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EFFECTS OF IONIZING RADIATION
United Nations Scientific Committee on the
Effects of Atomic Radiation
UNSCEAR 2006
Report to the General Assembly,
with Scientific Annexes

VOLUME I

UNITED NATIONSNew York, 2008

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NOTE
The report of the Committee without its annexes appears as Official Records of the General
Assembly, Sixty-first Session, Supplement No. 46 and corrigendum (A/61/46 and Corr. 1).
The report reproduced here includes the corrections of the corrigendum.
The designation employed and the presentation of material in this publication do not imply theexpression 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, or concerning
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 timethe data 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.08.IX.6
ISBN 978-92-1-142263-4

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ANNEX B
Epidemiological evaluation of cardiovascular disease
and other non-cancer diseases following radiation exposure

Contents
Page

INTRODUCTION...........................................................................

325

I.

GENERAL ISSUES IN ASSESSING DATA ON NON-CANCER DISEASES . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. Cohort selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. Quality of the mortality data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. Confounding effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

327
327
327
328
328

II.

NON-CANCER DATA IN RADIATION-EXPOSED COHORTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

329

III.

DATA ON NON-CANCER MORTALITY FOR SURVIVORS OF THE ATOMIC BOMBINGS . . . . . . . . . . . . . . . .
A. Misclassification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. Biases and confounders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. Selection effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. Dose response and risk estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

337
338
338
339
340

IV.

CIRCULATORY DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. Patients receiving radiotherapy for cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Hodgkin’s lymphoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Childhood cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Breast cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Testicular seminoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Dose response and factors affecting the risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. Patients receiving diagnostic radiation or radiotherapy for non-neoplastic diseases . . . . . . . . . . . . . .
C. Radiologists and radiologic technologists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. Radiation workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
E. Survivors of the atomic bombings in Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Mortality (Life Span Study) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Incidence and morbidity data (Adult Health Study) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Subclinical changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
F. Mechanistic models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Microvasculature theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Inflammation theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Monoclonal theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

343
343
343
346
346
352
353
355
357
360
367
367
367
367
368
368
368
369

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V.

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

371

VI.

CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

373

VII.

FUTURE RESEARCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

375

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

377

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INTRODUCTION
1. The risks of cancer associated with exposure to ionizing radiation have been extensively studied and documented. Epidemiological data on the carcinogenic effects
of exposure to ionizing radiation are the subject of continuing reviews by UNSCEAR (see annex A to this report,“Epidemiological studies of radiation and cancer”, and, forexample, references [U2, U4, U6]). The effects of exposure to radiation expressed as diseases other than cancer
were most recently reviewed in the 1982 [U8] and 1993
UNSCEAR Reports [U5]. In these reports, the effects
expressed as diseases other than cancer were regarded as“deterministic”, resulting from “direct” changes occurringin cells. The deterministic model assumes the presence ofa minimum dose—the threshold dose—below which radiation effects are not detected, although a threshold dose isdifficult to define and may vary according to tissues, biological end points and measuring techniques [U8]. In 1992,
the analysis of mortality data from the Life Span Study(LSS) cohort of survivors of the atomic bombings in Japandemonstrated a statistically significant association between
radiation dose and some diseases other than cancer (noncancer diseases) [S1]. Excess non-cancer disease mortality risks in the LSS were evident at levels of dose lower
than those hitherto considered as a threshold, e.g. 4–5 Gy,for various deterministic effects. While some of these
non-cancer diseases are neoplastic though benign innature, significant excess risks are mostly seen for
mortality from stroke, heart disease, and diseases of therespiratory and digestive systems, which are of a nonneoplastic nature.

2. The Committee considered it necessary to assess the epidemiological evidence of radiation effects expressed as diseases other than cancer at low doses, because the phenomenon
is potentially important for radiation risk assessment at thesedose levels, and there is a considerable lack of consistency
among the available epidemiological data. The Committee considered it important to focus on cardiovascular disease as the
major end point of interest, because cardiovascular disease isamong the most common diseases in many populations worldwide and thus may be important for radiation risk assessment.
3. This annex first provides an overview of current epidemiological data on mortality from broad categories of noncancer diseases obtained from studies of populations exposed
to radiation at doses of less than 1–2 Gy. In assessing theevidence on radiation effects, the annex considers several
methodological issues that are especially relevant for noncancer data, such as cohort selection, quality of the mortality data, confounding and publication bias. It then provides
a general overview of data currently available on major noncancer disease categories from various irradiated populations.
The annex goes on to consider radiation effects on diseasesof the circulatory system and specifically on cardiovascular(heart) disease. Although the primary focus of this annex isthe effect of exposure to low doses of radiation, the risks ofcardiovascular disease associated with exposure to highdoses are also addressed. This is because much is known
about the clinical and biological effects of exposure at highdose levels, and this may be helpful for considering possible biological mechanisms of effects at low dose levels.

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I. GENERAL ISSUES IN ASSESSING DATA ON NON-CANCER DISEASES
4. Annex A of this report describes features that areimportant in conducting or interpreting epidemiologicalstudies. In addition, when assessing published epidemiological data on non-cancer diseases, several methodologicalissues are especially relevant. These include the selectionof exposed populations (including the “healthy worker”
effect and the presumed “healthy survivor” effect), the quality of the mortality data, the confounding effects of nonradiation risk factors and publication bias.

ticularly strong for chronic non-malignant diseases, such as
cardiovascular disease, compared with cancer or precancerous conditions that are dormant or clinically less evident at
the time of beginning or during employment. The empirical estimates are that the healthy worker effect represents a
20–30% reduction in comparison with the mortality rate of
the whole population [C8]. Several features of the healthy
worker effect are notable. The effect is greatest during theinitial period of follow-up and diminishes with increasing
follow-up time, and the length of time during which theeffect persists has been reported to range from 5 to 30 years
or longer [B9]. The magnitude of the healthy worker effectalso varies among different occupational groups, and may
be particularly large in nuclear worker cohorts because of
the strict health selection associated with security clearancesin the industry [B9]. Thus a simple ratio of the observed tothe expected number of deaths, or standardized mortality
ratio (SMR), is not a useful measure of radiation risk for
non-cancer disease in occupational cohorts.

A. Cohort selection
5. The nature of an exposed population needs to be considered when study subjects are irradiated for medical reasons. Data on non-cancer diseases are reported from someof the medically exposed cohorts that have been studied toassess cancer risks. Groups of individuals with certain nonneoplastic medical conditions for which they were irradiated may have underlying rates of non-cancer diseases that
may not be representative of the general population rates,
even if the underlying cancer rates of these individuals are
not affected by their medical conditions. For example, thyroid hormone exerts a major influence on the cardiovascular system, and patients with hyperthyroidism often havecardiovascular symptoms [L9]. Angina pectoris and congestive heart failure may develop when there is underlying
heart disease. Women with some benign gynaecological disorders are in a hyper-oestrogenic status, and thus may havean increased underlying risk of cardiovascular disease.
When the observed number of cases (or deaths) with thedisease of interest is compared with the number expectedfrom the general population (external comparison), estimates of the risk may be biased. However, comparison of
disease rates in exposed and unexposed persons within thesame cohort population (internal comparison) is less likely
to produce biased risk estimates.

7. It has been suspected that a selection process that issimilar to that underlying the healthy worker effect may
have occurred in the cohort of the atomic bombing survivors[P4, S1]. This effect, called the “healthy survivor effect” isapparently different in nature from the healthy worker survivor effect seen in those who remain employed. Rather,several features suggest that it is similar in nature to thehealthy worker effect caused by the selection of healthierpersons at the time of cohort entry.

B. Quality of the mortality data
8. Mortality follow-up is the principal method used inmost studies of radiation-exposed cohorts. Imprecise reportsof the causes of death on death certificates often lead tomisclassification of diseases from or with which subjects
died. Since mortality rates for cancer generally increase withincreasing radiation dose, the misclassification of death fromcancer as death from non-cancer disease on death certificates can spuriously produce a dose-related increase in mortality rates for non-cancer disease or overstate the effect ofradiation on non-cancer disease rates. In the analysis by
Sposto et al. [S6] of the LSS death certificate data, correcting for the misclassification of cancer deaths as noncancer deaths using autopsy diagnoses reduced the estimateof excess relative risk (ERR) for non-cancer disease by
about 20% (although the non-cancer dose response still
remained significant after this correction). The problem of

6. The “healthy worker effect” is an observed decrease inmortality in cohorts of workers when comparison is madewith the general population. This effect occurs because of
the initial selection process by which healthy people are
more likely to be employed than unhealthy ones. Decreased
mortality in workers may also occur for several other reasons, for example the beneficial effect from better healthcare (referred to as the “worker healthier effect”), or continuing selection due to healthier people remaining
employed (referred to as the “healthy worker survivor
effect”) [C7]. The healthy worker effect is known to be par327

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misclassification of causes of death is likely to exist in manyof the radiation-exposed cohorts studied, but the LSS is the
only study to date in which the impact of disease misclassification on the estimates for risk of non-cancer disease has
been evaluated.

C. Confounding effects
9. Cardiovascular disease and the other non-cancer diseases with which this report is concerned are multifactorialdiseases involving lifestyle and other personal factors.
Underlying rates for major non-cancer diseases, especiallycirculatory diseases, are relatively high and vary amongpeople with different socio-economic status, from different
geographical locations and with different lifestyles. Because
the risk of non-cancer effects associated with radiation
exposure is relatively small—about one third the risk ofcancer, as indicated by the atomic bombing survivor data—
the power to detect radiation effects is reduced and the likelihood of the influence of confounding factors is increased.
Simple comparisons of exposed versus unexposed groups
are susceptible to confounding as well as selection bias andshould be given limited credibility, while radiationdose–response analyses provide more credible evidence
regarding the effect of radiation exposure.

D. Publication bias
10. Cancer has been the primary focus of epidemiological research on radiation effects. Radiation effects expressed
as non-cancer diseases have been less systematically studied and reported. Only occasionally have associations ofradiation with non-cancer diseases been reported as supplemental findings of studies designed to assess cancer
risks. Findings related to non-cancer effects may have beenreported because they are statistically significant or “interesting”. On the other hand, non-cancer data may simply nothave been analysed because the investigators were not interested in the data. Reviews of studies in the social and medical sciences show that studies with significant results or
favourable results are more likely to be published, but themagnitude and nature of publication bias and other relatedbiases are uncertain [S5]. Favourable results may be thosefindings that are congruent with ruling paradigms at thetime. This also suggests that when positive results are unexpected, they may be rigorously analysed, while null results,
when expected, may not be critically examined. For example, unexpected positive findings may cause investigators
to examine the possible sources of bias or confounding, butnull findings that are expected may be accepted at facevalue. While there is a concern for a potential publication
bias in published non-cancer data, the direction of biases inpublished data is unpredictable.

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II. NON-CANCER DATA IN RADIATION-EXPOSED COHORTS
11. The objectives of this annex include the identificationof cohort studies that may provide epidemiological information for assessing the relationship of radiation exposureand non-cancer diseases and to judge the usefulness andconsistency of their findings for various non-cancer diseasecategories. Table 1 lists cohort populations exposed tomostly low-linear-energy-transfer (LET) radiation andrecords any major non-cancer findings. These cohorts wereselected from those considered in the UNSCEAR 2000
Report (table 2 in annex I, “Epidemiological evaluation ofradiation-induced cancer”) [U2], supplemented and updated
by a separate literature search. The cohorts in table 1 wereselected a priori on the basis of considerations of population size and reported radiation doses to relevant organs,and then data on non-cancer mortality were sought inpublished material.

doses to different target organs. This should be kept inmind when comparing findings for different populations orwhen examining different non-cancer diseases within thesame population.
13. Table 1 presents associations reported from these studies regarding radiation exposure and major non-cancer disease categories (infectious diseases, circulatory diseases,
respiratory system diseases, digestive system diseases,
genito-urinary system diseases and other diseases). The
associations are described in terms of whether they weresignificantly positive (P, increased risk associated with radiation exposure), significantly inverse (I, reduced risk associated with radiation exposure), not significant (NS, nosignificant association) or lacking data on non-cancer disease (–). The types of analysis used in obtaining the results
are described as follows: “dose–response analysis”, including analyses using dose categories; “internal comparison”
based on only a comparison of exposed versus unexposedgroups with no dose data; or “external comparison” with
SMRs or observed/expected (O/E) ratios for the exposedcohort only.

12. In table 1, the LSS cohort of the survivors of theatomic bombings in Japan is presented together with the
Adult Health Study (AHS) cohort, which is a subset of the
LSS.1 Cohort populations irradiated for treatment ofcancer include those treated for cervical cancer, childhood
cancer and childhood lymphoma. These patients received
doses ranging between <1 Gy and 10 Gy to various organs,and they represent high-dose exposure populations. Table
1 excludes a large number of studies of cardiovascular disease risks following high-dose radiotherapy for Hodgkin’s
lymphoma or breast cancer, as these will be the focus ofdetailed examination later in this annex. Patients with avariety of benign diseases (childhood skin haemangioma,
benign lesions in the locomotor system, ankylosing
spondylitis, tinea capitis, post-partum mastitis, thymic
enlargement, tonsil enlargement, benign breast disease,benign gynaecological disorders, lymphoid hyperplasia
and peptic ulcer disease) who were irradiated at a rangeof moderate doses are considered next. Individuals irradiated for diagnostic purposes (fluoroscopic examination,scoliosis) were exposed to relatively low doses, as were
occupationally exposed populations, and these are considered separately. The atomic bombing survivors and occupationally exposed populations are characterized bywhole-body radiation exposure, whereas medically
exposed populations had localized exposures with varying

14. Of these cohort studies, 60% provided mortality or
morbidity data for heart disease, cerebrovascular disease ordiseases of the circulatory system as a whole. The use ofdifferent disease categories in different studies makes it difficult to assess the consistency of the associations. On thebasis of dose–response analysis or trend analysis using dose
categories, significant associations of radiation and circulatory disease (heart disease, cerebrovascular disease or both)were reported from nine cohort studies (atomic bombing
survivors for both heart disease and cerebrovascular disease;
peptic ulcer patients for coronary heart disease; scoliosis
patients for diseases of the circulatory system; and six occupational cohort studies, i.e. the International Agency for
Research on Cancer (IARC) three-country nuclear worker
study for circulatory disease; studies in the United Kingdom
on workers at Sellafield for ischaemic heart disease and at
Springfields uranium production facility for cerebrovasculardisease; the Canadian National Dose Registry study for circulatory disease; and studies on Chernobyl recovery operations workers for both ischaemic heart disease andcerebrovascular disease). The lack of a significant association for circulatory disease was reported from eight cohort
studies (two populations of patients with benign gynaecological disorders and six occupational studies: in the United
Kingdom, the National Registry for Radiation Workers(NRRW) and the studies of the Capenhurst uranium workers and the Chapelcross workers; in the United States, the1 Authors of atomic bombing survivor studies have provided dose estimatesin terms of weighted colon doses, which are the sum of the gamma-ray
dose estimate and 10 times the neutron dose estimate. Early papers often
used grays (Gy) for the units of these weighted doses, while more recent
papers use sieverts (Sv). Throughout this annex, the Committee uses theconvention of sieverts for the units of the weighted colon doses whenaddressing the specific results of the atomic bombing survivor studies.

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Hanford–Oak Ridge National Laboratory (ORNL)–Rocky
Flats weapons plant study and the study at Hanford only;
and in the Russian Federation, the study of workers at the
Mayak nuclear complex). In one of the two studies ofpatients with benign gynaecological disorders, the association of heart disease with radiation exposure was of borderline significance. In the United States nuclear power
utility worker study, dose–response analyses for circulatory
disease and ischaemic heart disease showed significant associations, but trend analyses using dose categories showed
the associations as not significant.
15. Fewer data were available for other non-cancer diseases. About half of the studies provide data on digestive
diseases, 47% on respiratory diseases, 36% on infectious
diseases and 33% on genito-urinary diseases. The specificdisease categories analysed differed among the studies.
16. In addition to the evidence from the studies of the survivors of the atomic bombings, a significant association for
diseases of the digestive system was reported from thefollow-up of patients receiving X-ray monitoring for
scoliosis, though no data were presented [D9], and from two
occupational cohorts (the Springfields uranium production
workers when exposures were lagged for 20 years, andthe Chernobyl recovery operations workers). No significant

association was found in seven cohort studies (the benign
gynaecological disorder patients and six occupational
cohorts: the IARC three-country cohort and the NRRW,
Sellafield, Chapelcross, Capenhurst and Hanford cohorts).
17. A significant association for diseases of the respiratory system has been reported from studies on five cohorts:
the atomic bombing survivors, patients with scoliosis(though data were not presented), NRRW workers (for respiratory diseases unrelated to smoking), Sellafield workers(for pneumonia) and Chapelcross workers (for bronchitis).
The lack of a significant association was found for ninecohorts: benign gynaecological disorder patients, IARC
three-country cohort, Chapelcross workers, Springfields
uranium workers, Capenhurst uranium workers, Canadian
National Dose Registry study, Hanford–ORNL–Rocky Flats
workers, Hanford workers and Chernobyl recovery
operations workers.
18. Data on infectious diseases or genito-urinary diseases
were very scarce, with only one study reporting a significant association for each disease category: patients withscoliosis (for infectious diseases) and patients with benign
gynaecological disorders (for genito-urinary diseases).
The absence of a significant association was reported fromseveral other cohort studies.

StudyNumber of subjects

All non-cancer
diseases

Infectious
diseasesCirculatory
diseases

Respiratory
diseasesDigestive
diseases

Genito-urinary
diseases

Other
diseases

Type of analyses
performed for
non-cancer diseases

Exposure to atomic bombings
P

NSP(stroke, heartdisease)

P

P

NS

P
(blooddisease);I(suicide)

AHS[K5, W5, Y3]

9 641 persons (subset of
LSS)

Mean b 0.83 Sv (exposed
persons)––P(hypertension,
myocardial
infarction)–P(liver disease,cirrhosis)

P(renal andureteralstones)P(uterine
myoma, thyroid
disease)Dose–response
analysis; confounding
effects examined

Dose–response
analysis

Treatment of malignant disease
Cervical cancer
cohort [B10]82 616 exposed women
99 424 unexposed women

Typical doses:
oesophagus, 0.14–0.28;
stomach, 0.7–1.2 [T1]

–

–

–

–

–

–

Non-cancer diseases
not analysed

Hodgkin’s
lymphoma latemortality [H1]2 001 exposed persons
231 unexposed persons

Mediastinum, <30–44––

P(myocardial
infarction, otherheart disease)

–

–

–

Internal comparison(two dose categories:
0–30 Gy, >30 Gy)

Childhood cancers[D6] (France andUnited Kingdom)

3 109 exposed persons
1 291 unexposed persons

Individual doses: breast,
0.7–11; digestive tract,
0.5–13; brain, 0.3–25

–

–

–

–

–

–

Non-cancer diseases
not analysedChildhood Hodgkin’s
lymphoma [B11]

1 380 persons

Individual doses:
oesophagus, 1.5–3.95;
stomach, 10–28 [T1]

–

–

–

–

–

–

Non-cancer diseases
not analysed

Treatment of benign disease
Childhood skinhaemangioma,
Stockholm [L7, L8]

14 351 exposed persons

Childhood skinhaemangioma,
Gothenburg

11 914 exposed persons

Benign lesions inlocomotor system[D7]

20 024 exposed persons

Individual organ doses,
mean: lung, 0.15

Individual red bonemarrow doses, mean:<0.2–>0.5

–

–

–

–

–

–

Non-cancer diseases
not analysed

–

–

–

–

–

–

Non-cancer diseases
not analysed

–

–

–

–

–

–

Non-cancer diseases
not analysed

Page 331

Individual estimatesfor several organs:colon dose b, 0–4 Sv;
mean 0.29 (exposed
persons)

3:44 pm

50 113 exposed persons
36 459 unexposed persons

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LSS [P4, S21]

ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]Non-cancer disease associations found a
Doses: range and mean
(Sv)

UNSCEAR REPORT-PART 6.qxp

Table 1 Studies on radiation-exposed cohorts and reported associations with non-cancer diseases

331Number of subjects

Circulatory
diseases

Respiratory
diseasesDigestive
diseases

Genito-urinary
diseases

Other
diseasesNS–

P(cerebrovascular disease,other circulatory
diseases)P(bronchitis)P(peptic
ulcer, othergenito-urinary
diseases)–P(violence)

O/E ratios, external
comparisons

NS

NS

NS

NS

NS

NS

Internal comparison(exposed versus unexposed or sibling)

1 in 15 sample of the
population, mean:
gastrointestinal tract,
2.43; heart, 2.49; pulmonary region, 1.64

Israel tinea capitis[R11]

10 834 exposed persons
16 226 unexposed persons

Individual doses, mean:
brain, 1.5; thyroid, 0.09

New York tinea
capitis [S11]2 226 exposed persons
1 387 unexposed persons

Individual doses

NS

NS

NS

–

–

–

Internal comparison(exposed versus
unexposed)

New York postpartum mastitis [S12]571 exposed persons
993 unexposed persons

Individual doses:
breast, 0.6–11.5

–

–

–

–

–

–

Non-cancer diseases
not analysed

Rochester thymic
irradiation [H10]2 652 exposed persons
4 823 unexposed persons

Individual doses, mean:breast, 0.69

–

–

–

–

–

–

Non-cancer diseases
not analysed

Tonsil irradiation[S13, S14]

2 634 exposed persons

Individual doses, mean:
thyroid, 0.58

–

–

–

–

–

–

Non-cancer diseases
not analysed

Swedish benign
breast disease[M10]

1 216 exposed persons
1 874 unexposed persons

Individual doses,
mean: lung, 0.75; liver,
0.66; stomach, 0.66;
oesophagus, 0.23

–

–

–

–

–

–

Non-cancer diseases
not analysed

Metropathia haemorrhagica [D8, S3]

2 067 exposed persons

Individual doses, mean:lung, 0.04

–

–

NS
(ischaemic heartdisease)––NS(diseasesof genitals,
breasts,
ovaries, etc.)

