(J. D. Boice Jr. et al., eds.). Raven Press, New York, 1984.
Wakabayashi, T., H. Kato, T. Ikeda et al. Studies of the mortality of A-bomb survivors, report
7. Part III. incidence of cancer in 1959-1978, based on the tumor registry, Nagasaki. Radiat
Res 93(1): 112-146 (1983).
Wakeford, R. The risk of childhood leukaemia following exposure to ionising radiation--areview. J Radiol Prot 33(1): 1-25 (2013).
Walker, S.J., L.A. Whiteside, W.H. McAlister et al. Slipped capital femoral epiphysis
following radiation and chemotherapy. Clin Orthop Relat Res 159: 186-193 (1981).
Wall, B.F., R. Haylock, J.T.M. Jansen et al. Radiation risks from medical X-ray examinations
as a function of the age and sex of the patient. HPA-CRCE-028. Health Protection Agency,
Chilton, 2011.
Wallace, W.H., S.M. Shalet, E.C. Crowne et al. Ovarian failure following abdominal
irradiation in childhood: natural history and prognosis. Clin Oncol (R Coll Radiol) 1(2): 75-79(1989).
Wallace, W.H., S.M. Shalet, L.J. Tetlow et al. Ovarian function following the treatment ofchildhood acute lymphoblastic leukaemia. Med Pediatr Oncol 21(5): 333-339 (1993).
Wallace, W.H. Oncofertility and preservation of reproductive capacity in children and young
adults. Cancer 117(10 Suppl): 2301-2310 (2011).
Walsh, L., P. Jacob and J.C. Kaiser. Radiation risk modeling of thyroid cancer with special
emphasis on the Chernobyl epidemiological data. Radiat Res 172(4): 509-518 (2009).
Wanebo, C.K., K.G. Johnson, K. Sato et al. Breast cancer after exposure to the atomic
bombings of Hiroshima and Nagasaki. N Engl J Med 279(13): 667-671 (1968).
Wanless, I.R. Micronodular transformation (nodular regenerative hyperplasia) of the liver: areport of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular
nodules. Hepatology 11(5): 787-797 (1990).
Watanabe, N., S.C. De Rosa, A. Cmelak et al. Long-term depletion of naive T cells in patientstreated for Hodgkin's disease. Blood 90(9): 3662-3672 (1997).
Weaver, R.G., Jr., A.R. Chauvenet, T.J. Smith et al. Ophthalmic evaluation of long-term
survivors of childhood acute lymphoblastic leukemia. Cancer 58(4): 963-968 (1986).
Weiss, H.A., S.C. Darby and R. Doll. Cancer mortality following X-ray treatment forankylosing spondylitis. Int J Cancer 59(3): 327-338 (1994).
Werner, S.C., H. Hamilton and M.R. Nemeth. Therapeutic effects from repeated diagnostic
doses of I131 in adult and juvenile hyperthyroidism. J Clin Endocrinol Metab 12(10): 13491355 (1952).
Whelan, K.F., K. Stratton, T. Kawashima et al. Ocular late effects in childhood and adolescentcancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer
54(1): 103-109 (2010).
White-Koning, M.L., D. Hemon, D. Laurier et al. Incidence of childhood leukaemia in thevicinity of nuclear sites in France, 1990-1998. Br J Cancer 91(5): 916-922 (2004).
WHO. Health effects of the Chernobyl accident and special health care programmes. Report of
the UN Chernobyl Forum Expert Group "Health". (B. Bennett et al., eds.). World HealthOrganization, Geneva, 2006.
Wilde, G. and J. Sjostrand. A clinical study of radiation cataract formation in adult life
following gamma irradiation of the lens in early childhood. Br J Ophthalmol 81(4): 261-266(1997).
Willi, S.M., K. Cooke, J. Goldwein et al. Growth in children after bone marrow transplantation
for advanced neuroblastoma compared with growth after transplantation for leukemia oraplastic anemia. J Pediatr 120(5): 726-732 (1992).
Williams, E.D., A. Abrosimov, T. Bogdanova et al. Thyroid carcinoma after Chernobyl latent
period, morphology and aggressiveness. Br J Cancer 90(11): 2219-2224 (2004).
Willman, K.Y., R.S. Cox and S.S. Donaldson. Radiation induced height impairment inpediatric Hodgkin's disease. Int J Radiat Oncol Biol Phys 28(1): 85-92 (1994).

