-d

United Nations Scientific Committee
on the Effects of Atomic Radiation

1977 report to the General Assembly, with annexes

NOTE
The report of the Committee without its annexes appears as Official Records of the General
Assembly, Thirty-second Session, Supplement No. 40 (A/32/40).
In the text of each annex, Arabic numbers in parentheses are references listed at the end.
The designations 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 thedelimitation of its frontiers or boundaries.

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ANNEXG
Radiation carcinogenesis in man

CONTENTSParagraphs

Paragraphs

INTRODUCTION . . • . . . . . . . . . . . . . . . .
I. GENERAL CONSIDERATIONS . . . . . . .
A. Length of survey and latent period fordevelopment of malignancies . . . . . .
B. Ascertainment . . . . . . . . . . . . . .
C.
Information on absorbed dose
D. Suitability of dose level and dose
distribution . . . . . . . . . . . . . . . .
E. Suitability of comparison populations .
F. Further factors affecting the precisionof risk estimates . . . . . . . . . . . . .
G. Weighting factors for neutrons

II. LEUKAEMIA . . . . . . . . . . . . . . . . . .
A. Leukaemia in A-bomb survivors
B. Leukaemia in populations in the Mar·
shall Islands irradiated from fallout
C. Leukaemia following pelvic irradiation
D. Leukaemia following treatment of ankyE.
F.

losing spondylitis by x-irradiation
Leukaemia following other radiologicalprocedures . . . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . .

III. THYROID CA.NCER . . . . . • . . . . . . . .
A.
B.

D.

Thyroid cancer in A-bomb survivors ..
Thyroid cancer in populations in the
Marshall Islands exposed to thyroid
irradiation from fallout . . . . . . . . .
Thyroid cancer in patients therapeuti·cally irradiated from external sources
Thyroid cancer in patients treated withE.

Summary

C.

131

I

..•.....•..•.....•..
................ .

1-2
3-62
4-12
13-18
19-27
28-36
37-42
43-47
48-62
63-96
63-76

77
78-82.

IV. BREAST CANCER . . . . . . . . . . . . . . .
A.

B.
C.
D.

V. LUNG CANCER
A.
B.
C.

200-226201-207
208-222223-226237-302253-256257-263264-265266-276277-282283-285

A.
B.
C.

F.
G.

E.

H.

Brain . . . . . . . . . . . . . . . . . . . .
Salivary glands . . . . . . . . . . . . . .
Mucosa of cranial sinuses . . . . . . . .
Digestive organs : . . . . . . . . . . . . .
Pelvic organs . . . . . • . • . . . . . . .
Liver . . . . . . . . . . . . . . . . • . . .
Malignant lymphoma and multiple myeloma . . . . . . . . . . . . . . . . . . . .
Skin . . . . . . . . . . . . . . . . . . . .

VIII. MALIGNANCIES IN PRE-NAT ALLY EXPOSED CHILDREN . . . . . . . . . . . . . .
IX. CONCLUSIONS

112-138A.
B.

139-141
142-150

ReferencesI.
In assessing the harm that might result from any
form of human exposure to ionizing radiation, it isnecessary to identify the types of injury that may becaused and to estimate the frequency with which each

175-188
189-199

VII. OTHER CANCERS

85-89
90-96

Introduction

165-174

227-236

D.

108-111

Lung cancer in A-bomb survivors . . . .
Lung cancer in workers exposed tohigh radon levels . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . .

151-199
151-164

VI. BONE TUMOURS

83-84

97-150100-107

Breast cancer in A-bomb survivors .. .
Breast cancer following exposure in
diagnostic radiology . . . . . . . . . . .
Breast cancer following radiotherapy tothe breast . . . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . .

Carcinogenesis in different organs . . . .
Indications for future work . . . . . . .

286-292
293-302303-308309-332309-319320-332
Page

417

will occur following a given radiation exposure. Since
the radiation may involve the whole body more or lessuniformly or individual organs or tissues selectively, it isnecessary to examine the sensitivity of the different
tissues as well as of the body as a whole. Moreover, to beof value in estimating the effect of environmental or361

occupational exposures, the estimates should beapplicable over a range of doses down to very low ones
delivered either at low dose rates, or in separate repeatedfractions delivered at high or low dose rates.
2.
There is increasing evidence that in human beings(as in animals; see Annex I, paragraph 26), the inductionof malignancies represents the most important effectproduced at low doses in the exposed individual, and thefrequency with which such changes are induced indifferent tissues has been examined by the Committee in
its previous reports. It is at present impossible to deducethese frequencies of radiation carcinogenesis in manfrom experimental work in animals (see Annex L
paragraph 5). The following review, therefore, is ofestimates of the induction of malignancies by radiationthat can be derived from studies of human populations
in which the whole body or individual organs have been
irradiated; it is intended to update information
presented in the 1972 report of the Committee!