Internal comparisons(three dose categories)

Benigngynaecologicaldisorders [I2]4 483 exposed persons

Individual doses:
lung, 0.04–0.06

–

NS

NS

NS

NS

P

Internal comparisons(four dose categories)

Lymphoid
hyperplasia
screening [P5]1 195 exposed persons
1 063 unexposed persons

Individual doses, mean:
thyroid, 0.24

–

–

–

–

–

–

Non-cancer diseases
not analysed

Peptic ulcer[C9, G1]

1 831 exposed persons
1 778 unexposed persons

Individual doses, mean:
heart, 2.1; left lung,
1.79; right lung, 0.55;
left kidney, 14.2; rightkidney, 2.07

–

NS

P
(coronaryheart disease);NS(other heartdisease, stroke)

NS

NS

NS

Dose–response
analysis for circulatory
disease; internal
comparison (exposed
versus unexposed) for
other diseases

Page 332

13 914 exposed persons

UNSCEAR 2006 REPORT: VOLUME I

Ankylosing
spondylitis [D3, L1]

3:44 pm

Infectious
diseases

10/7/08

All non-cancer
diseases

Type of analyses
performed for
non-cancer diseases

UNSCEAR REPORT-PART 6.qxp

Study

332

Non-cancer disease associations found a
Doses: range and mean
(Sv)

Number of subjects

All non-cancer
diseases

Infectious
diseasesCirculatory
diseases

Respiratory
diseasesDigestive
diseases

Genito-urinary
diseases

Other
diseases

Type of analyses
performed for
non-cancer diseases

Diagnostic examinations
NS(all except
tuberculosis
andrespiratory)NS(tuberculosis)

NS

NS

NS

O/E ratios, internal
comparisons (exposed
and unexposed)

Canadian
tuberculosis
fluoroscopy[H11, H12]

25 007 exposed persons
39 165 unexposed persons

Individual exposures:
lung, 0–>3

–

–

–

–

–

Scoliosis [D9]5 573 women with scoliosis
receiving repeated radiographic examinations

Individual doses, mean:bone marrow, 0.01;
lung, 0.041

P(infectious
diseases)P(circulatory
diseases)P(respiratory
diseases)P(digestive
diseases)P(musculoskeletal
conditions)

Dose–response
analysis

–

–

–

P
(externalcauses)

Dose–response analysis for total non-cancer
mortality onlyP(circulatory
diseases)NS

NS(liver cirrhosis)

NS(externalcauses)

Dose–response
analysisNS(smoking-relateddiseases, including coronary
heart disease,aortic aneurysm,
bronchitis,
emphysema,chronic obstructive pulmonary
diseases)P(nonsmokingrelated
respiratory
diseases)NS

I(unknown
causes)

Dose–response
analysis–Non-cancer diseases
not analysed

Occupational exposures
Nuclear workers inJapan [I4]

119 484 workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0153

NS

Nuclear workers
in Canada, United
Kingdom and UnitedStates [C6]95 673 workers (Hanford,
32 595; Rocky Flats,
6 638; ORNL, 6 591;
Sellafield, 9 494; United
Kingdom other than Sellafield,
29 000; Atomic Energy ofCanada Limited, 11 535)

Recorded exposures toexternal radiation: mean
cumulative dose, 0.04

NS

NRRW, United
Kingdom [M5]

124 743 workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.03–

NS

Page 333

Individual exposures,mean: lung, 0.84

3:44 pm

6 285 exposed persons
7 100 unexposed persons

10/7/08

Massachusetts
tuberculosis
fluoroscopy [D4]ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]Study

UNSCEAR REPORT-PART 6.qxp

Non-cancer disease associations found a
Doses: range and mean
(Sv)

333

Sellafield, United
Kingdom Atomic
Energy Authority (UKAEA) andAtomic Weapons
Establishment(AWE) [C10]40 761 monitored workers(Sellafield, 10 028;
UKAEA, 9 389;
AWE, 9 389)

Sellafield [O1]

All non-cancer
diseases

Infectious
diseasesCirculatory
diseases

Respiratory
diseasesDigestive
diseases

Genito-urinary
diseases

Recorded exposures
to external radiation:mean cumulative doses:
Sellafield, 0.1329;
AEA, 0.0406;
AWE, 0.011

NS

–

–

–

–

10 382 monitored workers

Recorded exposures toexternal radiation–I(tuberculosis)

P(ischaemic
heart disease)P(pneumonia)

NS

NS

Chapelcross [M11]2 628 monitored workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0836

–

–

NS

P
(bronchitis)

NS

NS

Springfields uranium
production [M12]

13 960 monitored workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0228

–

NS

P
(cerebrovasculardisease)

NS

P

NS

Capenhurst uranium
enrichment [M7]

3 244 monitored workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0098

–

NS

NS

NS

NS

NS

Canadian National
Dose Registry [A2]

206 620 monitored workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.06

–

NS

P
(circulatory
diseases)

NS

–

NS

Hanford, ORNL
and Rocky Flats
weapons plant [G6]44 943 monitored workers(Hanford, 32 643;
ORNL, 6 348;
Rocky Flats, 5 952)

Recorded exposures
to external radiation:mean cumulative doses:
Hanford, 0.026;
ORNL, 0.022;
Rocky Flats, 0.041

NS

–

NS

NS

P
(cirrhosis)

Other
diseases

Type of analyses
performed for
non-cancer diseases
Dose–response
analysis

10/7/08

Internal comparisons(seven dose categories)

P(nervous andsense organdiseases,
prostatic
hyper-trophy,
accidents/
violence)

Internal comparisons(seven dose categories)

Internal comparisons(seven dose categories)

P(accidents)

Dose–response
analysisNS(externalcauses)Internal comparison(six dose categories)

Page 334

Dose–response analysis (ischaemic heartdisease, pneumonia,
mental disorders);
internal comparisons(tuberculosis, digestiveand genito-urinary
diseases, accidents/
violence)

UNSCEAR 2006 REPORT: VOLUME I

P(mentaldisorders);
I(accidents/
violence)

3:44 pm

Number of subjects

UNSCEAR REPORT-PART 6.qxp

Study

334

Non-cancer disease associations found a
Doses: range and mean
(Sv)

Number of subjects

All non-cancer
diseases

Infectious
diseasesCirculatory
diseases

Respiratory
diseasesDigestive
diseases

Genito-urinary
diseases

Type of analyses
performed for
non-cancer diseases

Otherdiseases

NS

–

NS

NS

NS
(cirrhosis)

NS(externalcauses)Internal comparison(five dose categories)

Portsmouth Naval
Shipyard [R12]8 960 monitored workers

Recorded exposures toexternal radiation: <1.5
(range)

–

–

–

–

–

–

Rocketdyne/
Atomics
International [R13]

4 563 monitored workers

Recorded exposures
to external radiation:
cumulative dose 0–0.2

–

–

NS

NS

NS

NS

NS

External comparison,
single SMR values

Mound facility [W6]3 229 monitored workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0297

–

NS

NS

NS

NS

NS

NS
(injuries)

External comparison,
single SMR values

Nuclear power utilities, United States[H13]

53 698 monitored workers

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0257

P

NS

P
(circulatory system,
arteriosclerotic
heart disease)

NS

NS

NS

Chernobyl recovery
operations workers,
Russian Federation[I1]

68 309 workers

Assessed external radiation doses: 0–0.02+

NSP(essential
hypertension,
cerebrovasculardisease)NS(hypertensive
heart disease,ischaemic heartdisease)

NS

P

NS

P
(endocrine/
metabolicdiseases,mentaldisorders)Dose–response
analysis

Chernobyl recovery
operations workers,
Estonia [R14]4 742 workers

Recorded radiation
doses: mean, 0.11

–

–

NS

–

NS

–

P
(suicide)

External comparisons,
SMRs only

Mayak workers[B12]

15 601 persons monitored
for external radiation

Recorded doses toexternal radiation, mean:lung, 3.8–35

–

–

NS
(cardiovasculardisease)

–

–

–

–

Circulatory disease data
significant by dose–
response analysis;
not significant by trend
tests using dose
categories

Internal comparisons(three dose categories)

Page 335

Recorded exposures toexternal radiation: mean
cumulative dose, 0.0233

3:44 pm

37 971 monitored workers

10/7/08

Hanford [G7]ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]Study

UNSCEAR REPORT-PART 6.qxp

Non-cancer disease associations found a
Doses: range and mean
(Sv)

335

Number of subjects

All non-cancer
diseases

Infectious
diseasesCirculatory
diseases

Respiratory
diseasesDigestive
diseases

Genito-urinary
diseases

Type of analyses
performed for
non-cancer diseases

Otherdiseases

–

–

–

–

–

–

Danish radiotherapy
staff [A5]4 151 radiotherapy workers

Recorded exposures toexternal radiation

–

–

–

–

–

–

–

Chinese X-ray
workers [W2]

27 011 X-ray workers

Recorded exposures toexternal radiation

–

–

–

–

–

–

–

United Statesradiologic
technologists [H3]90 284 radiologic
technologists

Recorded doses toexternal radiation–P(ischaemic heartdisease, stroke)

–

–

–

Internal comparisonsusing exposure surrogates (periods of
employment); adjusted
for confounding effects

United Kingdom
radiologists [B4]2 698 radiologists

NS

NS

–

–

–

United Statesradiologists [M2]

6 500 radiologists–

P(cardiovasculardisease)

–

–

–

NS

NS
(externalcauses)Internal comparisonsusing exposure surrogates (periods of
employment)Internal comparisonsamong different medical professions andcalendar years

a P = positive, I = inverse, NS = not significant; (–) indicates no published data.
b Dose estimates are provided in terms of weighted colon doses, which are the sum of the gamma-ray dose estimate and 10 times the neutron dose estimate. This annex uses as a convention sieverts for the units ofweighted colon doses.

Page 336–

3:44 pm

Recorded exposures toexternal radiation

10/7/08

9 179 radiologic
technologists

UNSCEAR 2006 REPORT: VOLUME I

Japanese radiologic
technologists [Y2]UNSCEAR REPORT-PART 6.qxp

Study

336

Non-cancer disease associations found a
Doses: range and mean
(Sv)

UNSCEAR REPORT-PART 6.qxp

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Page 337

III. DATA ON NON-CANCER MORTALITY FOR SURVIVORSOF THE ATOMIC BOMBINGS
19. This section examines the LSS data on non-cancer
mortality in some additional detail, because the analyses ofthe mortality data on the LSS cohort represent the mostthorough evaluation to date of the association between radiation exposure and non-cancer disease risks. The LSS mortality data provide evidence of a dose response for mortality
from heart disease, stroke, respiratory diseases (largely
pneumonia, 67%) and digestive diseases (including a large
proportion of liver cirrhosis, 44%). Non-cancer risk estimates and dose responses for different disease categories
presented in table 2 and figure I are derived from the analysis of the full follow-up period from 1950 to 1990 [S20].
The LSS non-cancer mortality data were updated more
recently, to 1997, and were analysed in more detail [P4,Z1], as discussed later in this annex, but the overall risk
estimates for the full follow-up period remained essentiallyunchanged. There is no evidence of a dose response for mortality from infectious diseases (largely tuberculosis) andother diseases (including diseases of the genito-urinary
system). Several potential sources of bias and confounding
have been considered [S20], including: (a) the possibility
that the construction of this cohort five years after the bombings may have led to the selection of study subjects in amanner that would bias the non-cancer disease outcomes;(b) possible misclassification of causes of death that may
give rise to a spurious association between non-cancer mortality and radiation dose; and (c) the possibility that radiation dose, which is closely correlated with distance from the
hypocentre, may be confounded by other factors affecting
non-cancer disease rates. The impact of these potential
biases, which was analysed by pooling non-cancer mortality (excluding blood diseases), is discussed below.

Figure I. Dose–response curve of mortality from all diseases except neoplasms and blood disease
Both cities, both sexes, all ages at the time of bombing, 1950–1985. Bars indicate 90% confidence interval of relative risk [S20]2.0

RELATIVE RISK

1.5

1.0
0.9
0.8

0
0

1

2

3

4

WEIGHTED COLON DOSE (Sv)337

5

UNSCEAR REPORT-PART 6.qxp

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3:44 pm

338

Page 338

UNSCEAR 2006 REPORT: VOLUME I

Table 2 Number of deaths and ERR estimates for major categories of non-cancer disease
Life Span Study 1950–1990 [S20]
Cause of death

Number of deaths

ERR per unit weighted
colon dose a (Sv–1)

90% confidence interval

p-value(1-sided)

Stroke

7 859

0.09

(0.02, 0.17)

0.02

Cerebral haemorrhage

3 687

0.03

(–0.06, 0.14)

Cerebral infarction

1 611

0.07

(–0.09, 0.25)

Other

2 561

0.20

(0.06, 0.35)

Heart diseases

6 826

0.14

(0.05, 0.22)

Coronary heart disease

2 362

0.06

(–0.06, 0.20)

Hypertensive heart disease

1 199

0.21

(0.00, 0.45)

Other

3 265

0.17

(0.05, 0.31)

Respiratory diseases

3 163

0.18

(0.06, 0.31)

Pneumonia

1 828

0.20

(0.04, 0.37)

Asthma397

0.08(–0.18, 0.45)

Other

938

0.19

(–0.02, 0.43)

Digestive diseases

2 742

0.11

(0.00, 0.24)

Liver cirrhosis

920

0.18

(0.00, 0.40)

Other

1 822

0.07

(–0.07, 0.23)

Infectious diseases

1 705–0.002(–0.13, 0.15)

Tuberculosis

1 368

0.01

(–0.13, 0.19)

Other

337

–0.07

(<–0.10, 0.29)

Other diseases

4 822

0.01

(–0.08, 0.11)

Chronic renal disease

551

0.003

(–0.22, 0.30)

Senility

1 906

0.09

(–0.08, 0.29)

Other

2 365

–0.02

(–0.13, 0.10)

0.003

0.005

0.05

>0.50

0.41

a The authors express the weighted colon dose in sieverts as the sum of the gamma-ray dose and 10 times the neutron dose.

A. Misclassification
20. Using data from a large number of autopsies carriedout in the LSS as the diagnostic reference, it was estimatedthat on average 20% of cancer deaths are misclassified ondeath certificates as being due to non-cancer causes (“cancer
to non-cancer misclassification”), while 3.5% of deaths
from causes other than cancer are mistakenly classified ascancer deaths (“non-cancer to cancer misclassification”)[R5, S6]. Sposto et al. [S6] demonstrated that after correction for the cancer to non-cancer misclassification rates byage, sex, time and city, estimates for ERR of non-cancer
mortality were reduced by about 20% relative to estimatesthat ignored the misclassification. In conclusion, in the LSS,
disease misclassification on death certificates has an effecton estimates of risk for non-cancer disease, but the dose
response for non-cancer disease remains highly significant
even after correcting for this effect.
21. Because misclassification rates vary among different
causes of death (they are especially high for respiratory

diseases, for example), their impact on estimates for causespecific mortality from non-cancer disease will vary but
remains unassessed [R5]. Sposto et al. [S6] suggested twoalternative ways to correct for misclassification for a specific disease entity. One was to create two disease categories, e.g. heart disease and all other causes combined, andto estimate the misclassification probabilities. Alternatively,
more than two classifications could be used, pooling causesof death that are similar.

B. Biases and confounders
22. Because radiation doses were dependent on the distance from the hypocentre, a spurious dose effect could
arise if proximal and distal survivors differed with respect
to socio-economic status, lifestyle or other risk factors.
First, this question was directly examined by assessing thepossible confounding effect of smoking and other factors[S20] using data obtained from mail surveys conductedUNSCEAR REPORT-PART 6.qxp

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Page 339

ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]among the LSS cohort subjects during the 1960s and 1970s.
Potential factors, such as educational level, occupation,
physical activity at work, house size per person (as a surrogate measure of socio-economic level), marital status,
smoking status, regular alcohol use and percentage ofJapanese food in diet, were analysed. Non-cancer underlying mortality rates varied significantly with each of thesefactors. The magnitude of the effects of many of these factors was comparable to, or even larger than, the differencein risk associated with exposure to 1 Sv. For example,
smoking at the time of the mail surveys increased the noncancer mortality rates by 37%. However, the associations
between these factors and dose were not strong enough tosignificantly alter the risk associated with radiation doses;
for example, there was only a 2% difference in the frequency of smoking associated with exposure to 1 Sv versus
0 Sv. Statistical adjustment for smoking reduced the estimate of ERR per unit dose only from 0.083 Sv–1 to 0.079
Sv–1 (table 3). In no case did the failure to allow for anyof the other factors have an appreciable impact on the risk
estimate for non-cancer disease from radiation exposure.
When five factors (smoking, marital status, education,
occupation and house size per person) were all taken into
account, the estimate for ERR per unit dose for non-cancer
disease was reduced from 0.097 Sv–1 to 0.087 Sv–1. Thesefindings indicate that the observed association between
radiation and non-cancer mortality cannot be explained by
the confounding effect of any of these factors, although thepossibility of confounding by other unidentified or unmeasurable factors cannot be eliminated.
23. In further analysis [S20], the dose–response analyses
for non-cancer disease were limited to the 61,000 proximal
survivors (those exposed within 3 km of the hypocentre).
The ERR estimate obtained from this subcohort was
0.11 Sv–1, which was consistent with the estimate derived
from the full cohort data. Furthermore, a significant

339

radiation dose effect was found even when the analysis waslimited to about 3,000 survivors who were between 0.9 and1.2 km from the hypocentre, a span of 300 m in whichweighted colon radiation dose estimates ranged from 0.35
to 5.8 Sv (median dose 1.1 Sv). It was considered implausible that there would be enough dose-correlated variation
in socio-demographic characteristics over this narrow distance band to account for the observed dose response. It
should be noted that atomic bombing survivors have showna high prevalence of infection with the hepatitis C virus,
an important cause of both liver cancer and liver cirrhosis[S19]. This may have played a cofactor role in the occurrence of liver disorders among exposed atomic bombing
survivors.

C. Selection effects
24. The presence of cohort selection effects was suggested
by temporal patterns of the LSS underlying rates of noncancer diseases. The underlying rates of non-cancer diseasein the year 1950 were about 15% lower for proximal survivors (i.e. those who were within 3 km of the hypocentre,
generally an urban area, but for whom doses were estimatedas zero because of shielding) than for distal survivors withzero dose (who were between 3 and 10 km of the hypocentre, generally a rural area), but this difference diminished
to about 2% in the late 1960s [P4]. While this small difference in the rates of non-cancer disease seemed to persist, and may reflect the urban–rural, socio-economic orother differences affecting underlying rates, the diminishing difference in rates with time in the earlier years wasconsidered to be due to the selection of healthy survivors,
resembling the healthy worker effect seen in studies ofoccupational cohorts. Thus proximal survivors included in
the LSS may have been initially healthier than the general

Table 3 Risk estimates for non-cancer disease due to radiation with and without adjustment for potential confounders
Life Span Study 1950–1990 [S20]
Risk factor

ERR per unit dose a (Sv –1)

Number of subjects with data available
Unadjusted

Adjusted

Highest education level

38 035

0.086

0.088

Occupation

36 766

0.098

0.097

Physical activity at work

7 364

0.088

0.097

House size per person

26 562

0.071

0.068

Current marital status

37 543

0.104

0.097

Current smoking status

38 975

0.083

0.079

Current alcohol use

34 470

0.133

0.144

Per cent of Japanese food in diet

7 292

0.085

0.084

a Weighted colon dose.