268

W26
W27
W28
W29
W30
W31
W32
W33
W34
W35
W36
W37
W38
W39
W40
W41
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Y1
Y2
Y3
Y4
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UNSCEAR 2013 REPORT

Wilson, C.L., K.K. Ness, J.P. Neglia et al. Renal carcinoma after childhood cancer: a reportfrom the childhood cancer survivor study. J Natl Cancer Inst 105(7): 504-508 (2013).
Wingard, J.R., L.P. Plotnick, C.S. Freemer et al. Growth in children after bone marrowtransplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body
irradiation. Blood 79(4): 1068-1073 (1992).
Winship, T. and R.V. Rosvoll. A study of thyroid cancer in children. Am J Surg 102: 747-752(1961).
Winther, J.F., J.D. Boice, Jr., B.L. Thomsen et al. Sex ratio among offspring of childhood
cancer survivors treated with radiotherapy. Br J Cancer 88(3): 382-387 (2003).
Winther, J.F., J.D. Boice, Jr., J.J. Mulvihill et al. Chromosomal abnormalities among offspringof childhood-cancer survivors in Denmark: a population-based study. Am J Hum Genet 74(6):1282-1285 (2004).
Winther, J.F., J.D. Boice, Jr., A.L. Svendsen et al. Spontaneous abortion in a Danish
population-based cohort of childhood cancer survivors. J Clin Oncol 26(26): 4340-4346(2008).
Winther, J.F., J.D. Boice, Jr., K. Frederiksen et al. Radiotherapy for childhood cancer and risk
for congenital malformations in offspring: a population-based cohort study. Clin Genet 75(1):50-56 (2009).
Winther, J.F., J.D. Boice, Jr., A.L. Svendsen et al. Induced abortions in Danish cancer
survivors: a population-based cohort study. J Natl Cancer Inst 101(9): 687-689 (2009).
Winther, J.F., J.D. Boice, Jr., J. Christensen et al. Hospitalizations among children of survivorsof childhood and adolescent cancer: a population-based cohort study. Int J Cancer 127(12):2879-2887 (2010).
Winther, J.F., J.H. Olsen, H. Wu et al. Genetic disease in the children of Danish survivors ofchildhood and adolescent cancer. J Clin Oncol 30(1): 27-33 (2012).
Withycombe, J.S., J.E. Post-White, J.L. Meza et al. Weight patterns in children with higher
risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood
Cancer 53(7): 1249-1254 (2009).
Wong, F.L., M. Yamada, H. Sasaki et al. Noncancer disease incidence in the atomic bomb
survivors: 1958-1986. Radiat Res 135(3): 418-430 (1993).
Wong, F.L., E. Ron, T. Gierlowski et al. Benign thyroid tumors: general risk factors and theireffects on radiation risk estimation. Am J Epidemiol 144(8): 728-733 (1996).
Wong, F.L., J.D. Boice, Jr., D.H. Abramson et al. Cancer incidence after retinoblastoma.
Radiation dose and sarcoma risk. J Am Med Assoc 278(15): 1262-1267 (1997).
Wood, J.W., H. Tamagaki, S. Neriishi et al. Thyroid carcinoma in atomic bomb survivors
Hiroshima and Nagasaki. Am J Epidemiol 89(1): 4-14 (1969).
Woodard, H.Q., A.G. Huvos and J. Smith. Radiation-induced malignant tumors of bone inpatients with Hodgkin's disease. Health Phys 55(4): 615-620 (1988).
Worgul, B.V., Y.I. Kundiyev, N.M. Sergiyenko et al. Cataracts among Chernobyl clean-up
workers: implications regarding permissible eye exposures. Radiat Res 167(2): 233-243(2007).
Xuan, X.Z., J.H. Lubin, J.Y. Li et al. A cohort study in southern China of tin miners exposed
to radon and radon decay products. Health Phys 64(2): 120-131 (1993).
Yaar, I., E. Ron, B. Modan et al. Long-lasting cerebral functional changes following moderate
dose x-radiation treatment to the scalp in childhood: an electroencephalographic power
spectral study. J Neurol Neurosurg Psychiatry 45(2): 166-169 (1982).
Yamada, M., F.L. Wong, S. Fujiwara et al. Noncancer disease incidence in atomic bomb
survivors, 1958-1998. Radiat Res 161(6): 622-632 (2004).
Yamaguchi, Y. Age-dependent effective doses for external photons. Radiat Prot Dosim 55(2):123-129 (1994).
Yamashita, S. and Y. Shabita Chernobyl: A Decade. The Fifth Chernobyl Sasakawa Medical
Cooperation Symposium. Elsevier, Kiev, 1996.
Yeh, H., G.M. Matanoski, N.-Y. Wang et al. Cancer incidence after childhood nasopharyngeal
radium irradiation: a follow-up study in Washington County, Maryland. Am J Epidemiol
153(8): 749-756 (2001).