I. GENERAL CONSIDERATIONS
3.
The strength of the available information depends
heavily upon the consistency of estimates obtained
under different conditions, even though individual
estimates may be subject to a variety of ·defects.
Optimally, a valid estimate of the carcinogenic effect ofradiation on a given tissue will depend upon thefollowing factors:(a) Study of the irradiated population over a
prolonged period of several decades after exposure
during which malignancies may become detectable;(b) A criterion of diagnosis which ensures that
all malignancies induced or all fatalities from such
malignancies are recorded;(c) Knowledge of the absorbed dose and doserate, or any fractionation of the dose, and of the variation of absorbed doses in different individuals;(d} A sufficiently uniform distribution of dosethrough the body or through the tissue of interest;( e)

A valid control population;(!) A number of malignancies in the irradiatedpopulation sufficient to give statistical reliability to theexcess over that expected on the basis of the control
population:(g)
An adequate basis for comparing the
carcinogenicity of radiations of different quality at
different dose levels.
1•
In th)s An~ex, the term "carcinogenesis" is used tomclude the mduct1on not only of carcinoma but also ofleukaemia or any other form of malignancy (sarcoma, lymphomaetc.). The word "malignancy" is used when the reference is to allsuch malignant conditions, including leukaemia as well as solidcancers, since "cancer" or "malignant tumour" should refer only
to solid or focal malignancies. The term "tumour" is usedwithout qualification when it is either clear from the context or~important, whether a malignant or a benign tumour' ismtended.