UNSCEAR REPORT-PART 6.qxp

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340

UNSCEAR 2006 REPORT: VOLUME I

population, since they were able to survive the effects ofthe bombings and/or the difficult living conditions in thetwo cities in the immediate post-war period.

of about 0.55 Sv. For the period before 1968, the data suggest a non-linear dose response. The non-linearity in theearly LSS data is reduced but not totally accounted for by
adjustments based on proximal–distal comparisons; thismay be due to a residual proximal–distal effect that remains
after the simple adjustment above [P4].

D. Dose response and risk estimates
25. The shape of the dose–response curve for non-cancer
diseases is influenced by making allowance for the presumed healthy survivor effect, which depends on time anddistance, and causes a small but persistent urban–rural difference in underlying rates [P4]. Because the effect is more
pronounced in the earlier years of follow-up, the analysis
restricted to the period before 1968 reveals significant curvature in the dose response (figure II, left panel), while there
is no evidence of non-linearity in the later period,
1968–1997 (figure II, right panel). The small urban–rural(proximal–distal) differences in underlying rates add asmaller curvature to the dose response in the full cohort
compared with the proximal survivors in both the pre-1968
and the 1968–1997 periods (figure II, left and right panels).
26. Figure III shows fitted linear and smoothed
dose–response curves for the 1968–1997 period with noadjustment for proximal–distal differences in underlying
rates [P4]. There is no indication of significant non-linearity in the dose response. However, there is considerable
uncertainty regarding the dose response or even the existence of an effect at doses of below about 0.5 Sv. There isno evidence against a threshold of zero, and the maximumlikelihood estimate of the threshold in the adjusted analysis is about 0.15 Sv, with an upper 90% confidence bound27. The non-cancer mortality data for the period of
1950–1967 show that a linear–quadratic or quadratic
dose–response model may be adequate [P4]. However, since
the distance-dependent selection effects among the proximal survivors are likely to have biased the estimates ofvalues for dose–response parameters for this period, generalization of these estimates to other populations or
different exposure situations may not be warranted.
28. Analysing the same LSS non-cancer mortality data forthe period 1968–1997, Little used a variety of generalized
relative risk models assuming 25%, 35% and 45% geometric standard deviation (GSD) dosimetric errors [L10].
When linear–threshold, quadratic–threshold, or linear–quadratic–threshold relative risk models were fitted, there
was no evidence of threshold models significantly different
from the linear, quadratic or linear–quadratic models. Thesefindings were true irrespective of the assumed dosimetricerrors. There was also little evidence of excess risk below
0.5 Sv. In general, these findings were true for the four
major disease categories considered, i.e. stroke, coronary
heart disease, digestive disease and respiratory disease.
29. Because the ERR for mortality from non-cancer
disease is considerably smaller than that for mortality fromsolid cancers, and because underlying rates of non-cancer

Figure II. Fitted curves of mortality from non-cancer diseases in the LSS cohort for early (1950–1967, left panel) andlate (1968–1997, right panel) periods of follow-up [P4]
Solid curve fits use only proximal survivor data; dashed curve fits are based on the full cohort without allowance for selection effects

0.6

0.6

1950-67

1968-97
Proximal only
Unadjusted

EXCESS RELATIVE RISKEXCESS RELATIVE RISK

Proximal only
Unadjusted

0.4

0.2

0.4

0.2

0.0

0.0

0.0

0.5

1.0

1.5

2.0

2.5

WEIGHTED COLON DOSE (Sv)

3.0

0.0

0.5

1.0

1.5

2.0

2.5

WEIGHTED COLON DOSE (Sv)

3.0

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Page 341

ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]341

Figure III. Mortality from non-cancer disease in the LSS cohort versus dose for the period 1968–1997 [P4]
Individual points are dose-category-specific ERR estimates. The thin straight solid line is the fitted linear ERR model without any effectof age at exposure, sex or attained age. The thick solid curve provides a smoothed estimate derived from the individual points, withthe two dashed curves indicating ±1SE (standard error). The right panel represents the same data as in the left panel, but shows the
low-dose portion of the fitted curve in greater detail

0.2

EXCESS RELATIVE RISK

0.6

0.4
0.1

0.2
0.0

0.0
-0.1
0.0

0.5

1.0

1.5

2.0

2.5

3.0

WEIGHTED COLON DOSE (Sv)disease are much higher than rates of cancer, any modifying effect of age, time and sex on the risk is difficult to
detect. The ERR for non-cancer disease decreases withincreasing age at exposure, decreases with attained age andis lower for men than for women, although none of theseeffects is statistically significant [P4]. Others [L10, Z1] who
have analysed the LSS data have also found that age at
exposure has no significant effect on the risk of non-cancer
disease.
30. There are two main sources of uncertainty in the current LSS dose–response data for estimating the lifetime riskof non-cancer disease due to radiation exposure. First,
because of the uncertainty about how the risk varies withage, sex and age at exposure, three different risk models
are used: (a) the constant ERR model; (b) an alternative
ERR model with age-at-exposure and sex effects; and (c)an excess absolute risk (EAR) model with no age-at-

0.00

0.25

0.50

0.75

1.0

WEIGHTED COLON DOSE (Sv)exposure effects. Age-specific underlying rates of noncancer disease have declined rapidly in Japan, but the timeconstant ERR model provides lifetime risk estimates thatare insensitive to age at exposure. In contrast, the other twomodels (ERR and EAR) depend on age at exposure, andpredict decreasing risks with increasing age (figure IV). In
any case, the results suggest that the lifetime risks of noncancer disease among those exposed as children may be half
the risks or less than those for solid cancer, while persons
exposed at age 50 may have lifetime risks of non-cancer
disease equal to those for solid cancer [P4]. Second, because
there is great uncertainty about the shape of thedose–response relationship at low doses, the current estimates for lifetime risk are presented for exposure at 1 Sv,
where the estimates are little affected by the shape of thedose–response curve. The magnitude of the risk of
non-cancer disease at lower dose levels, e.g. 0.5 Sv, is atpresent very uncertain.

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Figure IV. Estimates of lifetime risk (two upper graphs) and of years of life lost per excess death (two lower graphs)
at 1 Sv weighted colon dose (from LSS Report 13 [P4])The two left-hand graphs show the estimates for women, the two right-hand graphs those for men. Estimates represented by thedark solid curves are based on constant ERR models. Estimates based on age-at-exposure and sex-specific ERR models (dashedcurves) or on an EAR model (dash-dotted curves) are also shown

LIFETIME RISK (%)

Women

Men

20

20

15

15

10

10

5

5
Constant ERR
Age at exposure and sex dependent ERR
EAR

0

0

LIFE LOST PER EXCESS DEATH (YEARS)

0

20

40

60

12

12

8

8

4

4

0

20

40

60

0

20

40

60

0

0
0

20

40

60

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IV. CIRCULATORY DISEASES
31. Diseases of the circulatory system (circulatory diseases) are leading causes of morbidity and mortality among
adults worldwide, and are the cause of 30–50% of all deaths
in many countries. In comparison, malignant neoplasms are
the cause of 15–30% of all deaths. Atherosclerosis is a generalized underlying condition for the majority of circulatory
diseases in adult populations and has three major clinicalmanifestations: cerebrovascular disease, coronary (orischaemic) heart disease and peripheral vascular disease.
Coronary heart disease and stroke are the major causes ofdeath from circulatory diseases. Risk factors for atherosclerotic disease traditionally have included high blood pressure, cigarette smoking, hypercholesterolaemia (especially
increased low-density lipoprotein (LDL) cholesterol) anddiabetes. Factors such as obesity, family history of premature coronary heart disease and oestrogen replacement therapy have also been associated with coronary heart disease.
Heavy alcohol intake increases mortality from coronary
heart disease, but moderate intake appears to have a protective effect against the disease [T6].

and Related Health Problems (ICD-10) [W7]. “Circulatory
disease” will be used to refer to the entire group of diseasesof the circulatory system (I00–I99), including any form ofheart disease (I00–I02, I05–I09, I10–I15, I20–I25, I26–I28,
I30–I52), cerebrovascular disease (I60–I69), and diseases of
the arteries, diseases of other vessels and diseases not elsewhere classified (I60–I69, I70–I79, I80–I89). “Heart disease” will refer to any form of disease of the heart as defined
above. “Ischaemic heart disease” (I20–I29), which is often
used synonymously with coronary heart disease in the literature, will include angina pectoris, myocardial infarction
and its complications. “Cerebrovascular disease” (I60–I69)
includes stroke, haemorrhagic infarction or unspecified,and its sequelae. “Stroke” is used synonymously with thisdisease category.

A. Patients receiving radiotherapy for cancer
34. The heart at one time was considered to be a radiation-resistant organ; only isolated examples of radiationinduced carditis were available in the early literature. Thiswas in part due to the limitations on thoracic irradiation
posed by the much greater radiosensitivity of the lungs. In
the mid-1960s, cases of radiation-induced heart diseasebegan to be reported from a large series of Hodgkin’s lymphoma patients who had survived irradiation of the mantle
field. Therapeutic doses were very high, exceeding 30–40
Gy in most cases. Damage to the heart is considered to be
due to tissue destruction from such high doses. The changes
in heavily irradiated patients can involve all structures of
the heart (including the pericardium, myocardium, valves,
conduction system and coronary arteries), but most characteristically the pericardium, and can include pericardial effusion, fibrosis and constrictive pericarditis [A3, F1]. The term“radiation-induced heart disease” has been used to refer tosuch conditions [S2]. Initially, coronary heart disease or
myocardial infarction was only occasionally reported, but
starting in the early 1990s, an excess risk of myocardial
infarction after radiation treatment began to be noted inpatients with Hodgkin’s lymphoma or breast cancer. Much
information has since been accumulated on the risk of coronary heart disease subsequent to cancer radiotherapy.

32. Diseases of the heart may be broadly categorized asischaemic heart disease (most importantly myocardial infarction), hypertensive heart disease, valvular heart disease, nonischaemic (primary) myocardial disease and congenital heartdisease. These different types of heart disease markedly
differ in pathogenesis, aetiology, clinical presentation andprognosis. Ischaemic heart disease is the late manifestationof coronary atherosclerosis and is responsible for the majority (80–90%) of the cardiac deaths in most countries [S18].
The effects of radiation exposure at low doses on this category of heart disease and underlying atherosclerotic changes
are of special concern in this annex. Hypertensive heart disease occurs in response to systemic hypertension, leading toheart dysfunction or congestive heart failure, among others.
Valvular heart disease may be caused by congenital disorders or by various acquired diseases, including rheumaticheart disease. Primary myocardial disease may occur as aresult of inflammatory disease (myocarditis), immunologicaldisease, systemic metabolic disorders, muscular dystrophies,
genetic abnormalities or other unknown causes. These different categories of heart disease can be coded using theInternational Classification of Diseases (ICD) scheme
adopted by most epidemiological follow-up studies.
33. In the literature, the term “cardiovascular disease” isused interchangeably to refer to the broad category that
includes all diseases of the circulatory system or more
specifically to heart disease. This annex follows the nomenclature used in the International Classification of Diseases

1. Hodgkin’s lymphoma patients
35. Until 1960, the treatment of Hodgkin’s lymphoma
was usually considered palliative, but starting around 1960,
343

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curative treatment of this disease began to evolve rapidly
with new radiotherapy and chemotherapy regimens. With
the introduction of megavoltage radiotherapy, techniques
to treat extensive fields became available. With the development of mantle field irradiation and total lymphoid irradiation, radiotherapy became the cornerstone of thetreatment of Hodgkin’s lymphoma [C1]. Megavoltage
equipment delivered a dose to deeper parts of the body.
In the 1960s, doses of 40–44 Gy were often given to
involved fields [K1, N1]. Before 1960, if radiation was
employed at all, smaller doses were used to treat earlystage Hodgkin’s lymphoma, although at some medical centres doses of 25–30 Gy were administered to involved
nodal and proximal areas [D1].
36. In the late 1970s and early 1980s, it became apparent
that radiotherapy given to extended fields at high doses
could induce late mortality from lung damage, myocardial
infarction and second cancers. Modifications were thenintroduced to reduce radiotherapy fields and doses whenever possible. From the mid-1970s to 1994, 30–40 Gy wascommonly given when radiotherapy was used without cytotoxic drugs, while an average of 30 Gy was administeredwhen used in combination with chemotherapy [D2]. Before
the early 1970s, similar therapy was given to paediatric andadult Hodgkin’s lymphoma patients. Thereafter, treatmentof Hodgkin’s lymphoma in children was modified to use
lower doses (15–25 Gy to involved fields); therapy regimens for fully developed adolescents still incorporated
larger doses (35–44 Gy) [M1].
37. Some earlier literature linked coronary artery disease
to cancer treatment [K2]. Among the earliest follow-up
studies was one by Boivin et al. [B1]. In a cohort of 4,665
Hodgkin’s lymphoma patients treated at 11 cancer treatment
centres in the United States and Canada (Boston, Houston,Montreal and Toronto), 124 cases who died either directlyfrom or with coronary heart disease were compared with
489 controls randomly selected from the entire cohort. The
age-adjusted relative risk of death with any coronary heartdisease after radiotherapy was non-significantly elevated(1.87), but the relative risk of death with myocardial infarction was significantly elevated (2.56). When the analysis
was restricted to coronary heart disease as the direct causeof death, the age-adjusted relative risk associated with radiotherapy was significantly increased (3.11). The patients
included both children and adults diagnosed between 1940
and 1985. Cardiac radiation doses were not available. The
relative risk for those treated in the early period (before
1965–1970), when high-dose orthovoltage irradiation wasused, was higher, but not significantly, than for those treatedin later years.
38. To date, the most detailed analysis of risk of mortality from heart disease after radiotherapy for Hodgkin’s lymphoma comes from the cohort study of 2,232 paediatric andadult patients irradiated during 1960–1990 at Stanford
University Medical Centre (table 4) [H1]. The patients were
followed on average for 9.5 years; 1,609 patients received

mediastinal irradiation from mantle therapy; 369 received
less extensive, limited field irradiation; 23 received irradiation for recurrent disease; and 231 received no mediastinal irradiation. Mean mediastinal doses were lower among
patients treated before 10 years of age (21.5 Gy) and after
50 years of age (28.7 Gy) than for other age groups(36.7–40.5 Gy). Of the 88 deaths from heart disease, 55
were from acute myocardial infarction and 33 from othercardiac diseases.
39. The relative risk (RR) of death from acute myocardial infarction calculated on the basis of comparison with
the United States Life Tables was 3.2 for the entire cohort,with no significant sex difference. The RR was higher forpatients treated with radiation alone (RR = 4.1, mean dose
50.7 Gy) than for those treated with both chemotherapy andradiation (RR = 2.7, mean dose 43.3 Gy) or for those who
received no mediastinal irradiation (RR = 1.7) (table 4). A
significantly elevated RR of 3.5 was found for patients irradiated at ≥30 Gy (mediastinum dose); the RR of 4.2 forthose irradiated at <30 Gy was derived from only two
subjects.
40. Of the 33 deaths from cardiac diseases other thanacute myocardial infarction, about half (15) were deaths
from chronic pancarditis or pericarditis. The RR of othercardiac deaths was elevated both for patients treated withradiation alone (RR = 3.2) and for those treated withchemotherapy and radiation (RR = 3.6) (table 4).
41. In this cohort, very few patients were treated withcombination chemotherapy, mostly MOPP, without radiotherapy. The relative risk for all cardiac disease mortality
for this group of patients was elevated (1.6), but not significantly, and this was consistent with the earlier analysis
by the same investigators, which indicated the absence ofan excess risk of coronary heart disease in Hodgkin’s
lymphoma patients treated with chemotherapy [H14].
42. Several risk-modifying effects were noted. As discussed in more detail later, the most notable were the effects
of age at treatment. A higher risk of heart disease, bothmyocardial infarction and other heart diseases, was foundamong patients treated at young ages, especially at less than
20 years. Also, the relative risk of acute myocardial infarction and other cardiac diseases increased with time after
treatment. Blocking to limit cardiac exposure (subcarinal
block) reduced the relative risk of cardiac diseases otherthan myocardial infarction from 5.3 to 1.4, but not that ofacute myocardial infarction (RR = 3.7 versus 3.4).
Subcarinal blocking reduces the volume of the heart
exposed to irradiation but does not provide protection to theproximal part of the coronary arteries [A3].
43. Although information on smoking was not available
for the entire cohort of Hodgkin’s lymphoma patients, a
subset of the subjects participated in a questionnaire andinterview study. Among the Hodgkin’s lymphoma patients,
52.6% had never smoked cigarettes and 24.5% had formerly

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Table 4 Risks of death from myocardial infarction and other cardiac diseases after treatment for Hodgkin’s lymphoma
Stanford Study [H1]Group
(number of patients at risk)

All patients

Acute myocardial infarction

Other cardiac diseases

Numberobserved/expected

Relative risk
(95% CI)

Absolute risk

Numberobserved/expected

Relative risk
(95% CI)

Absolute risk

55/17.3

3.2 (2.3, 4.0)

17.8

33/11.5

2.9 (1.9, 3.9)

10.2

Male (1 316)

47/14.3

3.3 (2.3, 4.2)

27.0

24/8.32.9 (1.7, 4.1)

13.0

Female (916)8/3.0

2.6 (1.2, 5.0)

5.5

9/3.2

2.8 (1.4, 5.1)

6.4

Radiation alone a (1 183)

35/8.44.1 (1.2, 5.5)

25.7

17/3.33.2 (1.9, 4.0)

11.4

Combined treatment (1 119) a

14/5.22.7 (1.5, 3.8)

9.7

12/3.33.6 (2.0, 6.1)

9.6

6/3.6

1.7 (0.7, 3.5)

4/2.9

—b
—b

Mediastinum radiation
treatment:
None (254)2/0.5

4.2 (0.7, 13.8)

—b
—b

0/0.3

1.4 (0.4, 3.4)—b47/13.3

3.5 (2.5, 4.5)

18.6

29/8.43.5 (2.2, 4.7)

11.4

26/7.03.7 (2.3, 5.1)

24.7

23/4.35.3 (3.1, 7.5)

23/6.83.4 (2.0, 4.8)

13.9

6/4.3

1.4 (0.6, 2.9)

24.2
—b

6/0.1444.1 (17.8, 91.6)

11.3

4/0.1921.5 (6.8, 52)

7.3

20–29 (749)8/1.1

7.3 (3.4, 13.8)

9.0

7/0.798.8 (3.8, 17.4)

8.1

30–39 (448)14/2.75.1 (2.9, 7.4)

27.4

7/1.5

4.8 (0.5, 5.1)

40–49 (169)9/3.0

3.0 (1.4, 5.5)

3/1.6

1.9 (0.5, 5.1)

>50 (148)

12/6.81.8 (1.0, 3.0)

43.6
—b

13.4
—b

8/4.6

1.7 (0.8, 3.3)—b

0–4 (NA) c

12/6.02.0 (1.1, 3.3)

6.4

6/4.1

1.5 (0.6, 3.0)—b

5–9 (NA)

17/4.7

3.6 (2.2, 4.5)

20.1

10/3.13.2 (1.6, 5.7)

10–14 (NA)

11/3.73.0 (1.6, 5.2)

20.5

5/2.4

2.1 (0.8, 4.6)

11.3
—b

15–19 (NA)

11/2.25.0 (2.6, 8.7)

54.2

8/1.4

5.8 (2.7, 10.9)

40.7>20 (NA)

4/0.7

5.6 (1.8, 13.6)

70.6

4/0.5

8.8 (2.8, 21.3)

76.1

0–30 Gy (131)>30 Gy (1 830)
Before 1972 (553)
After 1972 (1 448)
Age at irradiation, years:<20 (487)

Years after treatment:a Includes mediastinum.
b Risk was not significantly elevated.
c NA = number of patients at risk not available.

smoked cigarettes. These figures were comparable to thosereported for United States adults (of whom 51.2% had neversmoked and 24.1% were former smokers), so it seems
unlikely that the increased risk of acute myocardial infarction observed among the cohort of Hodgkin’s lymphoma
patients is explained by their smoking habits.
44. Other studies, generally of cohorts smaller in size thanthe Stanford cohort, have also reported increased risk (asmeasured by SMR) of mortality from myocardial infarction
after radiotherapy for Hodgkin’s lymphoma (table 5) [A7,C2, H9, K3, M6, R1]. Radiation doses received by the
Hodgkin’s lymphoma patients in these studies were in therange 35–45 Gy, except for the paediatric patients who weretreated in 1980–1900 and received 20 Gy [H9].