ANNEX B: EFFECTS OF RADIATION EXPOSURE OF CHILDREN

Y6
Y7

Y8
Y9
Z1
Z2
Z3
Z4
Z5

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Yonehara, S., A.V. Brenner, M. Kishikawa et al. Clinical and epidemiologic characteristics offirst primary tumors of the central nervous system and related organs among atomic bomb
survivors in Hiroshima and Nagasaki, 1958-1995. Cancer 101(7): 1644-1654 (2004).
Yoshihara, S., G. Yanik, K.R. Cooke et al. Bronchiolitis obliterans syndrome (BOS),
bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious
pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol
Blood Marrow Transplant 13(7): 749-759 (2007).
Yoshimoto, Y., H. Ezaki, R. Etoh et al. Prevalence rate of thyroid diseases among autopsy
cases of the atomic bomb survivors in Hiroshima, 1951-1985. Radiat Res 141(3): 278-286(1995).
Yoshimoto, Y., S. Yoshinaga, K. Yamamoto et al. Research on potential radiation risks inareas with nuclear power plants in Japan: leukaemia and malignant lymphoma mortality
between 1972 and 1997 in 100 selected municipalities. J Radiol Prot 24(4): 343-368 (2004).
Zablotska, L.B., E. Ron, A.V. Rozhko et al. Thyroid cancer risk in Belarus among children
and adolescents exposed to radioiodine after the Chornobyl accident. Br J Cancer 104(1): 181187 (2011).
Zankl, M., W. Panzer and G. Drexler. Tomographic anthropomorphic models. Part II: Organdoses from computed tomographic examinations in paediatric radiology. GSFForschungszentrum, Institut für Strahlenschutz, Oberschleissheim, 1993.
Zarrabi, M.H. and F. Rosner. Acute myeloblastic leukemia following treatment for nonhematopoietic cancers: report of 19 cases and review of the literature. Am J Hematol 7(4):357-367 (1979).
Zeman, W. and M. Solomon. Effects of Radiation on Striated Muscle. p. in: Book Effects ofRadiation on Striated Muscle. Willliams & Wilkins, Baltimore, 1971.
Zou, J., Z. Tao, Q. Sun et al. Cancer and non-cancer epidemiological study in the highbackground radiation area of Yangjiang, China. Int. Congress Series 1276: 97–101 (2005).

unscear.org

This publication contains:
VOLUME II

Scientific findings on effects of radiation exposure of children

Scientific Annex with appendices
Annex B.: Effects of radiation exposure of children
Appendix A. Dosimetry
Appendix B. Malignant neoplasms
Appendix C. Deterministic effects

E VA L U AT I N G R A D I AT I O N S C I E N C E F O R I N F O R M E D D E C I S I O N - M A K I N G
In 1955 the United Nations General Assembly established the Scientific Committee on the Effectsof Atomic Radiation (UNSCEAR) in response to concerns about the effects of ionizing radiation
on human health and the environment. At that time fallout from atmospheric nuclear weapons
tests was reaching people through air, water and food. UNSCEAR was to collect and evaluate
information on the levels and effects of ionizing radiation. Its first reports laid the scientific grounds
on which the Partial Test Ban Treaty prohibiting atmospheric nuclear weapons testing was
negotiated in 1963.
Over the decades, UNSCEAR has evolved to become the world authority on the global leveland effects of atomic radiation. UNSCEAR’s independent and objective evaluation of the science
are to provide for—but not address—informed policymaking and decision-making related toradiation risks and protection.

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