362

A. LENGTH OF SURVEY AND LA TENT PERIODFOR DEVELOPMENT OF MALIGNANCIES
4.
It has repeatedly been shown that after radiation
exposure, malignant tumours may continue to become
detectable in excess in the exposed population for Jong
periods, often several decades. Much of the ·'latent
period" observed in practice between the exposure andthe detection of a tumour must be due to the timerequired for sufficient increase in size of the tumour tomake it detectable. The estimated mean latency of agiven type of tumour will therefore depend in part upon
the methods used to detect it and upon the closeness of
surveillance of the exposed population. It will depend
upon the rate of cell division, cell survival and forms of
local spread or metastasis of the particular type oftumour. It will also depend upon the ease of
examination of the organ in which the tumour arises.
detection of a small tumour obviously being much mor~
efficient in the thyroid than, say. in the liver orpancreas. In statistics based on mortality from tumours,
the interval between irradiation and death will vary alsowith the widely differing speed at which different
clinically diagnosable tumours cause death, and this may
depend on the forms of treatment available. It is
uncertain whether part of the latency is also due to any
form of induction period before the initially affected
cell or cells start to divide and form a tumour, or before
the tumour assumes "malignant" characteristics ofgrowth and spreading. It is clear from some investigations in animals that at short intervals after irradiation
the thyroid gland is found to contain tumours that are
only of "benign" histological character (22), and thatmalignant tumours become detectable at later stages. In
a recent detailed study in man (58) on the other hand,
this sequence was not evident, benign tumours being
detected after a longer latency, particularly in males,than malignant tumours. Some biological transition
period may indeed be involved, as well as the simple
growth of an initially malignant tumour to detectablesize. It has, however, been shown that lung tissue from
irradiated rats may show no tumours detectable by serial
sectioning at short intervals of 2-3 months after
exposure. Yet if sections of these lungs are transplanted
into mice of a type lacking the immune mechanisms thatwould prevent the growth of transplanted tissues,
characteristic tumours develop in the recipient mice,
showing that abnormal processes are in fact acting in theirradiated lung earlier than it is practicable to detect
them, even by det~iled microscopic examination (79).
5.
The progressive increase in size which causes
human tumours to become detectable is likely todepend. as in animals (see Annex I. paragraph 74), upon
the rate of tumour cell division and the balance between
processes of cell production and cell destruction. The
estimated "doubling time" differs widely for tumours ofdifferent types. in man as well as in animals.
6.
The mean latency and the distribution of latent
periods of any type of tumour may thus depend upon anumber of factors characteristic both of the tumour andof the circumstances of surveillance and ascertainment in
the exposed population (Annex I, para. 105). Moreover,in some instances the latency of tumour development
appears to depend upon the age of the person irradiated(for example as discussed later for thyroid and breast
cancers), and the latency for development of tumours iscertainly short following irradiation of the foetus inutero (148). It is also likely that latency may vary withthe size of the absorbed dose, as appears to be the casefor example for osteosarcomas following radium-226
incorporation in the skeleton (41) and for thyroid
cancers following external irradiation (58), althoughapparently not significantly for leukaemia resulting from
A-bomb irradiation at Hiroshima and Nagasaki (para. 64
and table 3). A similar variation of latency withdose is observed with chemically induced cancers inanimals. In all such studies it is of course important tobase conclusions upon the mean latency, or the latency
for a given percentage of tumours, as studied overprolonged periods after irradiation. The "latent period"that elapses until the first tumour is detected will, on
purely statistical grounds, be shorter after large doses
than after smaller ones if larger doses produce larger
numbers of tumours and if tumours.appear after varying
time intervals. The relationship between latency oftumour detection and dose size in experimental
carcinogenesis is discussed in detail in Annex I(para. 109).
7.
The distribution of latent periods for different
tumours cannot therefore be expected to conform to
any single relationship of frequency with time (7).
Additional cases of cancer apparently induced byradiation may however continue to be detected for atleast 30 years following exposure. Estimates of the
carcinogenic effect of radiation, based on shorter periodsof observation, may thus require correction, and noreliable distribution curve oflatencies may be available onwhich to base an exact correction factor. For leukaemia,
several surveys are now sufficiently prolonged from thetime of exposure to demonstrate that further cases areceasing to be detected. The distribution oflatent periods
under the conditions of exposure and ascertainment of
those surveys can thus be defined. In particular, data
published by the Japanese Life Span Study indicatesthat by 1972 the incidence of leukaemia in exposed
survivors was close to that in the comparison group (seeparagraph 63). From the data of Moriyama et al. (97),the mean time interval from irradiation to death has
been about 14 years (see table 3).
8.
For other malignancies, apart from those following
irradiation in utero, no prospective survey appears yet tohave been sufficiently prolonged to record all malignancies attributable to the exposure. The Life Span Studysurvey shows a small reduction in the rate at which
excess deaths from malignancies other than leukaemia
were occurring during 1970-1972 as compared withearlier periods (in those exposed at over 10 rad T65 inboth cities, both sexes and all ages, in excess of thecomparison populations (97); see paragraph 239), but
this fall is not statistically significant.
9.
Nor is the necessary information available fromany retr'Jspective survey (for example. of the date ofradiation exposure of subjects subsequently diagnosed as
developing cancers that are presumed to be radiationinduced). In such cases the distribution of latency would
be unbiased only if the frequency of significant
irradiation in the population within which the diagnoses

were made had remained constant for long periods (e.g.
50 years) and if the likelihood of ascertainment andpresentation for diagnosis were independent of timesince irradiation (apart from the possibility of priordeath from other causes, for which correction could
ordinarily be made). These conditions fail in many cases(for example, as discussed later for the development of
thyroid malignancies following thymic irradiation). since
this procedure was practised only for a limited period,
largely prior to 1960, and the distribution of observed
latencies is probably still truncated by exclusion of thelonger latent periods. Similarly, many "retrospectiveprospective" surveys (for example, of the late effect of aperiod of radiotherapeutic practice), will underestimate
latency until they have been continued for several
decades after the period of the practice.
10. In many instances, particularly of the latency withwhich tumours are detected after irradiation of patientsof different ages, no correction is in fact made fordiminution of the exposed population due to death fromother causes. This results in an underestimation of thenumber of long latencies that would otherwise beobserved, particularly in studies on those irradiated atolder ages.
11. Values quoted as mean latencies for tumour
detection are, however, unlikely to overestimate the true
value, and certain surveys indicate that this value mustbe large, at least for some types of malignancy andconditions for ascertainment. A number of the publishedestimates of mean latency of radiation-induced malignancies give values exceeding 20 years (table I).