45. Elevated SMRs ranging from 2 to 5 are in generalagreement with the relative risks (which are actually SMRs)
reported from the Stanford study [H1]. The very high SMRof 22 for cardiac death in paediatric patients irradiatedbetween the ages of 3 and 22 years [H9] involved six deaths
from cardiac disease, five of which were from myocardial
infarction and occurred in males receiving 35–37 Gy fromextended radiotherapy. Three of these six cases had received
concomitant cyclophosphamide chemotherapy, which may
also have contributed to cardiac myocyte injury.
46. Most results reported from follow-up of irradiatedHodgkin’s lymphoma patients are based on external comparisons, with a few studies using limited internal comparisons. Nevertheless, the reported SMRs, which are sometimes

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Table 5 Risks of heart disease after radiotherapy for Hodgkin’s lymphoma, other than the Stanford study
Study and year

Study population

Age at treatment(years)Length of follow-up(years)Results a

Dose
(Gy)

King et al., 1996 [K3]326 patients treatedbetween 1954 and 1989;
Rochester, New York,
United States

25.6 (mean);
5–72 (range)

13.3 (mean);
3–37 (range)

Central cardiac dose:
44.3 (mean);
35–60.4 (range)

Increased SMR (2.8) for
fatal myocardial infarction among the irradiatedpatients

Reinders et al., 1999
[R1]

258 patients treatedbetween 1965 and 1980;
Netherlands

28 (median);
5–78 (range)

14.2 (median);
0.7–26 (range)

Mediastinum inferiordose:
37.2 (mean)

SMR = 5.3 for ischaemic heart disease among
the irradiated patients

Cosset et al., 1991 [C2]499 patients treatedbetween 1971 and 1984;
Villejuif, France

Not available

Not available

Mediastinal dose:
39–41 (68%);
35–37 (11%);
41–43 (7%)

Increased RR of 3.25
for pericarditis among
patients irradiated at>41 Gy; no elevated RR
of myocardial infarction

Mauch et al., 1995 [M6]794 patients treatedbetween 1969 and 1988;
Boston, Massachusetts,
United States

24 (median);
3–69 (range)

11 (median)Mediastinal dose:
35–40 Gy

Increased SMR of 2.2
for cardiac deaths for thecohortAleman et al., 2003 [A7]1 261 patients treatedbetween 1965 and 1987;
Netherlands<40

17.8 (median)

Not available

Cardiovascular SMR:
7.2 (RT), 5.5 (RT and CT),
5.9 (salvage treatment);
Myocardial infarction
SMR: 1.3 (RT), 0.7 (RTand CT), 2.0 (salvage
treatment)

Hudson et al., 1998 [H9]387 paediatric patientsdiagnosed between
1968 and 1990;
Memphis, Tennessee,
United States

14.4 (median);
3–25 (range)

15.1 (median)Mediastinal dose:
35–44 Gy
(1968–1979);
20 Gy(1980–1990)

Increased SMR (22.2)
for cardiac diseasea RT: radiotherapy; CT: chemotherapy.

referred to as relative risks in these studies, are in the range
2–5 in different populations (with the exception of paediatricpatients), providing consistent evidence of the effects of highdose radiotherapy (at about 30–40 Gy) on ischaemic heartdisease. Modern radiotherapy for Hodgkin’s lymphoma has
incorporated newer techniques, exposing a smaller volume ofthe heart to a much lower dose, but little is known about theeffects of the lower-dose radiotherapy currently in use (from15 to 25 Gy). More information could be expected fromfollow-up studies of patients treated with modern radiotherapy, but analysis will be complicated by the combined useof doxorubicin and related drugs, which have been shown tohave long-term cardiotoxic effects [K8, L11].

cardiac disorders were diagnosed in 89 patients, including
24 with heart failures and 65 with other asymptomatic,
echocardiographic changes (abnormal fractional shortening,ejection fraction and end systolic meridonal wall stress)[G10]. All these children had received anthracyclins and
125 had received radiotherapy. Radiation doses delivered toseven points in the heart were estimated for all patients who
had received radiotherapy [D10]. Adjusted for potential
confounders, the cardiac disorder risk was found to belinearly related to radiation dose; the RR was 1.63 forradiation doses of >0–5 Gy, 6.48 for doses of 5–20 Gy
and 4.40 for doses of >20 Gy compared with patients withno radiotherapy [P6]. There was no indication of aninteraction between radiation dose and cumulative dose ofanthracyclins known to be cardiotoxic.

2. Childhood cancer patients
47. The long-term risk of heart disease following radiotherapy and chemotherapy for childhood cancer has beenreported [A3], but few studies have examined a dose
response. In a clinical follow-up of 229 patients treated fora variety of cancers before the age of 15 years at the Institut
Gustave Roussy, Villejuif, France, between 1968 and 1985,

3. Breast cancer patients
48. Today, the majority of breast cancers diagnosed inwomen in most Western countries are detected at an earlystage. Surgery is the primary treatment, but subsequently
adjuvant therapy (including radiotherapy, chemotherapy or

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ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]hormonal treatment) is also given. The treatment fields usedin irradiating the breast or chest wall include a portion of
the heart. The radiation dose to the heart depends on theradiation treatment technique used. Especially in older seriesof post-mastectomy radiotherapy, a large portion of theheart was irradiated [F2, R2]. Early randomized trials oftreatment for breast cancer, as discussed below, havedemonstrated that radiotherapy is an effective treatment
modality for reducing mortality from breast cancer, but they
have also provided evidence of increased mortality fromcardiovascular disease associated with the radiotherapy.
49. Recent radiation techniques used in conjunction withbreast-conserving surgery deliver radiation to a smaller portion of the heart. The strategy for breast-conserving treatment is to remove the bulk of the tumour surgically and touse moderate doses of radiation to eradicate any residual
cancer. The volume of the heart irradiated has been significantly reduced in patients treated with modern techniques(mostly megavoltage radiotherapy after conservative surgery) compared with patients treated with earlier techniques(mostly by post-mastectomy orthovoltage radiation) [F2].
However, even with contemporary megavoltage radiotherapy, left-side breast cancer may result in exposure of theleft anterior descending coronary artery to a substantial radiation dose, because the artery lies within or near the target
field [F2]. Several studies, also reviewed below, haveattempted specifically to evaluate the risk associated withmodern radiotherapy.
50. There are two major sources of data useful for assessing the risk of heart disease following radiotherapy in breast
cancer patients: randomized clinical trials and laterality
studies. In randomized clinical trials, breast cancer patientswere randomly assigned to radiotherapy and other methodsof treatment. Because of the random selection, results are
expected to be unbiased, and thus well-executed randomized trials are regarded as the most credible. In “laterality
studies”, the risk of cardiac disease is calculated by comparing the disease rates after radiotherapy for left-sided
breast cancer with that for right-sided breast cancer. Thistakes into account the fact that radiotherapy given for leftsided breast cancer exposes a larger volume of the heart toradiation and with a higher dose than treatment for rightsided breast cancer. Laterality studies are observational (notrandomized), but they offer the advantage that differencesin heart disease risk between left-sided and right-sided
breast cancer patients are unlikely to be explained bypossible confounding or patient selection.
(a) Randomized clinical trials
51. An increased risk of mortality from cancer other thanbreast cancer among irradiated breast cancer patients was
initially suggested by Cuzick et al. [C3, C4], who reviewed
data from several early breast cancer clinical trials—one
comparing radical mastectomy without radiotherapy against
simple mastectomy with radiotherapy in patients treatedduring 1951–1975, and the other evaluating post-operative
adjuvant radiotherapy in breast cancer patients treatedduring 1949–1979. The data showed a detrimental impact
on long-term (10–15 year) survival associated with radiotherapy, which was attributed to excess cardiovascularmortality [H2, H4, J3].
52. Radiotherapy regimens used in the initial series variedwith respect to the energy of the beam, fields irradiated,
duration of treatment and dose range. Cuzick et al. [C5]Figure V. Effect of radiotherapy on cause-specific survival in breast cancer patients in the EBCTCG [E3]

100

100

Breast cancer
deaths only

CONTROL ( )8080

SURVIVAL (%)

SURVIVAL (%)

RADIOTHERAPY ( )60

CONTROL ( )40

RADIOTHERAPY ( )60Deaths other thanbreast cancer

40

20

20
0

5

10

15

20

TIME FROM RANDOMIZATION (YEARS)

347

0

5

10

15

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subsequently extended the follow-up and showed thatamong the survivors of ≥10 years, cardiac-related deaths
were increased in the radiotherapy arm by 82% comparedwith the control arm.
53. Since 1984–1985, data from randomized trials in earlybreast cancer, the Early Breast Cancer Trialists’Collaborative Group (EBCTCG), have been evaluated periodically. Results have shown reduced mortality from breast
cancer in the adjuvant radiotherapy group [E2]. Mortality
from diseases other than breast cancer, however, wasincreased among those who received radiotherapy. The
meta-analysis of data from follow-up of the radiotherapy to
1995 in 40 unconfounded randomized trials involved 19,583
women with early breast cancer and showed that radiotherapy increased mortality from causes other than breast
cancer by 21.2%; the 20-year survival was 69.5% among
those who were allocated to radiotherapy compared with
73.8% among controls (figure V) [E3].
54. Vascular mortality was significantly increased by radiotherapy (radiotherapy/control death rate ratio = 1.30, standard
error 0.09) (table 6). The relative excess of vascular deaths
appeared to be similar during and after the first decade offollow-up, but the absolute rates were about three times
higher in the latter period, reflecting the increasing underlying mortality with increasing follow-up time. No information
was available, however, on radiation doses or on laterality ofbreast cancer (as a surrogate for cardiac exposure).
55. The latest analysis of the EBCTCG data involves
42,000 women in 78 randomized comparisons allowing
analysis of 15 or more years of follow-up data [E4]. Aswith the previous analysis, there was a significant excess
of mortality from non-cancer diseases in irradiated women,
mainly involving heart disease (radiotherapy/control death
rate ratio = 1.27, p = 0.001). The excess seemed to be lessduring the first 5 years of follow-up but was significant
for the periods 5–14 years and 15 years or more after
follow-up. The mean dates of randomization were 1975
and 1970, respectively, for those who died 5–14 years and
15 or more years after randomization. This is consistent
with the possibly greater hazards of the radiotherapy

regimens in the early 1970s versus the lower late hazards
of modern radiotherapy.
56. More recent data, from the Danish Breast Cancer
Cooperative Group, are relevant for assessing the risk associated with the most recent therapy techniques. In this trial,
3,083 women who were at high risk of breast cancer recurrence after mastectomy were randomly assigned to adjuvant
systemic treatment with or without radiotherapy [H7].
Breast cancer patients were treated with electron-based
techniques that minimized the portion of the heart volume
irradiated. In the 12-year follow-up, the relative hazard(radiotherapy/non-radiotherapy ratio of the cumulative
hazard function) of morbidity and mortality from ischaemic
heart disease among women treated with radiotherapy was
0.86 (95% CI: 0.6, 1.3), which was not significantly different from that of 0.84 (95% CI: 0.4, 1.8) among those
without radiotherapy (figure VI). The volume of the heart
irradiated was considered small, but the exact heart volume
in the radiation field was unknown. The conservative estimate was that less than 15 mm of the anterior surface ofthe heart received an absorbed dose per day of 1.7–1.9 Gy,
given in 25 fractions, 5 fractions per week. The number ofsubjects (46 morbidity cases and 12 deceased cases withischaemic heart disease) was rather small, and the authors
cautioned that further follow-up would be necessary toassess the long-term effects on the heart.
(b) Laterality studies
57. Laterality studies are methodologically innovative,
taking advantage of the heart being closer to the left breast
than the right. However, left- versus right-sided comparisons
may lead to an underestimate of the radiation-related risk,
because the heart also receives a low dose of scattered radiation from radiotherapy for the right-sided breast. In addition, most of the laterality studies lack information on theradiotherapy used, and radiation doses are rarely estimated.
58. Table 7 summarizes the main results regarding the riskof heart disease from laterality studies. The largest study of
myocardial infarction after adjuvant radiotherapy for leftversus right-sided breast cancer was conducted by Paszat

Table 6 Non-cancer causes of death
Early Breast Cancer Trialists’ Collaborative Group [E3]Underlying cause of death whenbreast cancer had not recurred

Number of deaths

Radiotherapy/control ratio of annual
death rates (standard error)

Allocated to radiation treatment

Adjusted control

Vascular437

322

1.30 (0.09)

Non-vascular

382

313

1.15 (0.09)

Unknown

339

292

1.09 (0.09)

Total

1 158

927

1.18 (0.05)

Follow-up duration(103 woman-years before recurrence)

82.1

74.8

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Figure VI. Cumulative mortality (left) and morbidity (right) for ischaemic heart disease among patients treated
with/without radiotherapy, from the Danish Breast Cancer Cooperative Group study of high-risk breast cancer patients
after adjuvant post-mastectomy systemic treatment with/without radiotherapy [H7]0.08

Mortality
CUMULATIVE INCIDENCECUMULATIVE INCIDENCE

0.08

No radiotherapy

0.06

Radiotherapy

0.04

0.02

0

Morbidity

0.06

0.04

0.02

0
0

2

4

6

8

10

12

0

TIME FROM RANDOMIZATION (YEARS)

2

4

6

8

10

12

TIME FROM RANDOMIZATION (YEARS)
Patients at risk

Patients at risk
No radiotherapy

1 521 1 316 1 052 666

645

340

154

No radiotherapy

1 521 1 311 1 043 657

631

329

151

Radiotherapy

1 525 1 322 1 099 946

737

410

194

Radiotherapy

1 525 1 316 1 092 939

727

402

188

et al. [P1]. This was based on over 200,000 breast cancer
patients identified by the Surveillance, Epidemiology and
End Results (SEER) registries in the United States. The subjects were women aged 20 years or older and diagnosed
between 1973 and 1992. A total of 703 deaths from myocardial infarction occurred during the follow-up, which averaged 74 months. Analysis of actuarial probability of deaths
showed a greater likelihood of fatal myocardial infarction
among women given adjuvant radiotherapy for left-sided
breast cancer than for right-sided breast cancer (figure VII,two left-hand graphs). In contrast, there was no significant
difference in the probability of death from myocardial
infarction among non-irradiated women between left-sided
and right-sided breast cancer (figure VII, two right-handgraphs). Since no individual information was available on
the specific type of radiotherapy, the authors compared data
for two time periods, 1973–1982 and 1983–1992, assuming
major differences in radiation treatment practices (seetable 7) between the two periods. The relative risk of
myocardial infarction after irradiation for left-sided breast
cancer patients was significant among those who were diagnosed before age 60 years during the earlier time period(table 7) but not among those aged 60 years or more at
diagnosis, during either the earlier or the later period.
Cardiac events were too few among breast cancer patientsof less than 60 years of age and diagnosed in the later
period, when use of post-lumpectomy (breast-conserving
surgery) radiation treatment was more frequent.
59. Rutqvist and Johansson [R3] analysed mortality data
among about 55,000 breast cancer patients reported to the
Swedish Cancer Registry during 1970–1985. The registry

does not record information on treatment, but previous population-based surveys had indicated that about 50% of allbreast cancer patients received radiotherapy, usually withsupervoltage techniques. The relative risk of death frommyocardial infarction was significantly elevated for leftversus right-sided tumours (1.09; 95% CI: 1.02, 1.17). The
relative risk appeared to increase with follow-up time, but
was not significant. Assuming that about half of all breast
cancer patients in this study had radiotherapy, the relativerisk associated with radiation was estimated to be 1.2. Thismagnitude of relative risk from the Swedish study wasslightly lower than that previously reported from the United
Kingdom Cancer Research Campaign (CRC) trial, in which
the relative risk associated with treatment for left-sided
tumours showed a twofold excess over that for right-sided
tumours (2.26 versus 1.20) [H2]. However, in the latterstudy, the relative risk associated with orthovoltage radiation was higher (1.86) than that with megavoltage techniques (1.27). The Swedish relative risk value was similar
to the value reported from the CRC trial for cardiac deathassociated with supervoltage radiation (1.35 for left-sided
tumours).
60. Analysing mortality data for 89,407 women aged
18–79 years with unilateral breast cancer in Sweden
between 1970 and 1996, Darby et al. [D5] reported anincreased relative risk of death from cardiovascular disease(RR = 1.10) occurring more than 10 years after treatment(table 7). No information was available regarding the specific radiation techniques used, but most of the cardiovascular deaths involved women treated for breast cancer inthe 1970s. For women treated in the 1980s, when radiation

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Table 7 Breast cancer laterality studies

Heart disease
Study and year

Number of breast cancer
patients, years treatedand country

Follow-up duration(years)Treatment, breast tumour
dose (Gy)

Number of deaths orcases

Relative risk
(left- versus right-sided
breast cancer)

Mortality follow-up
Paszat et al.,1998 [P1]

206 523 women
1973–1992
United States

Mean 6.2

1973–1982, adjuvant
radiotherapy;
1983–1992, mostly
post-lumpectomy
radiotherapy

Total 361, aged 60+,
1973–1982;
Total 125, aged 20–59,
1973–1982;
Total 218, aged 60+,
1983–1992;
Total 19, aged 20–59,
1983–1992

RR = 1.98 for age
20–59, 1973–1982;
RR = 1.17 for age 60+,
1973–1982 (NS);RR = 1.02 for age 60+,
1983–1992 (NS)Rutqvist and Johansson,
1990 [R3]54 617 women
1970–1986
SwedenMedian 9;
range 1–17

Usually supervoltage
technique

1 803 (left)
1 566 (right)

RR (myocardial
infarction) = 1.09

Darby et al.,2003 [D5]89 407 women
1970–1996
Sweden<10

Unknown

5 739

RR (all cardiovasculardisease) = 1.01 (95%
CI: 0.96, 1.07) at <10years, 1.10 at 10+ years
after diagnosis

10+

3 426

Nixon et al.,1998 [N2]745 women
1968–1986
United States

Maximum 12

Breast-conserving surgery plus megavoltage,
tangential;
typically 45–50

Total 18 (9 left-sided; 9right-sided)

RR (cardiac death) =1.04 (NS)Rutqvist et al.,1998 [R4]684 women
1976–1987
SwedenMean 9;range 3–16

Breast-conserving
surgery plus tangential
photon field;
46–54 (96%),
10–16 (1.9%)

Total 12(7 left-sided;
5 right-sided)

RR = 0.86 (NS)

Vallis et al.,2002 [V1]2 128 women
1982–1988
Toronto, Canada

Median 10.2;
range 7.7–15.1

Post-lumpectomy
radiotherapy (coplanar
tangential);
typically 40

Total 49
(26 left-sided;
23 right-sided)

RR = 1.1 (NS), all ages;
RR = 1.6 for age <60;
RR = 0.9 for age 60+

Paszat et al.,1999 [P2]3 006 women
1982–1997
Ontario, Canada

Median 8.8

Post-lumpectomy
radiotherapy;
mean 43

Total 74(44 left-sided;
30 right-sided)

RR = 2.10 (all ages);
RR = 8.76 (age 60+
versus 20–59)

Giordano et al.,2005 [G8]27 283 women
1973–1988
United States

15

Not available

All patients (in situ,
localized, regional
disease):
RR = 1.28 (13.1%
versus 10.2%) for
1973–1979;
RR = 1.08 (9.4%
versus 8.7%) (NS) for
1980–1984;
RR = 1.04 (5.8% versus5.2%) (NS)Total:
Ischaemic heart disease(825 left-sided;
769 right-sided)

Hazard ratio = 1.05 (NS)Morbidity follow-up
Patt et al.,2005 [P7]

16 270 women(8 363 with left-sided
breast cancer)
1986–1993
United Statesmean 9.5;
range 0–15

Primary surgicaltherapy and adjuvant
radiotherapy

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Adjuvant radiotherapy received

7

PROBABILITY OF DEATH FROM MYOCARDIAL INFARCTION (%)

PROBABILITY OF DEATH FROM MYOCARDIAL INFARCTION (%)

Figure VII. Probability of death from myocardial infarction in women of all ages (upper panels) and in women aged
20–59 years or 60+ years (lower panels) with cancer of the left or right breast who received adjuvant radiotherapy
or no radiotherapy [P1]

Cancer of left breast
Cancer of right breast

6

5

4

3

2

All ages
10

No radiotherapy received

7

Cancer of left breast
Cancer of right breast

6

5

4

3

2

All ages
1

0
0

2

4

6

8

10

12

14

16

18

20

22

0

2

4

6

Cancer of left breast
Cancer of right breast

16

14

12

10

Age: 60 years and above8

6

4

Age: 20-59 years

2

0
0

2

4

6

8

10

12

14

16

18

20

22

YEARS FROM DIAGNOSIS

doses to the breast were presumably lower, the relative risk
was still elevated (1.1), but had a wide confidence interval.
61. Several studies (discussed below) attempted to assess
the risk of myocardial infarction specifically associated withradiotherapy given after conservative surgery of the breast.
The results are mixed. An absence of significantly increased
relative risk of myocardial infarction following radiotherapy treatments for left- versus right-sided breast cancer has
been reported by: Nixon et al. [N2], who followed 745
breast cancer patients in Boston, United States, for up to 12
years; Rutqvist et al. [R4], who followed 684 Swedish
breast cancer patients from 3 to 16 years; and Vallis et al.
[V1], who followed 2,128 breast cancer patients in Toronto,
Canada, for about 8 to 15 years (table 7). The numbersof cases with myocardial infarction in these studies are
generally small (fewer than 50).

PROBABILITY OF DEATH FROM MYOCARDIAL INFARCTION (%)

PROBABILITY OF DEATH FROM MYOCARDIAL INFARCTION (%)

Adjuvant radiotherapy received

18

8

10

12

14

16

18

20

22

YEARS FROM DIAGNOSISYEARS FROM DIAGNOSISNo radiotherapy received

18

Cancer of left breast
Cancer of right breast

16

14

12

10

Age: 60 years and above8

6

4

Age: 20-59 years

2

0
0

2

4

6

8

10

12

14

16

18

20

22

YEARS FROM DIAGNOSIS

62. An increased risk of myocardial infarction wasreported from another study by Paszat et al. [P2], which
included 3,000 breast cancer patients in Ontario, Canada,with a record of lumpectomy as maximal breast surgery anda record of post-lumpectomy radiotherapy. The relative riskof mortality from myocardial infarction for women who
received post-lumpectomy radiotherapy for a left-sided
cancer was 2.10 (95% CI: 1.11, 3.95) compared with thosewith right-sided cancer (table 7). The increased likelihoodof mortality from myocardial infarction among the leftsided breast cancer patients was significant among women
aged 60 years and older (table 7). There is an overlap inthe breast cancer patients included in this study and the one
by Vallis et al. [V1] cited above, which did not find anincreased risk of myocardial infarction. While the subjects
in the [P2] study were identified from a province-wide registry, the [V1] study included patients seen at a specializedUNSCEAR REPORT-PART 6.qxp

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cancer centre. The patients included in the [V1] study had
carcinoma in situ as well as invasive cancers and tended tobe younger. Thus there may have been some differences in
cardiac dose or dose volume between the two series ofbreast cancer patients.
63. More recently, Giordano et al. [G8] followed 27,283
women treated with adjuvant radiation for breast cancer
identified from the SEER programme in the United States.
These patients were stratified into three subcohorts on thebasis of the year of diagnosis: 1973–1979, 1980–1984 and1985–1989. To ensure an equal time of follow-up for thedifferent subcohorts, follow-up was censored at 12–15
years. Among the women diagnosed between 1973 and1979, there was a statistically significant difference in the
15-year mortality from ischaemic heart disease between
patients with left-sided (13.1%) and right-sided (10.2%)
breast cancer. No significant difference was found for
women diagnosed between 1980 and 1984 (9.4% versus
8.7% for left- and right-sided, respectively) or between 1985
and 1989 (5.8% versus 5.2% for left- and right-sided,
respectively). Thus the differences in rate for women with
left- and right-sided breast cancer have diminished withtime, but continued follow-up will be necessary to determine whether excess cardiovascular mortality disappears
completely [C11, G8].
64. Also using the SEER database, Patt et al. followed
16,270 women with breast cancer who received adjuvant
radiotherapy during 1986–1993 [P7]. The subjects were followed for up to 15 years by linkage to the Medicare database. This database provides morbidity information from
hospitalization for individuals aged 65 years and older, but
the completeness of coverage is not clear. No significant
differences were found in left- versus right-sided breast
cancer patients for hospitalization for ischaemic heart disease (9.7% versus 9.6%) or other heart disease, with theage-adjusted hazard ratios for ischaemic heart disease being
1.05 (95% CI: 0.94, 1.16).
65. Data on cardiac risks following breast cancer radiotherapy have also been reviewed by Taylor et al. [T3] andProsnitz et al. [P9]. Both reviews concluded that modern
radiotherapy techniques for breast cancer have reduced radiation exposure to the heart, but it is not clear whether current regimens are free from cardiac risks. Taylor et al.
pointed out that none of the observational studies (mostly
laterality studies) of breast cancer patients receiving radiotherapy have attempted to reconstruct dosimetric calculations for dose–response analysis for heart disease.
66. Subclinical vascular abnormalities have also been
observed following thoracic irradiation. In breast cancer
patients treated with modern radiotherapy, myocardial perfusion scintigraphy studies demonstrated perfusion defects
to occur more frequently for left- than for right-sided breast
cancers up to 18 years after radiotherapy [G9]. The frequency of perfusion defects was correlated with the volumeof the left ventricle exposed to the radiation field, as these

defects occurred in 25% of patients who had from 1 to 5%of the left ventricle in the tangent field compared with 55%
of patients with >50% of the left ventricle in the field[M15]. The clinical significance of perfusion defects is
unclear, but the findings suggest that subtle cardiac injury
may still occur even with modern techniques [P8].

4. Testicular seminoma patients
67. About 15–25% of patients with stage I seminoma havemetastases to the drainage lymphatics, and are treated withelective irradiation to the lumbar periaortic and ipsilateral
ilioinguinal lymph nodes. Some patients are given bilateralpelvic irradiation. Previously, elective irradiation frequently
was given to the mediastinum and supraclavicular areas ofstage I patients, and elective mediastinal irradiation was
administered to most patients with stage II disease.
Currently, for patients with stage I disease, megavoltage
irradiation is recommended using daily doses of 1.8–2 Gy,
for a total of 20–25 Gy over 2–3 weeks, to the primaryzone of nodal drainage in the lumbar and periaortic andipsilateral ilioinguinal regions. When elective mediastinal
irradiation is administered, 20 Gy is given over 2–3 weeks.
For patients with stage II seminoma with metastases inlymph nodes below the diaphragm, irradiation is similar tothat used in stage I patients, but the dose is increased to
30–40 Gy over 4–5 weeks. Elective mediastinal irradiationis administered to all stage II B patients [W3].
68. Early data from irradiated seminoma patients showedvariable findings regarding heart disease risk [B6, P3, W4].
A more recent study of 124 patients with seminoma treatedbetween 1968 and 1984 reported an increased risk of heartdisease after mediastinal irradiation [L2]. Of the 124
patients, 57 had mediastinal as well as infradiaphragmatic
irradiation, while others had treatment limited mostly to theinfradiaphragmatic field only. The median dose to the mediastinum among the patients was 2.4 Gy. Four patients, allin the group that received mediastinal irradiation, developed
heart disease (three with myocardial infarction or relatedheart disease and one with constrictive carditis), and two
died from sudden death thought to be of cardiac origin. No
cardiac disease was observed in the group not treated withmediastinal irradiation.
69. Huddart et al. [H8] analysed long-term risks of cardiovascular disease in a larger follow-up (up to 20 years)
study of 992 testicular seminoma patients (390 withchemotherapy only, 130 with chemotherapy and radiotherapy, 230 with radiotherapy and 242 with surveillance only)
treated between 1982 and 1992 at the Royal Marsden
National Health Service Trust in the United Kingdom [H8].
The relative risk of cardiac events (myocardial infarction,
angina or related cardiovascular episode) was significantly
elevated (RR = 2.40) among patients treated with radiotherapy, with or without chemotherapy, compared with thereference surveillance group. No significant differenceswere found in smoking behaviour or cholesterol levels

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ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]between different treatment groups, but patients receiving
radiotherapy and chemotherapy had a higher frequency ofhistory of hypertension than the surveillance group. On thebasis of computed tomography scans in six patients, themean cardiac dose was estimated to be 0.76 Gy (range:
0.54–1.35 Gy), with a mean maximum cardiac dose of
3.36 Gy (range: 0.82–14.1 Gy), and on average 14% of the
cardiac volume received a dose of 0.9 Gy or more, indicating that direct cardiac irradiation was uncommon. Only
30 patients received mediastinal irradiation, while themajority of the remaining patients received infradiaphragmatic radiotherapy. The risk of cardiovascular diseaseremained elevated after excluding patients who had mediastinal irradiation. These data suggest an elevated cardiac
risk associated with partial irradiation and/or low scattereddoses, although radiation-induced nephropathy (frominfradiaphragmatic irradiation) could be an alternative
explanation for the excess heart disease risk. This finding,however, is at odds with a more recent study of a larger
cohort of 2,512 5-year survivors of testicular cancer in the
Netherlands [V3]. After a medical follow-up of 18.4 years,
694 cardiovascular events occurred, including 141 acute
myocardial infarctions. Mediastinal irradiation was associated with a 3.7-fold increase in myocardial infarction risk
compared with surgery alone, but infradiaphragmatic irradiation was not associated with an increase in myocardial
infarction risk.

5. Dose response and factors affecting risk
70. Dose–volume histograms and “normal tissue complication probability” models have been used to describe thecardiac response to irradiation. In these models, an organ isthought to consist of multiple functional subunits arranged
serially or in parallel. For serially structured organs, suchas the gastrointestinal tract or nervous tissue, damage to one
portion of the organ may render the entire organ dysfunctional [H5]. In organs with parallel structure (e.g. lung and353

liver), damage to a small number of functional subunits may
not impair the entire organ function, because the remaining
subunits operate independently from the damaged subunits,
and clinical injury occurs when a critical volume of theorgan is damaged. When the dose distribution is inhomogeneous or when part of the organ is irradiated, the probability of a specific organ response can be estimated by anormal tissue complication probability model [G4]. In thecase of the heart, little is known about structures within theheart that are liable to radiation-induced damage. However,dose–response curves have been constructed for radiationinduced heart disease, including coronary heart disease,assuming that the entire heart volume is equally radiosensitive. Applying the relative seriality model to the
Stockholm and Oslo randomized trial data, Gagliardi et al.
[G3] estimated a threshold dose of 20 Gy for ischaemic
heart disease mortality. The serial assumption may not bevalid because, as the Hodgkin’s lymphoma data suggest (seethe section on partial irradiation below), there may bedifferences in sensitivity to radiation by tissue type andlocation [H1].
71. In a study of a small number of Swedish breast cancer
patients enrolled in a randomized trial of pre- or post-operative radiation therapy (45 Gy over 5 weeks) versus surgery alone [R2], the different radiotherapy techniques usedwere classified into three groups depending on the calculated dose volume: low (right-sided tangential 60Co fields),
intermediate (electron fields) and high (left-sided tangential
60Co fields). The subset of patients who received the highest dose volume had significantly increased risk of deathfrom ischaemic heart disease compared with surgical controls (table 8). Mortality from ischaemic heart disease in thegroups with low and intermediate dose volume was similar
to that among non-irradiated controls. No other differenceswere statistically significant. Since the dose and the irradiated heart volume were correlated, it was not possible todetermine whether the dose, the volume or both were
important for the increased cardiac mortality.

Table 8 Mortality by estimated radiation dose volume in breast cancer patients with adjuvant radiation therapy versus
surgery alone
Rates in the table are deaths per 1000 persons per year; absolute numbers of deaths are given in parentheses [R2]
Radiation therapy: radiation dose volume
Cause of death

Surgery alone(n = 321)

Low(n = 164)

Intermediate(n = 314)High(n = 161)

Trend test

Breast cancer

33.9 (120)26.1 (51)25.6 (93)31.2 (57)

Not significant

Other cancer

4.2 (15)

3.6 (7)

3.6 (13)

1.6 (3)

Not significant

Ischaemic heart disease

2.3 (8)1.5 (3)2.2 (8)7.1 (13)p < 0.05

Other cardiovascular disease

2.8 (10)

2.6 (5)2.5 (9)1.6 (3)

Not significant

Other causes

2.5 (9)2.0 (4)3.0 (11)

3.3 (6)

Not significant

All causes

45.7 (162)35.8 (70)36.9 (134)44.9 (82)

Not significant

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UNSCEAR 2006 REPORT: VOLUME I(a) Partial irradiation
72. Gagliardi et al. [G3] reviewed data from two randomized breast cancer trials: the Oslo breast cancer trial of
post-operative radiotherapy as an adjuvant to radical mastectomy [H4] and the Stockholm breast cancer trial of adjuvant pre- or post-operative radiotherapy versus surgery
alone [R2]. The end points used were mortality frommyocardial infarction in the Oslo trial and mortality fromischaemic heart disease in the Stockholm trial. Based on
three-dimensional dose distributions reconstructed for different treatment techniques in 10 model breast cancer
patients [G3], the dose–response curves were quite similar
for different cardiac volumes irradiated (100%, 66% and33%), suggesting that volume dependence is small.
73. Eriksson et al. [E1] further compared the dose
response for heart disease mortality obtained from 157
Hodgkin’s lymphoma patients with the five meandose–volume histograms for breast cancer patients studied
by Gagliardi et al. [G3]. The dose–response curve from thebreast cancer radiotherapy was much steeper than that fromthe Hodgkin’s lymphoma treatment. This was thought to be
due to the different portions of the heart irradiated for thetwo types of treatment; the typical irradiation geometry for
the Hodgkin’s lymphoma treatment is almost complementary to that of the breast cancer treatment. These findings
suggest the presence of heterogeneity in tissue response toradiation within the heart.
74. Heterogeneity in tissue response was also suggestedby the Stanford study of Hodgkin’s lymphoma [H1], inwhich subcarinal blocking was associated with a reductionof the relative risk for non-myocardial infarction from 5.3
to 1.4, but not of the relative risk for myocardial infarction(3.7 versus 3.4). Subcarinal blocking reduces the irradiatedvolume for the entire heart but does not protect the proximal part of the major coronary arteries from irradiation.
This finding, however, is also consistent with possible susceptibility to coronary artery injury at lower radiation doses[H1].
(b) Dose fractionation
75. Cosset et al. [C2] followed 499 patients irradiated for
Hodgkin’s lymphoma during 1971–1984 at the Institut
Gustave Roussy; 75% of the patients were treated using 4
weekly fractions of 2.5 Gy, 6% received 3 weekly fractionsof 3 Gy, 16% received 3 weekly fractions of 3.3 Gy, andthe remaining patients received an unusual fraction schedule and thus were not analysed. The 5-year cumulative incidence of pericarditis increased significantly with increasing
total cumulative dose (4.1%, 5.8% and 10.4% in dosegroups 35–37 Gy, 39–41 Gy and 41–43 Gy, respectively).
After adjustment for fractionation, the same increasing trend
was observed but was no longer significant. Multivariate
analysis adjusting for age, sex, mediastinal involvement andtype of chemotherapy showed the pericarditis risk to be significantly increased with total doses of 41 Gy or higher andat 3.0 Gy or higher per fraction. Although the cumulative
incidence of myocardial infarction in the irradiated patientswas significantly increased compared with that in 138
Hodgkin’s lymphoma patients without mediastinal radiotherapy, neither a dose nor a fractionation effect could bedemonstrated, possibly owing to there being only a small
number of events (13 cases of myocardial infarction). The
data suggest that dose fractionation may reduce the risk ofradiation-induced pericarditis, but the effect of dose fractionation on the risk of coronary heart disease is not clear.
In the study of irradiated Hodgkin’s lymphoma patients,
Reinders et al. [R1] failed to construct the “biologicallyequivalent dose”, accounting for variations in total dose,
fraction dose and treatment techniques, as a predictor ofischaemic heart disease risk, but this may have been in partdue to the small variation in these parameters.
(c) Age and time
76. The earlier case–control study by Boivin et al. of
Hodgkin’s lymphoma patients [B1] found the relative risksof myocardial infarction associated with mediastinal irradiation to be homogeneous among subgroups classified byage at diagnosis of Hodgkin’s lymphoma (0–39, 40–59 and60+ 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 [H1], which included a large number ofpatients treated at a wide range of ages and follow-up years.
Most remarkably, the relative risk of acute myocardial
infarction was highest (RR = 44) among those treated at anage of <20 years and decreased significantly with increasing age at treatment (irradiation) (see table 4). The absoluterisk, i.e. the excess number of cases per 10,000 persons,increased significantly with increasing age at treatment,
reflecting the increasing underlying rate for this disease
with increasing age. The relative risk of acute myocardial
infarction was already significantly elevated during the first
5 years after the initiation of therapy and remained elevated
20 years or more after treatment, and the risk increased withtime after treatment (table 4). Generally similar patterns
were observed for the risk of heart disease other than
myocardial infarction. The relative risk of heart disease
other than myocardial infarction was highest among patientstreated at an age of <20 years, decreased significantly withincreasing age at treatment (table 4), and increased significantly with increasing years after treatment.
77. Because of the narrow age range of breast cancer
patients, ages at irradiation were grouped into two age categories, i.e. <60 and 60+ years, in most studies of breast
cancer patients. In the study by Paszat et al. of breast cancer
patients who received adjuvant radiotherapy [P1], the relative risk (left-sided versus right-sided breast cancer) of fatal
myocardial infarction was significantly elevated for women
diagnosed at ages 20–59 years and treated during 1973–1982(RR = 1.98). The relative risk for women diagnosed at ages
60+ years was elevated but not significantly so. This is in
disagreement with the results from another study by Paszat

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ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]et al. of the Ontario, Canada, cohort of Hodgkin’s lymphoma
patients [P2], which reported that the relative risk (left-sided
versus right-sided breast cancer) of myocardial infarction
after post-lumpectomy irradiation was increased for women
diagnosed at age 60+ years (RR = 8.76) but not for women
who were diagnosed at <60 years of age.
(d) Smoking and other risk factors
78. Animal studies have provided varying results as towhether general atherogenic risk factors modify the effectof radiation on coronary heart disease. In an early study by
Fajardo and Stewart [F3, S15], irradiation of the heart inseveral hundred rabbits failed to produce coronary heart disease; a high-fat diet was found to be necessary for irradiation to induce atherosclerosis [A4]. However, in dogs,
plaques developed with a normal diet [L4]. In general, however, results from these and other studies [A6, B3] are inagreement that the combination of irradiation and a highfat diet accelerated atherogenesis.
79. Few human data are available on the possible modifying effects of non-radiation risk factors. In the study by
Boivin et al. [B1], the relative risks of myocardial infarction after irradiation for Hodgkin’s lymphoma did not differ
with history of cigarette smoking (yes or no), hypertension,
diabetes and previous coronary heart disease. Glanzmann etal. [G5] followed 352 irradiated Hodgkin’s lymphoma
patients with or without chemotherapy in Zurich,
Switzerland, and found the incidence of ischaemic heart disease to be higher than expected in the subgroup with cardiovascular risk factors (18 observed versus 7.60 expected)
but not in the subgroup without the risk factors (3 observed
versus 3.13 expected).

B. Patients receiving diagnostic radiation orradiotherapy for non-neoplastic diseases
80. Patients irradiated for diagnostic purposes or treatmentof non-neoplastic conditions are exposed at doses lower thanthose treated with radiation for cancer. Among the numerous patient populations in this category that have been studied, populations of special interest are patients with thymic
enlargement, mastitis, skin haemangioma, benign gynaecological disorders, tinea capitis and peptic ulcer (see table 1).
Most of the study results on circulatory diseases are basedon the comparison of observed numbers of events (mostly
deaths) with expected numbers derived from the general
population (i.e. external comparisons). Very few studies
have compared disease rates between irradiated and nonirradiated patients in the cohort (i.e. internal comparisons).
Causal inferences of findings from external comparisonsalone are problematic because of the possibility that individuals with disease may have underlying disease rates thatdiffer from those of the general population. Certain conditions for which patients were irradiated may also influence
the subsequent risk of circulatory disease.