TABLE I. EXAMPLES OF LONG MEAN LATENCIES RECORDED FOLLOWING THERAPEUTIC IRRADIATION
Reference

Number of
subjects

30
89
168
105

20
10
10

47

37

77

113

4

121
167

38
10
130

147

40

9

Site ofcancerThyroid
Bladder
BreastVarious, onhead and neck
Pharynx andlarynx
Various, onhead and neckSkin
Pharynx
Pharynx andlarynxSkin(basal cell)Meanlatency (years)
20.3
20.7
22.6
22.8
23.4
24.1
24.5
25.0
27.3
41.5

12. As an approximation in the absence of better
information, it seems appropriate therefore to assume amedian latency of about 25 years, so that the total ofcancers diagnosed within this time after radiation, atleast in young subjects with a long life expectancy, may
represent about half of all cancers likely to have been
induced. Data on otherwise undiagnosed cancers foundat operation on the thyroid 24 years after neckirradiation in childhood support this estimate (seeparagraph 133).
363

B. ASCERTAINMENT

I 3. Problems of complete or correct ascertainment
arise in a number of surveys referred to below, on whichrisk estimates depend. Moriyama and his colleagues (97)emphasize that, although death certification diagnosticof carcinoma is about 90 per cent accurate, the accuracyof specification of particular sites is much Jess precise.
Their analysis has therefore been limited to sites where
the accuracy of specification is high. The reliability ofdeath certification of primary malignant tumours ofbone is also regarded as being poor in many countries.
owing to death from carcinomatosis with metastases tobone often being recorded as due to primary bonetumours. This difficulty is likely to apply also to anumber of other organs in . which metastases fromtumours of other tissues commonly occur, and deathcertificates may give quite unreliable information as tothe primary site of cancer development.
14. In surveys based on malignant tumour incidence
rather than on mortality, retrospective analyses cansometimes be reliably based on efficient tumour
registries. Modan (92) however, points out that his
estimates for the frequency of tumours that cancommonly be removed by operation. such as those of
the thyroid and skin, are likely to be underestimates,
since the National Israeli Tumour Registry only cameinto operation 1 I years after the start of the irradiations
he studied and his additional check through deathcertificates did not detect the incidence of these
operable tumours. The lack of estimates for skin tumour
induction, in general, is probably due to the ease withwhich these tumours can be removed surgically as soon
as they are diagnosed. as well as to the low incidence ofsuch tumours when only small skin areas are irradiated.
15. In the thyroid. the ease with which small nodules
can be detected implies that ascertainment is likely to behigh in a population under close surveillance because ofa known previous radiation exposure. Thus for example,
the Marshall Islands populations exposed by fallout are
examined annually and operation is suggested if palpable
thyroid nodules develop. Indeed, if it is the case that in
the thyroid, radiation-induced malignant tumours may
develop from nodules which initially are histologicallybenign, this surveillance involves, as intended, a reduced
risk of the development of malignant tumours.

16.

On the other hand, the frequent Jack of symptoms
or distinctive signs from small malignant nodules of the
thyroid may imply that the incidence of thyroid cancers
is also underestimated in populations which are notrepeatedly examined medically, since these tumours may
not progress to cause death. This applies particularly tothe so-called "occult sclerosing papillary'' thyroid
tumours. For the purposes of risk estimation, however,
the omission of tumours which do not even become
clinically detectable during life, is of doubtful
importance.

I 7. In the case of most types of cancer discussed inthis Annex, an average of less than 25 per cent ofpatients remain alive 15 years after detection of thecancer-at least as judged by the survival statistics ofpatients with ··naturally occurring'' cancers of those364

types. In a few forms of cancer however. prolonged
survival is common, whether because of the effectivenessof surgical or other treatment. or because of slow
progress of the cancer. In most cases. the accuracy ofpresent risk estimates of cancer induction is insufficient
to justify the separate estimation of fatal and non-fatal
cancer induction. The following values were observed(124) for the percentage of patients registered as having
developed cancer in 1954 in England and Wales and who
were survivipg afte_r 15 years (values quoted are means
for males and females): leukaemia. 2: lung, trachea andbronchus, 3; myeloma, I 0; brain and nervous system.
13: bone, 20; large intestine. 24: rectum, 24; bladder.
25.
18. The thyroid average value, 28 per cent. results
essentially from the very short survival of patients withanaplastic cancers (SO-per-cent survival after 3 months(115)). The type of thyroid cancer induced by radiation,
however, an adeno-carcinoma arising from follicular
cells, has an unusually slow progress and a high cure rate,and here the difference between risks of cancer
induction and of fatal cancer induction is very large (seeparagraph 150). For the female breast and for the uterus
also. the 15-year survival rates are substantial, and are
estimated as 29 and 55 per cent respectively, while thatfor the salivary glands is 70 per cent.