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81. Ankylosing spondylitis patients received a total mean
cardiac dose of 2.5 Gy, with a 10–90% range of 0.04–4.75
Gy, from a single course of X-ray treatment [L1]. Doses
relevant for cerebrovascular disease are not clear but are
assumed to be much lower if a mean thyroid dose of 0.99
Gy is used as the surrogate. Cerebrovascular and other circulatory diseases (presumably mostly heart disease) wereamong the causes of death that originally were considered
to be normal among patients with spondylitis (referred toas Class D). The ratios of observed to expected deaths (O/E
ratios) from cerebrovascular and other circulatory diseases(based on age-, sex- and period-adjusted mortality rates inEngland and Wales) were significantly elevated (the O/E
ratios were 1.14 for cerebrovascular disease and 1.25 forother circulatory disease) (table 9). The finding was interpreted as not being attributable to the radiation treatment
because: (a) increased mortality was observed in Class D
for many other causes of death, including bronchitis, peptic
ulcer, other gastrointestinal disease and violence; (b) a similar excess had been observed in another population of nonirradiated spondylitis patients [R7]; and (c) the increased
risk of Class D diseases was more closely associated withattained age than with time since treatment, i.e. the risk
tended to decrease with time. When relative risks were estimated by comparing the O/E ratios for the irradiatedspondylitis cohort with those for a separate non-irradiatedspondylitis cohort [R7], the calculated relative risks were
below unity for cerebrovascular disease (RR = 0.66; 95%
CI: 0.40, 1.10) and other circulatory diseases (RR = 0.97;
95% CI: 0.70, 1.33) [M13].
82. Between the 1940s and the 1960s, radiation therapy
was frequently used at the University of Chicago, UnitedStates, to treat peptic ulcers. Radiotherapy for peptic ulcers
consisted of daily fractions of 1.5 Gy given in one or two
6-day to 14-day courses, with a total mean cardiac dose of
2.10 Gy. The heart received scattered radiation, and it wasestimated that up to 5% of the heart (the apex) was within
the direct irradiation field. In the earlier analysis of mortality data of 3,609 peptic ulcer patients, a significantly
increased relative risk of circulatory disease of 1.20 was
observed among the irradiated group [G1]. The relative risk
was based on the internal comparison of irradiated and nonirradiated patients with peptic ulcer and was adjusted forage, sex and other demographic variables as well as smoking. More recently, Carr et al. conducted an analysis of thedose–response relationship for mortality from coronary
heart disease [C12]. Among those who survived 10 or more
years after the treatment, the relative risk (adjusted for
demographic variables, smoking and other risk factors)
increased significantly, from 1.00 for the lowest cardiac
dose category (mean volume-weighted dose of 1.6 Gy, withmean in-field dose of 7.6 Gy) to 1.51 for the highest cardiac dose category (mean volume-weighted dose of 3.9 Gy
with mean in-field dose of 18.4 Gy) (table 9). There was
no indication of a dose response for heart disease otherthan coronary heart disease. A statistically significant
increased relative risk for coronary heart disease of 1.54
was seen for persons with a mean volume-weighted dose

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Table 9 Populations receiving diagnostic radiation or radiotherapy for non-cancer diseases
Cohort, country

Cohort description

Dose (Gy)

Number of deaths

O/E ratio or relative risk

Heart disease
Ankylosing spondylitis, United
Kingdom [D3, L1]

14 000 patients treated with asingle course of X-rays

Heart: 2.49 (mean);
0.04–4.75 (10–90% range)

Circulatory disease other thancerebrovascular disease:
990 observed/794 expected

O/E = 1.25

Peptic ulcer, United States[C12, G1]

1 859 irradiated patients and1 860 non-irradiated patients(men and women)

Heart: 1.6–3.9 (volumeweighted mean);
7.6–18.4 (assumed 5% in
direct X-ray beam)Coronary heart disease among
10+ year survivors:
551 exposed
546 unexposed

RR = 1 (referent,
non-irradiated)
RR = 1.00 (1.6 Gy, 7.6 Gy)
RR = 1.23 (2.3 Gy, 10.6 Gy)
RR = 1.54 (2.8 Gy, 12.9 Gy)
RR = 1.51 (3.9 Gy, 18.4 Gy)(volume-weighted mean dose,
in-field dose)

Metropathia haemorrhagica,
Scotland, United Kingdom[D8, S3]

2 068 women treated with
X-irradiation for metropathia
haemorrhagica

Bone marrow:
1.34 (mean);
0.07–1.9 (range)

Coronary heart disease:102 observed/100.9 expected

O/E = 0.70 (<1.25 Gy)
O/E = 1.27 (1.25–1.49 Gy)
O/E = 1.17 (>1.5 Gy)

Menorrhagia, Manchester,
United Kingdom [A1]2 049 women irradiated formenorrhagia

Ovary: 4.5–5; 12.5–15(age <40 years)

Coronary heart disease:
44 observed/36.9 expected

O/E = 1.19, not significant

X-ray menopause, Cambridge,
United Kingdom [B2]277 women with X-rayinduced menopause

Pelvis: approx. 7–10

Coronary heart disease:16 observed/9.68 expected

O/E = 1.65 (p = 0.04)

Cerebrovascular disease:
231 observed/202 expected

O/E = 1.14

Cerebrovascular disease
Ankylosing spondylitis, United
Kingdom [D3, L1]

14 000 patients treated witha single course of X-rays

Thyroid: 0.99 (mean);
0–2.06 (10–90% range)
Circulatory disease

Metropathia haemorrhagica,
Sweden [R15]788 exposed and 1 219
unexposed women treated forbenign bleeding disorders

Ovary: 6

Circulatory system disease:
308 exposed
257 unexposed

O/E = 0.92 exposed
O/E = 0.88 unexposed
RR = 1.05

New England benign
gynaecological disorders,
United States [I2]4 483 women irradiated forbenign gynaecological disorders; 10 hospitals in
New England, 1925–1965

Bone marrow: 0.53–2.5(tissue-weighted mean);Lung: 0.04–0.06

Circulatory system disease:
1 685 observed/1 734.6
expected

O/E = 0.8 (0.01–0.25)
O/E = 1.0 (0.26–0.50)
O/E = 1.0 (0.51–0.75)
O/E = 1.0 (≥0.76)
O/E = 1.1 (unknown)

Scoliosis, United States [D9]5 573 women with scoliosis
receiving repeated radiographic
examinations

Lung: 0.041 (mean)

Circulatory system disease:
number not reported

Significant dose response (nodata presented)

Massachusetts tuberculosis
fluoroscopy, United States [D4]6 285 patients (men andwomen) fluoroscopicallyexamined for an average of77 times; 7 100 unexposed
non-irradiatedpatients

Lung: 0.84 (mean);Circulatory system disease:
Number (SMR)
Female:309 (1.0) exposed
440 (1.1) unexposed
Male:
517 (1.0) exposed
925 (1.1) unexposed

RR = 0.9 for both womenand men (estimated byratio of SMR for exposed to
unexposed)of 2.8 Gy or in-field dose of 12.9 Gy (to 5% of the heart
volume). These relative risk values translate into an excess
relative risk of 0.13–0.19 at 1 Gy (volume-weighted dose).
It had previously been thought that peptic ulcer patients
who were selected for radiotherapy may have had otherconditions that made them unsuitable for surgical treatment, e.g. disposition for cardiovascular disease [G1], andthat this may have caused the apparent increased rate ofheart disease. However, such selection seemed unlikely. Ifsuch selection had occurred, the excess risk would havebeen observed sooner, within 10 years after treatment, andit was not.
83. During the 1930s and 1940s, the uterus and ovaries
of female patients were irradiated to treat abnormal uterine
bleeding. The conditions involved were mostly hyperplasiaof the endometrium, uterine fibroids, endometrial and cervical polyps, and chronic cervicitis; the underlying cause

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The target organ for radiotherapy was the ovary or uterus.
Typical doses for women treated with X-rays were of theorder of 6–15 Gy to the ovaries and 0.7–1.3 Gy to the bonemarrow. Cardiac doses were not estimated but were presumably very low because the dose dropped sharply withincreasing distance from the source and was very low fororgans outside of the pelvis or abdomen [I2, I3]. Because
the underlying condition (i.e. hyperoestrogenic status) may
affect cardiovascular disease rates, a simple comparison ofobserved numbers of cardiovascular events in irradiatedpopulations with numbers expected from rates in the general population is likely to be an inadequate measure of therisk associated with exposure.
84. Data on mortality from circulatory disease have beenreported in several studies of patients with benign gynaecological disorders. Interpretation of the results presented intable 9 and summarized in the next paragraph is difficult
because the underlying rates of circulatory disease may be
influenced by the presumed hyperoestrogenic condition forwhich these patients were treated. Cell-killing effects ofhigh-dose irradiation on the ovaries may affect the oestrogenic status, further complicating the assessment ofradiation effects.
85. Early studies of women irradiated for gynaecologicalconditions generally reported mortality from heart disease
close to the expected rate, although some studies suggested
an increased risk of coronary heart disease after radiotherapy. In the cohort of 2,068 women X-irradiated for
metropathia haemorrhagica at three Scottish radiotherapy
centres, the observed number of deaths from coronary heartdisease (102) was similar to the expected number (100.9)[D8, S3] (table 9). In this study, however, analysis basedon internal comparison showed the ratio of observed to
expected deaths from coronary heart disease to increase withan increasing bone marrow dose, with borderline significance for trend. The bone marrow dose ranged from 0.7 to
1.9 Gy [S3].
86. In another study of 2,049 women irradiated for menorrhagia at a Manchester (United Kingdom) hospital [A1],the observed number of deaths from coronary heart disease(44) was slightly higher than the expected number (36.9),
but the difference was not significant. Radiation doses were
not estimated for this group, but are presumed to be similar to those in the Scottish metropathia series. Significant
excess mortality from coronary heart disease was found ina study of 277 women who had an X-irradiation-induced
menopause in Cambridge, United Kingdom [B2]; 16 deaths
were observed when 9.68 were expected (table 9). No internal comparison was carried out. Most of the higher than
expected mortality occurred within 5 years after radiotherapy. Women in these series were mostly treated at ages
close to their natural menopause, and therefore it wasthought unlikely that results were explained by radiationinduced premature menopause.

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87. The largest and most recent study of women irradiated for gynaecological disorders was conducted by Inskip
et al. It originally involved 4,483 women irradiated at oneof 10 hospitals in New England (Massachusetts or Rhode
Island), United States, between 1925 and 1965 and followed
up until 1985 [I2]. Cardiac doses were not estimated, butlung doses were estimated to be 0.04–0.06 Gy. The
observed number of deaths (1,685) from circulatory disease
was similar to the expected number (1,734.5) (SMR = 0.97;
95% CI: 0.93, 1.02). SMRs for circulatory disease did not
differ with bone marrow dose (table 9). Bone marrow doses
ranging from 0.1 to >0.76 Gy in this cohort were somewhat
lower than the doses in the Scottish cohort. In a smaller
study of patients irradiated for metropathia haemorrhagica
in Sweden, the ratio of observed to expected deaths fromcirculatory disease was slightly higher in the exposed groupthan the unexposed group [R15]. The broad category of circulatory disease used is a weakness of the data from these
two studies.
88. No evidence of excess risk of cardiovascular disease
is available from a study of 6,285 tuberculosis patients who
received multiple chest exposures to fluoroscopic X-rays at
Massachusetts hospitals (fluoroscopy cohorts). Fluoroscopic
examinations were given on average 77 times. Doses to theheart were not estimated, but doses to the lungs were estimated to be 0.84 Gy (mean). Doses relevant for cerebrovascular disease were not estimated. The SMRs forcirculatory disease in the exposed patients were almost
equal to the SMRs for the unexposed patients [D4], withratios of the exposed to unexposed SMR being 0.9 for both
men and women (table 9). However, no dose–response
analysis was performed, and the disease category used was
broad.

C. Radiologists and radiologic technologists
89. Radiologists were among the earliest occupationalgroups exposed to excessive amounts of radiation. Thereare eight cohorts of radiologists and medical radiologicalpersonnel documented in the literature: three from theUnited States (radiologists, army X-ray technologists andradiologic technologists) and one each from Canada, China,
Denmark, Japan and the United Kingdom. Of these, published data on mortality from circulatory disease are available from only three studies: United Kingdom radiologists,
United States radiologists and United States Army technologists. The published Canadian medical radiation cohort
data do not distinguish medical from non-medical workers
and thus are reviewed in section D below, together withstudies of other radiation workers.
90. The cohort of about 2,700 United Kingdom radiologists, the data for which were most recently updated by
Berrington et al. [B4], includes radiologists who worked in
the earliest years of radiological practices. Those who
worked during 1897–1920 were largely pioneer British

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radiologists who were exposed to excessive amounts ofradiation. The authors estimated that radiologists in the
1920s and 1930s could have received exposures of 100
roentgens (equivalent to absorbed doses of approximately
1 Gy) each year [B5]. Smith and Doll previously stated thatannual exposure in this population was 0.1 Gy before the1950s and perhaps 0.05 Gy in the early 1950s [S4]. SMRs
for specific causes of death were compared for different calendar years of first registration with a radiological society.
The comparison indicates the declining levels of radiation
exposure among radiologists over time. Compared with therates of mortality in the general population, significantly
lower than expected numbers of deaths from all causes were
found among the radiologists (SMR = 0.77) and among
those who first registered after 1920. Compared with themortality rates for Social Class I (professional occupations)males or male medical practitioners, a significant deficit inall-cause mortality was found for the entire group (SMR =0.94 and 0.92, respectively), and this was primarily driven
by the deficit for those who registered most recently (i.e.
during 1955–1979) (SMR = 0.69 and 0.68, respectively).
The deficit in all-cause mortality appears largely to be due
to a deficit in non-cancer mortality, as the numbers of deaths
from cancer were generally close to expectation but werehigher than expectation among those entering the profession in the early years, especially before 1920. The observed
numbers of deaths from circulatory disease were generally
close to or lower than expectation (table 10). Comparedwith the mortality for male medical practitioners, thenumber of deaths from circulatory disease was significantly
lower than expected among those who first registered before
1920 (SMR = 0.79), during 1921–1935 (SMR = 0.83) andmost recently (1955–1979) (SMR = 0.59) (table 10). The
authors concluded that the absence of an elevated SMR for
non-cancer diseases in the earliest radiologists indicated thelack of evidence of a radiation effect.
91. It has been reported elsewhere, however, that general
medical practitioners have higher mortality on average,
largely from diseases associated with smoking (ischaemic
heart disease, respiratory disease and several types ofcancer, etc.), when compared with hospital physicians andsurgeons; on average general practitioners smoked 37%
more cigarettes than did hospital physicians and surgeons[S4]. This complicates the interpretation of SMR values
using medical practitioners as the comparison.
92. In the study of United States radiologists, mortality
rates were compared between radiologists and other physician specialists (who were considered less exposed to radiation) stratified by different calendar years of entry into
their specialty organization. In an earlier analysis of causespecific mortality data, the authors noted a significant difference in the cardiovascular–renal disease mortality ofradiologists (RSNA) and physicians (ACP) compared withthat of ophthalmologists and otolaryngologists (AAOO) in
the earliest subcohort (1920–1929) and of ophthalmologists
in the 1930–1939 subcohort [M2]. Further analysis of mortality data [M3] showed that radiologists had 15% higher

mortality from cardiovascular disease than did other physicians (table 10). Interpretation of the findings is difficult.
On one hand, the excess cardiovascular disease mortality
seen for all cohorts of radiologists tended to argue against
radiation effects. On the other hand, survival data showedthat the increased mortality from circulatory disease
occurred after age 55, as did the increased mortality fromcancer [M3], and this was thought to suggest a common
factor, such as radiation, for both cancer and cardiovascular disease. These facts clearly illustrate the limitations of
the “ecological” nature of both the United States and theUnited Kingdom radiologist data, owing to the lack of dataon individual doses, and emphasize the need for caution in
inferring a causal association.
93. Mortality data from a cohort of United States radiologic technologists showed an overall SMR of less thanunity for circulatory disease for the entire cohort [M14].
More detailed analyses of ischaemic heart disease and cerebrovascular disease risks by work history were carried out
in a subset of this cohort for which data on work history
were available from the mail survey conducted in the mid1980s [H3]. Relative risks of mortality from circulatorysystem diseases increased significantly among thetechnologists who started working in earlier years, whenradiation exposure was higher. For both ischaemic heart disease and cerebrovascular disease, the relative risks (adjusted
for confounding variables) increased significantly withdecreasing calendar year in which the subjects started working as technologists (table 10). There was no association
with the cumulative number of years worked for either
ischaemic or cerebrovascular disease, but the relative riskof circulatory system diseases and the subset of cerebrovascular disease increased significantly with increasing
number of years worked before 1950. In this analysis, theunderlying risk was estimated internally using stratified
models. Since the year first worked correlated with attained
age and calendar year, which also correlated with the underlying rates of circulatory disease, this can induce intrinsic
confounding leading to collinearity in extreme situations.
This possibility was considered unlikely since similar
results were obtained when external rates were used to estimate the underlying rate. The strength of this study is theanalysis based on internal comparison, taking into accountconfounding effects of smoking, alcohol consumption andsocio-economic variables. Surrogate measures of radiation
exposure based on work history and calendar year of
employment are limitations.
94. In the 1946–1974 follow-up study of a smaller cohortof United States Army radiologic technologists, a nonsignificantly higher frequency of arteriosclerotic and degenerative heart disease was reported among the technologists(4.31%) than among the controls (3.90%) (table 10) [J1].
The 1946–1963 follow-up data of the same cohort had
shown a significantly higher than expected number ofdeaths from respiratory cancer (17 observed versus 10.5
expected), while there was no significant excess of any
other cancer, including leukaemia [M4].

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Table 10 Radiologists and radiologic technologists
CohortCohort description

Type of disease
Circulatory disease
Year of first registration:

United Kingdom radiologists [B4]2 698 male radiologists registeredfrom 1897 to 1979

SMR
(i)

(ii)

(iii)

1897–1920

1.03

0.94

0.79**

1921–1935

0.96

0.96

0.83*

1936–1954

0.82**

1.03

0.98

1955–1979

0.41***

0.60***

0.59***

Expected deaths using rate for: (i) all men in England and Wales; (ii) all Social
Class I males; and (iii) all male medical practitioners. *p < 0.05; *p < 0.01;***p < 0.001
Atherosclerotic heart disease

United States radiologists [M2, M3]

6 500 male radiologists and 3 cohortsof other physician specialists

1920–1939:

SMR

RSNA (radiologists)

1.15

ACP (physicians)

1.00

AAOO (ophthalmologists andotolaryngologists)

0.91

1940–1969:
RSNA

1.15

ACP

0.95

AAOO (otolaryngologists)

1.06

AAOO (ophthalmologists)

0.93
Ischaemic heart disease

Year of first work:

United States radiologic
technologists [H3]

Relative risk a (number of deaths)<1940

1.22 (116)

1940–1949

1.00 (214)1950–1959

0.98 (157)1960+

1.00 (111)90 284 radiologic technologists(predominantly female)

Cerebrovascular disease
Year of first work:

Relative risk a (number of deaths)<1940

2.40 (52)

1940–1949

1.54 (54)

1950–1959

0.90 (27)1960+

1.00 (32)Arteriosclerotic and degenerative heart disease

United States Armytechnologists [J1]a Age- and time-adjusted.

X-ray technologists

283 (4.3%)

Controls

266 (3.9%)

6 560 male X-ray technologists
during Second World War and6 826 controls

Vascular lesions of the central nervous system
X-ray technologists

37 (0.6%)

Controls

42 (0.6%)

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95. There are three other cohorts of medical radiation workers that have been followed: 27,000 diagnostic X-ray
workers in China [W2], 4,100 persons who worked in radiotherapy departments in Denmark [A5] and 12,000 maleradiologic technologists in Japan [Y2]. There have been no
published data on non-cancer disease from these studies.

D. Radiation workers
96. Studies of nuclear workers and other populations
exposed at low doses can provide valuable information onrisks of non-cancer disease at levels of dose less than
0.5 Gy. However, there are important limitations. At low
doses, the disease risk attributable to radiation may be sosmall relative to the underlying risk that it may be undetectable. Furthermore, because the underlying disease rates
vary by amounts that are greater than the risk related to
low-dose exposure, it will be extremely difficult to reject
the possibility that any observed difference arises frombiases or other factors related to the disease of interest, evenin a population large enough for a small risk to be detected.
These limitations are well recognized in assessing the riskof cancer at low doses, but they become even more serious
in assessing the risk of circulatory diseases. This is because
the relative risk of non-cancer disease associated with radiation exposure is expected to be much smaller than the riskof cancer, and because underlying rates of circulatory disease are influenced by numerous lifestyle and socioeconomic factors.
97. In the three-country study of combined cohorts ofnuclear industry workers from Canada (Atomic Energy ofCanada Limited (AECL)), the United Kingdom (Atomic
Weapons Establishment (AWE), United Kingdom Atomic
Energy Authority (UKAEA) and Sellafield) and the UnitedStates (Hanford, ORNL and Rocky Flats), a positive association was found between mortality from circulatory disease and radiation dose (table 11) in the range 0–≥0.4 Gy[C6]. The analysis was adjusted for socio-economic status
within the facility as well as for age and other demographic
variables. The association with mortality from circulatory
disease was observed in three cohorts (AECL, Rocky Flatsand Sellafield). Since the information on socio-economic
status available for these three cohorts was less detailed thanthat for the other cohorts in this study, the authors suspected
residual confounding by lifestyle factors for which themeasure used for socio-economic status was an inadequate
proxy. Only limited information was available on smoking
and other lifestyle factors for workers in this study, but there
was little evidence for an association between cumulative
dose and mortality from smoking-related cancers, respiratory disease or liver cirrhosis.
98. Data from the United Kingdom NRRW demonstrated
an inverse, though not significant, association between radiation dose (with the dose range comparable to that in theabove three-country study) and smoking-related nonmalignant diseases, which included coronary heart disease,aortic aneurysm, emphysema and chronic obstructive
pulmonary disease (table 11) [M5]. A non-significant
inverse association was also found for circulatory diseases
not related to smoking.
99. The radiation workers of British Nuclear Fuels
Limited (BNFL) plants were included in the NRRW analyses [M5], but mortality and morbidity data for the Sellafield
workers, including plutonium workers, were analysed in a
separate study [O1]. Compared with the mortality rates forEngland and Wales, there was significantly higher than
expected mortality from ischaemic heart disease among all
workers (1,354 observed versus 1,217.7 expected), but theexcess was not apparent when compared with the Cumbrianmortality rates. Rate ratios (radiation-exposed to nonexposed) based on internal comparison showed a significant excess mortality from cerebrovascular disease (rateratio = 1.28), though not from ischaemic heart disease (rateratio = 0.96), for radiation workers compared with non-radiation workers (table 11). Analysis of mortality data against
cumulative external dose showed a significant externaldose-related trend for ischaemic heart disease, but data were
not presented. Plutonium workers also had higher mortality from cerebrovascular disease (rate ratio = 1.27), but notfrom ischaemic heart disease (rate ratio = 1.01), than did
non-radiation workers (rate ratio = 1.27). Another separate
analysis of mortality data among 470 male Sellafield
employees who were involved in the 1957 Windscale accident showed a higher than expected mortality from circulatory disease (SMR = 1.21) and ischaemic heart disease(SMR = 1.28) when compared against the national rates,
though not when compared against the Cumbrian rates[M8]. The elevated mortality for circulatory disease andischaemic heart disease occurred among the workers
involved in managing the fire, but was also evident for those
not involved. No dose–response analysis was performed.
100. Among the other BNFL sites, analysis of the mortality data of about 14,000 workers at the Springfields uranium production facility demonstrated a significant
dose-related trend for cerebrovascular disease when the
cumulative external dose was lagged by 10, 15 or 20 years,
but not for ischaemic heart disease (table 11). Studies ofabout 3,200 workers at the Capenhurst uranium enrichment
facility and 2,600 workers at the Chapelcross plant showedno significant trends for mortality from ischaemic heartdisease or cerebrovascular disease (table 11).
101. Large values for the excess relative risk per unit
dose, apparently incompatible with the data from the survivors of the atomic bombings, have been reported for the
Canadian National Dose Registry and for Chernobyl recovery operations workers (see table 11). The estimates of ERR
for circulatory disease from the Canadian National Dose
Registry are 2.3 (90% CI: 0.9, 3.7) Gy–1 for males and 12.1
(90% CI: –0.4, 24.6) Gy–1 for females [A2]. The authors
indicated several sources of uncertainty, including dose estimation and record linkage errors for follow-up. In particular, underestimation of lifetime dose may have occurred

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dose records. It has also been noted that the ERR estimatesfor “all causes” (ERR = 2.5 Gy–1 for males and 5.5 Gy–1
for females) were as high as for “all cancer” (ERR = 3.0
Gy–1 for males and 1.5 Gy–1 for females) and that the ERRs
for accidents were strikingly high (ERR = 8.8 Gy–1 and 6.1
Gy–1 for males and females, respectively). These results,
together with the very low standardized mortality ratio for
all causes (0.59 Gy–1 in males and 0.58 Gy–1 in females),raise the possibility of some bias, perhaps related to theascertainment of deaths [G2].
102. An analysis by Gilbert et al. [G6] of mortality data
for workers at the Hanford site, ORNL and Rocky Flats
involved a total of about 45,000 monitored workers withmean cumulative doses of 22–41 mGy (table 11). No significant effects of radiation on circulatory disease were foundin the combined mortality data. A separate analysis of themortality data for workers at the Hanford site also found no
significant association of radiation dose with circulatory
disease [G7]. Two other studies, of workers at the Moundfacility and at Rocketdyne/Atomics International, reported
only SMRs for circulatory disease [R13, W6] (table 11).
103. More recently, Howe et al. analysed mortality data of
United States nuclear power industry workers [H13]. This
cohort of 53,698 individuals employed in 15 nuclear utilities in the United States was followed for up to 18 years
between 1979 and 1997. Cumulative dose from whole-bodyradiation was estimated from dose records available at thefacilities, supplemented by the dose information maintainedby the United States Nuclear Regulatory Commission andthe United States Department of Energy. While the analysis
using dose categories revealed no significant trends for circulatory disease (table 11) or arteriosclerotic heart disease,linear analysis indicated a strong significant association
between radiation dose and circulatory disease, which was
driven primarily by the association for arteriosclerotic heartdisease. The ERR was 8.32 (95% CI: 2.30, 18.2) Gy–1 forcirculatory disease and 8.78 (95% CI: 2.10, 20) Gy–1 forischaemic heart disease. These estimates were higher thanthose from the LSS data, although the ERR estimates forleukaemia and solid cancer from this cohort were comparable to the LSS data. The authors pointed out that an artificially high or low ERR estimate may have resulted fromoutliers, and emphasized that caution is needed when interpreting the results.
104. Incidence data from the first 11-year follow-up(1986–1996) of the Chernobyl liquidators showed large risks
for some non-cancer disease categories [I1]. The ERRs were
not significantly elevated for diseases of the circulatory
system, hypertensive disease or ischaemic heart disease.
However, significantly elevated relative risks were found foressential hypertension (ERR = 0.52; 95% CI: 0.07,
0.98 Gy–1) and cerebrovascular disease (ERR = 1.17; 95%
CI: 0.45, 1.88 Gy–1). Furthermore, significantly increased
ERRs were observed for many other disease categories,

361

including endocrine and metabolic diseases (ERR = 0.58
Gy–1), mental disorders (ERR = 0.40 Gy–1) and diseases of
the nervous system and sensory organs (ERR = 0.24 Gy–1).
Incidence data derived from health examinations are liable
to potential bias. The authors also noted that psychologicaland emotional stress immediately after the accident was
especially strong among these liquidators. The exceedingly
large risks for many different disease categories are consistent with the possible presence of bias and confounding
effects. Without consideration of lifestyle and other factors,
the causal nature of the apparent excess risks is currently
unclear. Cardiovascular and cerebrovascular data wererecently updated up to the end of 2000 [I5]. ERR estimates
were 0.41 Gy–1 for ischaemic heart disease, 0.45 Gy–1 forcerebrovascular disease and 0.36 Gy–1 for essential hypertension. These risk estimates were not adjusted for smoking,alcohol consumption, weight and other risk factors.
105. About 9000 male workers employed at the Mayakradiochemical plant during 1948–1972 were followed to theend of 1991 for cardiovascular disease mortality [B12]. The
age-adjusted mortality rates for the male workers werelower than the general population rates (“controls” intable 11), possibly reflecting the healthy worker effect.
Among the Mayak workers, the age-adjusted rates for those
exposed to gamma irradiation of greater than 1 Gy were
not significantly different from the rates for those with lessthan 1 Gy (table 11).
106. Although doses from inhaled radon and radon decay
products to cardiovascular organs are very low, data from astudy of miners in Newfoundland, Canada, showed an association between mortality from coronary heart disease andradon exposure [V2]. This involved 1,772 undergroundminers and 352 surface workers employed at two fluorspar
companies. The relative risk of coronary heart disease mortality adjusted for smoking habits increased with cumulative
radon exposure (table 11), but the trend test was of borderline significance (p = 0.09). The coronary heart disease risk
also decreased with increasing duration of exposure(employment), suggesting the possible influence of thehealthy worker effect. Results from other miner populations
with radon exposure are also mixed. No associations withradon exposure were found for circulatory disease in the
French or Czech miners [T4, T5]. The joint effects of radon
and arsenic exposures on circulatory disease mortality foundin Chinese tin miners were difficult to interpret, since radon
exposure tended to increase the risk while arsenic exposure
tended to decrease the risk. In a large cohort study of
59,000 miners employed between 1946 and 1989 at a uranium mine in Wismut, Germany, 5,417 deaths from circulatory disease (3,719 from heart disease and 1,297 from
cerebrovascular disease) were identified in a follow-up to
the end of 1998 [K9]. Exposure to radon and its progeny,
external exposure to gamma radiation and long-lived alphaemitters were estimated by a job–exposure matrix. No significant trend was found in the mortality risk of all circulatory diseases in relation to cumulative exposure to radon,external gamma radiation or long-lived radionuclides.

CohortExposure characteristics

Follow-up duration(years)Radiation doseor exposure

Circulatory disease statistic(number of cases)

Comments

Nuclear workers in
Canada, the United
Kingdom and the UnitedStates [C6]95 673 workers (AECL,
Sellafield, UKAEA, AWE,
Hanford; Rocky Flats,
ORNL)

Recorded exposures toexternal radiation:mean cumulative dose,
0.04 Gy

23.7 (mean)

Cumulative dose (mGy)

Circulatory disease
O/E (deaths):<10

1.01 (4 689)

10–<200.93 (908)

20–<500.97 (954)

Positive association observed in Rocky Flats,
Sellafield and AECL cohorts where information
on socio-economic status was least detailed;suggestion of residual confounding, but little
evidence of smoking and alcohol strongly
associated with cumulative dose

1.01 (372)

200–<400

1.11 (313)≥400

1.07 (132)
UNSCEAR 2006 REPORT: VOLUME I

Trend p = 0.045
NRRW, United Kingdom[M5]

124 743 monitored workers
exposed in nuclear power
plants and in fuelprocessing and researchfacilities (AWE, BNFL,
CLRC, MOD, MRC-RBU,
NRPB, Nuclear Electric,
Magnox Generation, Nycomed Amersham, PMS,RRA, Scottish Nuclear,
UKAEA)

Recorded exposures toexternal radiation:mean cumulative dose,
0.03 Gy

Cumulative dose (mGy)

Smoking-related non-malignant
diseases — heart disease, aortic
aneurysm, respiratory disease
O/E (deaths):<10

1.00 (1 888)

10–<200.99 (477)

20–<500.99 (698)50–<100

1.00 (431)

100–<200

0.93 (288)200–<400

1.15 (244)≥400

0.90 (102)
Trend: NS

Sellafield [O1]

10 382 monitored workers
employed during
1947–1975

Recorded exposures toexternal radiation

Sellafield plutonium
workers [O1]5 203 workers monitored
for plutonium exposure

Monitored for plutonium
by urine samples

29.0

Rate ratio: radiation-exposed versus
non-exposed (deaths), trend:
IHD: 0.96 (371), NS
CVD: 1.28 (111), p < 0.05
SMR (deaths), trend:
IHD: 110 (498), p < 0.05;
CVD: 127 (137), p < 0.01

Significant positive trend with external cumulative dose for IHD (data not published)

Page 362

0.96 (487)

3:44 pm

50–<100
100–<200

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UNSCEAR REPORT-PART 6.qxp

362

Table 11 Findings on circulatory diseases in studies of radiation workers

Follow-up duration(years)Radiation doseor exposure

Circulatory disease statistic(number of cases)

2 628 monitored workers
employed during
1955–1995

Recorded exposures toexternal radiation:mean cumulative dose,
0.0836 Gy

24.3

Cumulative external dose(mGy)

O/E (deaths):

24.6

<10

0.99 (27)0.75 (6)10–<201.25 (20)

1.23 (4)20–<501.11 (35)

1.57 (11)50–<100

1.07 (38)0.97 (8)100–<200

0.70 (23)1.04 (9)200–<400

1.03 (33)0.72 (6)≥400

0.86 (5)0.71 (1)

Trend: NS

Trend: NS

Cumulative external dose(mGy)

O/E (deaths):
IHD

CVD

<10

1.02 (513)

1.08 (144)

10–<201.01 (207)

1.06 (62)20–<500.96 (273)0.85 (71)50–<100

0.98 (136)0.80 (30)

100–<200

1.10 (58)1.23 (16)200–<400

0.77 (4)1.94 (2)≥400

0.00 (0)8.00 (2)Trend: NS

p < 0.05(10-, 15- and 20-year lag)
Capenhurst uranium
enrichment [M7]

3 244 monitored
workers employed during
1971–1991

Recorded exposures toexternal radiation:mean external cumulative
dose, 0.0098 Gy

26.7

Cumulative external dose(mGy)

O/E (deaths):
IHD

CVD

0.98 (143)0.87 (23)

1.22 (32)1.45 (7)20–<501.10 (31)1.27 (5)50–<100

0.57 (5)0.76 (1)100–<200

0.35 (1)3.70 (1)200–<400

1.15 (1)0.00 (0)≥400

0.00 (0)0.00 (0)Trend: NS

NS

363

<10
10–<20Page 363

Recorded exposures toexternal radiation:mean external cumulative
dose, 0.0228 Gy

CVD

ERR (95% CI) estimates:
IHD: 0.51 (-0.81, 2.54) Gy–1
CVD: -0.96 (<-2.95, 2.34) Gy–1

3:44 pm

13 960 monitored workers
employed during
1946–1995

IHD

Comments

10/7/08

Springfields uranium
production [M12]

Exposure characteristics

ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]Chapelcross [M11]

CohortUNSCEAR REPORT-PART 6.qxp

StudyCanadian National Dose
Registry [A2]

206 620 monitored
workers, including dental,
medical, industrial andnuclear power plant
workers

Recorded exposures toexternal radiation:mean cumulative dose,
0.06 Gy

13.8 (mean)

44 943 monitored
workers:
Hanford: 32 643
ORNL: 6 348
Rocky Flats: 5 952

Recorded exposures toexternal radiation: mean
cumulative dose,
Hanford: 0.026 Gy
ORNL: 0.022 Gy
Rocky Flats: 0.041 Gy

Hanford, ORNL and Rocky
Flats [G6]

Radiation doseor exposure

Circulatory disease statistic(number of cases)
Circulatory disease
O/E (deaths):
Male: 0.61 (1 708), NS;
Female: 0.49 (243), NS

Cumulative external dose(mGy)

Circulatory disease
O/E (deaths):<10

1.03 (2 719)
0.92 (846)0.92 (143)

100–<200

0.93 (99)

200–<400

1.02 (78)1.53 (22)
Trend: NS

Hanford [G7]37 971 monitored
workers employed during
1944–1978

Recorded exposures toexternal radiation:mean cumulative dose,
0.0233 Gy

Cumulative external dose(mGy)

Circulatory disease
O/E (deaths):<10

1.03 (2 193)

10–<500.92 (642)50–<100

0.91 (102)

100–<200

0.91 (76)≥200

1.05 (81)
Trend: NS

Mound facility [W6]3 229 monitored workers

Recorded exposures toexternal radiation:mean cumulative dose,
0.0297 Gy

SMR for circulatory disease(deaths), trend:
0.82 (149), NS

Rocketdyne/Atomics
International [R13]

4 563 monitored workers

Recorded exposures toexternal radiation:
cumulative doses,
0–0.2 Gy

SMR (deaths), trend:
Circulatory disease:
0.63 (356), NS;
ASHD:
0.56 (223), NS;
Vascular lesions of CNS:
0.57 (33), NS

Male: 2.3 (95% CI: 0.9, 3.7)
Female: 12.1 (95% CI: -0.4, 24.6)

UNSCEAR 2006 REPORT: VOLUME I≥400

ERR (% for 10 mGy) for circulatory disease:

Page 364

10–<5050–<100

Comments

3:44 pm

Follow-up duration(years)

10/7/08

Exposure characteristics

UNSCEAR REPORT-PART 6.qxp

Cohort364

Study

53 698 workers in 15
nuclear power utilities

Exposure characteristics

Follow-up duration(years)Radiation doseor exposure

Circulatory disease statistic(number of cases)

Recorded exposures toexternal radiation:mean cumulative dose,
0.0257 Gy

13 (mean)

Dose (mGy)

Relative risk (deaths):
ASHD

CNS lesions

1.00 (141)1.00 (9)0.70 (72)

1.89 (4)50–<100

1.76 (20)

3.27 (0)≥1001.65 (15)

Assessed externalradiation doses,
0.109 Gy (mean)

Mayak workers [B12]

15 601 persons monitored
for external radiation

Recorded doses forexternal radiation:
lung, 3.8–35 Gy

Fluorspar miners,
Newfoundland, Canada[V2]

1 772 underground and352 surface workers
employed at fluorspar
companies between
1933 and 1960;
cumulative exposure,379 WLMInternal exposure toinhaled radon and its
decay products

14
IHD (10 942);
CVD (12 832)

To 1985

Total external gamma
irradiation (mGy):

CVD
mortality (age-adjusted):0 (controls)

513.3 ± 36.1

>0–<1 000

497.4 ± 18.0

≥1 000504 ± 25.7

Cumulative radon
exposure (WLM)

CHD relative risk0

1.0

>0–<250

0.90

250–<500

1.12

500–<1 000

1.57≥1 000ERR (95% CI):
IHD: 0.41 (0.05, 0.78) Gy–1;
CVD: 0.45 (0.11, 0.80) Gy–1

1.46
Trend p = 0.09

Uranium miners, France[T4]

Uranium miners, Czech
Republic [T5]

1 785 uranium miners
with underground mining
experience between 1946
and 1972

4 320 male uranium
miners, West Bohemia

Internal exposure toinhaled radon and its
decay productsInternal exposure toinhaled radon and its
decay products

To 1985

25 (mean)Circulatory disease SMR(number of deaths)
Total cohort

0.85 (69)First exposure 1946–1955

0.87 (40)First exposure 1956–1972

0.82 (29)779 deaths from circulatory disease
other than rheumatic heart disease;
O/E = 1.16

No significant trend with cumulative radon
exposure

Page 365

61 017 workers participating in clean-up work after
the Chernobyl accident

3:44 pm

Trend: NS

Trend: NS
Chernobyl recovery
operations workers,
Russian Federation [I1, I5]

ERR (95% CI):circulatory disease: 8.32 (2.30, 18.2) Gy–1;
ASHD: 8.78 (2.10, 20.0) Gy–1;
vascular lesions of CNS:
-2.05 (<-2.06, 353) Gy–1

10/7/08<1
1–<50

Comments
ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]Nuclear power utilities,
United States [H13]

CohortUNSCEAR REPORT-PART 6.qxp

Study

365

NA

Circulatory disease statistic(number of cases)
CHD (47 deaths);
CVD (302 deaths)

Radon exposure

CHD relative risk

Low (referent group)

1.0

Medium

0.8

High

1.7

Radon exposure

CVD relative risk

Low (referent group)

1.0

Medium

1.1

High

1.3

Significant joint effects of radon and arsenic
exposure

Circulatory disease (5 417 deaths)
Radon exposure (WLM)

All circulatory disease relative risk

0

1.00

>0–1000.96>100–400

0.93>400–800

0.98>800–1 600

0.92≥1 600

1.11

Exposure to long-lived
radionuclides (kBq·h/m3)

All circulatory disease
relative risk

0

1.00

>0–<1.0

0.98

1.0–<3.0

1.02

3.0–<10.0

0.91

≥10.0

0.94

Exposure to gamma
radiation (mSv)

All circulatory disease
relative risk

0

1.00

>0–<500.97

50–<100

0.92

100–<300

0.95

≥300

0.85

ERR for 100 WLM = 0.0006(95% CI: -0.004, 0.006)

ERR for 100 kBq·h/m3 = -0.02(95% CI: -0.5, 0.06)

ERR = -0.26(95% CI: -0.6, 0.05) Sv–1

Note: ASHD: arteriosclerotic heart disease; CHD: coronary heart disease; CNS: central nervous system; CVD: cerebrovascular disease; IHD: ischaemic heart disease; NA: not available; WLM: working level month.

Page 366

30.5 (mean)

Comments

3:44 pm

Cumulative exposure toradon, external exposure
to gamma radiation andlong-lived alpha particle
emitters estimated by ajob–exposure matrix

Radiation doseor exposure

10/7/08

59 001 male uranium
miners, employed
between 1946 and 1989

Internal exposure toinhaled radon and its
decay products

Follow-up duration(years)UNSCEAR 2006 REPORT: VOLUME I

Uranium miners, Wismut,
Germany [K9]17 143 tin miners

Exposure characteristics

UNSCEAR REPORT-PART 6.qxp

Tin miners, China [X1]

Cohort366

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ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]E. Survivors of the atomic bombings in Japan

1. Mortality (Life Span Study)
107. In the latest LSS report [P4], deaths from heart disease and stroke together accounted for 58% (8,431) of the
14,459 deaths from all non-cancer diseases (except for diseases of the blood and blood-forming organs) that occurred
during the period 1968–1997. The analysis of mortality datafrom 1968 or later indicated significant linear dose responses
for heart disease and stroke. The ERR was 0.17 (90% CI:
0.08, 0.26) Sv–1 for heart disease and 0.12 (95% CI: 0.02,
0.22) Sv–1 for stroke. Estimated numbers of radiation-related
deaths were 101 (2.2%) of the 4,477 deaths from heart disease and 64 (1.6%) of the 3,954 deaths from stroke during
the above follow-up period. As described earlier in thisannex, detailed analyses of the dose–response curve and themodifying effects of age, sex and time were performed for
non-cancer disease mortality as a group [P4, S1] and also
specifically for stroke and coronary heart disease [L10] (seesection II).

2. Incidence and morbidity data (Adult Health Study)
108. The AHS is a long-term clinical follow-up investigation of a subset of the LSS cohort. This subset consists of
20,000 subjects who have been undergoing biennial healthexaminations since 1958. Morbidity data and longitudinalclinical data from this study are useful for studies of specific non-cancer diseases and related clinical end points.
109. An increased prevalence of coronary heart disease inproximally exposed survivors was first noted in 1958–1960[Y1] but was not confirmed by subsequent studies of incidence of stroke and coronary heart disease in the first years(1958–1964) of the AHS follow-up [J2]. Cases were few andradiation doses were not available at that time. The studies
of stroke and coronary heart disease continued and the data
were updated several times, i.e. to 1974 [R6], to 1978 [K4]and to 1990 (or later) in the latest study, which is currently
under way. The latest AHS incidence data from biennial
health examination records show a significant quadratic
dose–response relationship for myocardial infarction among
those exposed at age ≤40 years, with a relative risk of 1.25
(95% CI: 1.00, 1.69) at 1 Sv, although the linear dose
response for overall myocardial infarction was not significant[W5, Y3]. It should be noted that the morbidity data describedabove are based on biennial health examinations and thus
may have missed some of the interim events, especially fatal
events. Date from surviving cases may have been biased.
110. In an attempt to ascertain all incident cases of cardiovascular disease, additional efforts have been made to
identify cases from a variety of AHS and other sources (i.e.
self-reported diagnoses, electrocardiograms, death certificates and autopsy reports) and to apply standardized diagnostic criteria. Cardiologists review records to identify cases367

on the basis of standardized criteria. [R6]. Cases of coronary heart disease were defined as those with evidence of
angina pectoris, myocardial infarction or death from coronary heart disease [R6]. The analysis of 288 incident casesof myocardial infarction (163 male and 125 female) that had
been ascertained up to the end of 1990 by this intensive
search [K5] showed a significant dose response. The relative risk at 1 Sv was estimated to be 1.17 (95% CI: 1.01,
1.36). The association between myocardial infarction andradiation dose remained significant after adjusting for bloodpressure and serum cholesterol levels as well as age and sex.

3. Subclinical changes
111. While morbidity or incidence data on clinically overt
disease from routine health examinations are prone to potential selection bias, subclinical (asymptomatic) end points or
clinical laboratory data are less likely to be affected by selection bias. A number of subclinical cardiovascular changes
or precursor lesions have been studied in the AHS cohort.
Growth curve models were applied to the analysis ofrepeated longitudinal cholesterol measurement data among
9800 AHS subjects for the period 1958–1986 [W1]. The
growth curves of individual subjects are assumed to varyrandomly about a population growth curve, and are appropriate for assessing a radiation effect, taking into accountthe changing serum cholesterol levels in the Japanese population. For each sex, temporal trends of cholesterol levels
were characterized with respect to age, body mass index,
city and birth year, and the question was examined as towhether the temporal trends differed by radiation dose. The
mean growth curve of cholesterol levels was significantly
higher in exposed than in non-exposed subjects. There wasno difference in dose response between Hiroshima andNagasaki, and cigarette smoking did not alter thedose–response relationship.
112. Using similar growth models, Sasaki et al. [S17]found that systolic and diastolic blood pressure levels
increased with radiation dose in subjects exposed at young
ages (≤16 years), but this trend was reversed in older subjects. A significant quadratic, but not linear, dose response
was also found for hypertension diagnosed at the AHS clinical examinations [Y3]. Other end points studied in the AHS
cohort include the prevalence of aortic arch calcification[K6], isolated systolic hypertension [K7] and pulse wave
velocity [U16], all of which have been found to be associated with radiation.
113. The AHS findings regarding the radiation effects on
hypercholesterolaemia and other cardiovascular end points,
which are well correlated with each other, offer little insight
into a possible role of radiation in the process of atherogenesis, but they are consistent with the possibility ofaccelerated atherogenesis associated with radiation exposure.
114. A statistically significant association between
radiation dose and increased inflammatory responses, asUNSCEAR REPORT-PART 6.qxp

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measured by leukocytosis, accelerated erythrocyte sedimentation rates or acute phase proteins, has been noted in thispopulation for some time [N3, S7]. This association has been
re-examined with updated clinical data using various inflammatory response markers. Among 7,463 subjects examined
during 1988–1992, the relationship between radiation doseand a series of inflammatory tests (including leukocyte
counts, neutrophil counts, erythrocyte sedimentation rate
(ESR), α-1 globulin, α-2 globulin and sialic acid) was examined [N4]. ESR is influenced by a variety of serum components, including acute phase proteins, which comprise α-1
globulin and α-2 globulin. Sialic acid is a glycoprotein component related to the surface membrane in the inflammatory
process. After allowing for the effect of covariates such ascity, age, sex and smoking, radiation dose was found to be
associated with increased leukocyte counts per unit bonemarrow dose (71.0 mm-1 Gy-1), ESR (1.58 mm h-1 Gy-1),
corrected ESR (1.14 mm h-1 Gy-1), α-1 globulin level(0.0057 g dL-1 Gy-1), α-2 globulin level (0.0128 g dL-1
Gy-1) and sialic acid level (1.2711 mg dL-1 Gy-1), though
not with neutrophil counts. No confounding effects of thepresence of dose-related inflammatory diseases, i.e. clinicallydetectable chronic thyroiditis or chronic liver disease, were
found.
115. Blood samples from 453 Hiroshima study participants
between 1995 and 1997, excluding those with a history ofcancer or an inflammatory disease, were studied by Hayashi
et al. [H6]. C-reactive protein (CRP) levels were associatedwith age, sex, body mass index and a history of myocardial
infarction. After adjusting for these factors, CRP levels
increased significantly with bone marrow dose (an increaseof about 28% at 1 Gy), as did IL-6 levels, by 9.3% at 1 Gy.
CRP is an acute phase reactant that increases during an
inflammatory response, and recent epidemiological evidence
indicates increased CRP levels as an independent risk predictor for cardiovascular disease [R8, R9]. IL-6, a primary
inducer of CRP, has also been found to be a predictor of
myocardial infarction.

F. Mechanistic models

1. Microvasculature theory
116. High-dose irradiation is capable of damaging all
structures of the heart, including the pericardium,myocardium, valves, conduction system and coronary arteries, as reviewed by Adams et al. [A3]. Histologically, radiation-induced tissue damage is characterized by marked
diffuse fibrosis, especially of the pericardium andmyocardium [A3, B7, F4, S9]. In an autopsy study of 16
young patients (aged 15 to 33 years) with heart disease who
received over 35 Gy and 10 controls, the arterial plaques inpatients treated with radiotherapy were largely composed offibrous tissues, with the media more frequently replaced by
fibrous tissues and more focal thickening of the intramuralcoronary arteries, than in the controls. Radiation-induced
microvascular injuries can contribute to late damage of
normal tissue. Capillaries are the most radiosensitive component of the vasculature [T2]. In a classic study of experimental radiation-induced heart disease in rabbits by Stewart[S10], electron microscopy studies of changes taking place
during the latent stage of disease development indicatedchanges in endothelial cells of the myocardial capillaries
with progressive obstruction of the lumen, resulting information of thrombi.
117. The dose–volume histogram and normal tissue complication models described in section IV.A.5 above [B7, S9]
are used to describe the pathophysiology for heart diseaseinduced by direct tissue damage from irradiation. Thesemodels are primarily applicable to damage from high-dose
exposures. On the basis of data from patients treated for
Hodgkin’s lymphoma, a fractionated dose of 40 Gy was previously considered as a threshold for clinical radiationinduced heart disease [F3, S16]. The extent to which thesemodels can explain heart disease, especially atherosclerotic
coronary heart disease induced by low-dose irradiation, is
not clear [T2]. It has been suggested [B7, J4] that damage
to coronary artery endothelial cells may be a primary eventin the pathogenesis of coronary heart disease. Irradiation
may cause fibrointimal hyperplasia, which leads to thrombus formation and potentially to lipid deposition. Subtle
changes to the blood vessels, such as abnormal vascular permeability, can occur at lower doses (down to 5 Gy) ([U8]p. 626, para. 496).

2. Inflammation theory
118. There have been a number of hypotheses for thepathogenesis of atherosclerosis, which underlies the development of ischaemic heart disease and cerebrovascular disease. Recent evidence suggests that atherosclerotic plaquesarise from endothelial injury or dysfunction induced by cardiovascular risk factors and develop through a series ofhighly specific cellular and molecular responses, which canbest be described as an inflammatory process [L3, L6, R10].
Initial endothelial injury may be induced by endotoxins,
hypoxia, infection or other agents, but it is generally thoughtthat haemodynamic disturbances and the adverse effects ofhyperlipidemia are most important. Among the processes
involving lipids in atherogenesis is their oxidative modification by free radicals, yielding oxidized low-density
lipoprotein (LDL). Oxidized LDL is taken up bymacrophages, contributes to monocyte recruitment and leads
to foam cell formation. Fibrous plaques then develop as a
growing mass of extracellular lipid with accumulating extracellular matrices derived from smooth muscle cells.
Cytokines and growth factors secreted by macrophages andT-cells play multiple roles in this process.
119. Infection by cytomegalovirus and other viruses
has recently been linked to atherosclerosis. Infectious organisms may incite a chronic inflammatory process. AnotherUNSCEAR REPORT-PART 6.qxp

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ANNEX B: EPIDEMIOLOGICAL EVALUATION OF CARDIOVASCULAR DISEASE AND OTHER NON-CANCER DISEASES […]plausible mechanism is stimulation of smooth muscle cell
migration by the virus-coded chemoine receptor [L6]. It has
been speculated that radiation-induced genomic instability
and/or bystander effects may set off inflammatory responses
that may persist for many years [H6, L5, N4].

3. Monoclonal theory
120. It was some 20 years ago that the monoclonal originof the atherosclerotic lesion was proposed. In studies using
the X-linked enzyme glucose-6-phophatase dehydrogenase(G6PD) to determine X chromosome inactivation patterns,
aortic media were found to contain a mixed pattern of G6PD

369

expression, whereas most atherosclerotic plaques contained
a single isoform of G6PD [B8]. This was interpreted as providing evidence that atherosclerotic plaques arise fromsingle progenitor cells. However, it has not been clear whenmonoclonal expansion occurs and what cell types give riseto the clone, owing in part to limitations in the G6PD methods [M9]. It was originally suggested that the monoclonal
patchiness of atherosclerotic lesions may involve a transformation of smooth muscle cells [L6]. However, recent
data indicated that the monoclonal populations result frompatches of pre-existing clones of cells [M9, S8]. There issome evidence, however, consistent with oncogene activation, of loss of heterozygosity and microsatellite instability
in human lesions [L6].

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V. SUMMARY
121. Until recently, the effects of ionizing radiation on diseases other than cancer (non-cancer diseases) had been
regarded as having a threshold in the dose response.
Threshold doses vary by tissues and other factors, but are
below a few grays for clinically evident diseases of the circulatory, digestive and respiratory systems following radiotherapy. Recent data from the follow-up of the LSS cohort
of atomic bombing survivors indicated that excess risk ofmortality from non-cancer diseases occurs at a level below
these threshold doses. The excess risk of fatal non-cancer
disease in the LSS was not explained by confounding, selection bias or disease misclassification, to the extent that thesefactors were evaluated. The effects on several specific noncancer diseases were also supported in part by morbidity andclinical data from the AHS subset of the LSS population.
The primary purpose of this annex was to evaluate
epidemiological data on various fatal non-cancer disease
outcomes from radiation-exposed populations. The annex
specifically focuses on circulatory diseases, as these areamong the most common non-cancer causes of disability andmortality in many populations.

the lower-dose radiotherapy currently in use (30–35 Gy for
adults and 15–25 Gy for children). Increased risk of heartdisease has been linked to breast tumour doses of
40–50 Gy from an early series of post-mastectomy radiotherapy. More recent radiotherapy used for early-stage
breast cancer typically exposes up to 5% of the left
ventricle to about 25 Gy. Studies show a diminished riskof heart disease associated with modern adjuvant radiotherapy for breast cancer, but longer follow-up is needed
because of the persistence of the risk, possibly lasting for
more than 3–4 decades, suggested by previous studies.
Additional information on the risk for heart disease after
low-dose radiotherapy may be expected from studies ofpatients irradiated for other cancers.
124. Some useful insights into factors that affect radiationrelated heart disease risk have also been obtained from highdose radiotherapy studies. Among the most prominent is thepersistence of excess heart disease risk that may span over
3–4 decades, and this is consistent with the data on theatomic bombing survivors. The effects of partial organ irradiation differ from those of whole-organ irradiation, andthere may be heterogeneity in response to radiation indifferent locations of the heart. The radiation-related heartdisease risk is strongly related to age at irradiation and is
especially high when exposure occurs during childhood oradolescence. Little is known about the possible effects ofsmoking and other risk factors on the radiation-related riskof heart disease.

122. Although non-cancer diseases have not been the subject of primary interest in major epidemiological studies of
populations exposed to radiation at low doses, many of theexisting cohort studies are potential sources of data on noncancer risk. A review of the literature, however, indicatedthat non-cancer disease data are currently available for only
a portion of these cohorts. However, data on circulatory disease mortality are the most frequently reported and are themost informative non-cancer data currently available forassessing the association with radiation exposure.
Epidemiological data on other fatal non-cancer diseases arelimited. Generally, published non-cancer findings are variable and inconsistent, and interpretation of the results is
problematic because of the possible selection of data published, differences in analytical methods used, differences indata quality and, in several studies, the difficulty in dealing
with the effects of potential confounders.

125. Patients irradiated for treatment of benign diseases orfor diagnostic purposes received much lower doses thancancer patients. In the ankylosing spondylitis patients, whoreceived an estimated mean cardiac dose of 2.5 Gy, theobserved numbers of deaths from cerebrovascular and othercirculatory diseases were higher than expected from the general population, but the relative risks compared with a separate group of non-irradiated spondylitis patients were notelevated. Detailed dose–response characterization wasreported from the follow-up study of patients irradiated for
peptic ulcer disease. Coronary heart disease mortality risk
adjusted for possible confounders among 10-year survivors
increased with increasing cardiac dose ranging from 1.6 to
3.9 Gy (volume-weighted cardiac organ) and from 7.6 to
18.4 Gy (5% of the heart). The elevated risk associated with
about 13 Gy to 5% of the heart indicates that excess coronary heart disease risk can occur at doses lower than the
30–40 Gy received from earlier radiotherapy for Hodgkin’s
lymphoma or breast cancer. A combined study of tuberculosis patients who received multiple fluoroscopic exposures123. Radiation-induced heart disease after high-doseradiotherapy for cancer has long been recognized as a medical sequela. It can involve all parts and structures of theheart. Long-term follow-up and randomized trials ofpatients receiving radiotherapy for Hodgkin’s lymphoma or
for breast cancer have demonstrated an increased risk ofheart disease, including coronary heart disease. Increased
risk of heart disease has been linked to mediastinal doses
in excess of 40 Gy from early radiotherapy for Hodgkin’s
lymphoma, but few data exist regarding the risk from371

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is of interest as there was a mean cumulative lung (surrogate cardiac) dose of about 1 Gy and the follow-up was for
up to 50 years. Circulatory disease (including both cardiovascular and cerebrovascular disease) mortality was not elevated in the irradiated group compared with non-irradiatedtuberculosis patients or the general population. No
dose–response analysis was performed.
126. Radiologists and other medical radiation workers
from the early half of the twentieth century received excessive doses of radiation. Cohort studies of radiologists provide conflicting evidence regarding the radiation effects on
mortality due to circulatory disease (including heart and/or
cerebrovascular disease). The results from the United Statesradiologic technologists using work history (e.g. calendar
periods or length of employment) as a surrogate measure of

exposure provide only indirect evidence regarding radiation
effects. The lack of individual dose estimates in thesecohorts is a common weakness.
127. Several major studies of occupationally exposed
workers at nuclear facilities provide little evidence forincreased risk of cardiovascular or cerebrovascular disease
related to radiation exposure. Few of the occupational studies have sufficiently controlled for possible confounding
effects.
128. Biological mechanisms by which low-dose radiation
exposure might increase circulatory disease risks are currently unclear. Although several plausible biological models
have been suggested, more research is needed to explore
possible mechanisms.

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VI. CONCLUSIONS
129. There is an increased risk of circulatory disease associated with high doses to the heart that may be incurredwith radiotherapy, but newer treatment techniques resulting
in lower cardiac doses have reduced the risk substantially.
To date, the evidence for an association between fatal cardiovascular disease and radiation doses in the range of lessthan 1–2 Gy comes only from the analysis of the data on
the survivors of the atomic bombings in Japan. Other studies have provided no clear or consistent evidence of a fatal
cardiovascular disease risk at radiation doses of less than
1–2 Gy. It is the judgement of the Committee that, given
the inconsistent epidemiological data and the lack of a biologically plausible mechanism, the present scientific data
are not sufficient to establish a causal relationship between
ionizing radiation and cardiovascular disease at doses of lessthan about 1–2 Gy. There also are insufficient epidemiological data for constructing appropriate risk models relative to these end points.

genetics and cholesterol level, need to be taken into accountwhen attempting to assess the risk associated with radiation.
Given the relatively small increase in risk associated withradiation at doses of less than 1–2 Gy, it is uncertain
whether epidemiological studies of mortality alone will beable to make a significant contribution to understanding thepotential for and the nature of any relationship between circulatory diseases and radiation at these levels of dose.
131. For mortality from diseases other than circulatory
diseases and cancer, evidence for an association with radiation at doses of less than about 1–2 Gy also comes only
from the atomic bombing survivor data. Studies of otherradiation-exposed populations linking other fatal non-cancer
diseases to radiation at doses of less than about 1–2 Gy haveyielded even less evidence than that which exists for circulatory diseases. For other non-cancer diseases, much lessepidemiological information is available than for circulatory
diseases, and the evaluation of the causal association is moredifficult, owing to the greater heterogeneity in disease aetiology and pathology and the more numerous risk factors
involved.

130. Circulatory diseases, which are multifactorial andheterogeneous in nature, occur commonly in non-exposed
populations. Numerous risk factors, including tobacco use,

373

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VII. FUTURE RESEARCH
132. Further studies of other irradiated populations areneeded. A clear conclusion derived from this epidemiological review is that, apart from the studies of the survivorsof the atomic bombings in Japan, there is a lack of data, interms of both quality and quantity, on non-cancer diseaserisk. Not only are there few data on non-cancer disease outcomes reported from potentially informative cohorts, butalso the disease outcomes addressed by published data aredisparate and mostly based on varying methods and analyses not relevant for risk assessment. Individual investigators should be encouraged to revisit non-cancer data
available in existing radiation cohorts and to conductdetailed dose–response analysis. A combined analysis
pooling non-cancer data from a large number of exposed
populations would also be desirable.

confounding that could give rise to such an association. The
effects of potential bias should be evaluated. Confounding isless likely to markedly bias results from dose–response
analyses than from exposed versus unexposed comparisons.
Thus, to the extent possible, analyses should make use ofdoses or dose surrogates, with attention to the effects ofuncertainty in these dose estimates on the risk estimates.
134. Mortality data are generally inadequate as the measure of the risk of non-cancer diseases, because of variablecase fatality. Incidence or morbidity data are preferred, provided that systematic ascertainment of morbidity data is possible. When using mortality data, consideration should also
be given to addressing the effect of disease misclassification on risk estimates. More attention should be given to
results for other disease entities, such as digestive or respiratory diseases, in addition to circulatory diseases.

133. In future, reporting of epidemiological studies of noncancer disease end points should include clear descriptionsof any limitations of the statistical methods used. Underlying
rates for non-cancer disease entities that can be used for risk
estimation are quite high, and the indications are that the
proportional increase (excess relative risk) per unit dose is
low in comparison with that for solid cancers. This reduces
the power to detect effects and limits the usefulness andcredibility of exposed versus unexposed or external comparisons, because confounding factors are more likely (thanfor cancer) to distort inference. Vague statements about
potential and unspecified confounding factors or bias should
be avoided. If an argument is made that an observed association arises because of confounding, it would be useful toprovide some indication of the nature and extent of the135. To the extent possible, future epidemiological studies should be designed to assess clinical and subclinical end
points as well as biomarkers, since this information is more
likely to lead to insights useful for developing mechanistic
models than simple epidemiological data limited to casecounts and rates. Mechanistic leads suggested by the studies of the atomic bombing survivors and others should betested in other irradiated populations, and radiation-related
subclinical changes suggested from therapy experienceshould be investigated in larger epidemiological cohorts.
Laboratory and clinical scientists should be consulted togenerate alternative and novel mechanistic hypotheses thatcan be tested in epidemiological studies.

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