C. INFORMATION ON ABSORBED DOSE
19. A number of epidemiological surveys demonstrate
the occurrence of radiation carcinogenesis but cannot be
used in risk estimation because the size of the original
doses is not known. It is important to recognize,
however, that these surveys may still have considerable
value if a number of different organs can be assumed tohave received about equal doses. Given an equally
efficient ascertainment of tumours arising in theseorgans, therefore, they can be graded quantitatively for
relative sensitivity to tumour induction. If. moreover,the carcinogenic risk is known for one, inferences can be
drawn for the others. Thus, it may be possible to infer
the sensitivity of the salivary glands from the ratio of
salivary cancers to thyroid cancers following neckirradiation and from independent data on thyroid
sensitivity.
20. It is equally valuable to identify the tissues inwhich no tumours develop when tumours do occur inequally irradiated organs. and so to establish an upper
limit to the risk for relatively insensitive tissues. This
inference can of course only be made if it is clear thatthe information examined is not selectively reporting
only tumours of significantly increased incidence.
21. In some instances, dose estimates are only
obtainable on a very indirect basis. Thus for example,
the external irradiation estimates of the thyroid glandsof the Marshall Island populations (paras. 108-111) are
derived from measurements which began within a few
days of the start of exposure and a theoretical basis for
extrapolation to deduce earlier doses. The internal doses
from concentration of radioiodine in the gland. however,are largely based on the activity that was being excreted
in the urine subsequent to the ingestion of theradionuclides and from data on the likely relationshipbetween excretion rates and retained activity at a given
interval after the period of ingestion.
22. In some instances of non-uniform internalradiation, there may be uncertainties as to dose
distribution or as to the tissues over which absorbed
c!oses should be averaged. Thus, it has become evident
that osteogenic sarcomas arise mainly from the endosteal
cells of bone and that the dose as averaged over tissues
lying within l Oµm of the bone surface is the relevant
one, while the mean dose throughout the bone is not.
Thus, it is necessary to use different models for
dosimetric calculations for short-lived radionuclides likeradium-224, from which most of the energy ofdisintegration is given up while the isotope is still present
at its initial site of deposition on bone surfaces, and forlong-lived nuclides like radium-226, which become
distributed throughout bone during the course of theirdisintegration. Materials with long effective half-lives intissue present further problems in determination of thedose relevant to risk estimation, since it cannot beknown how much of the dose delivered during the longlatent period of any tumours that occur is relevant totumour induction and how much is "wasted radiation"
occurring during the subsequent development of anestablished tumour.
23. The occurrence of osteosarcomas following incorporation of radium-226 is associated with the development of about one third as many carcinomas arisingfrom the comparatively small mass of mucous membrane
which covers bone surfaces in the mastoid and otherintracranial cavities ( 41 ). It is not possible at present,
however, to deduce the sensitivity of such membranes tocarcinogenesis, since· radon is formed from the radium
and retained in these cavities in concentrations that areat present still undetermined, and the relevant dose is
therefore unknown.
24. Rather similar problems arise in connection withthe carcinogenicity of ''thorotrast" where the incidenceof tumours in the liver (mainly cholangioendotheliomas) can be related to the level ofconcentration of the thorium dioxide in the liver. The
sensitivity of the liver to radiation carcinogenesis cannot
be established with certainty, however, for several
reasons. Particles of the thorium dioxide tend toaggregate and produce necrosis of the immediately
surrounding tissue, so that much of the alpha radiation isabsorbed either in dead cells or in the particles
themselves. Moreover, it remains possible, although not
likely, that the chemical properties of the thorium
dioxide, as well as the radiation emitted by the thorium
and its daughter products, contribute to its carcinogenicity (see paragraph 283).
25. The problems in deriving a risk per unit absorbed
dose for lung tissue from statistics of lung cancer
development in uranium miners are similar, since thedoses to the bronchi and alveoli of the lung depend
critically upon the deposition and location of productsof radon decay. Although a relationship is establishedbetween the radon concentration in air samples in mines
and the mortality amongst miners who have worked inthem, any radiation risk estimates derived for lungtissues as a whole are necessarily indirect.

26. Problems of a different type arise in attempting toderive the risk per unit absorbed dose of tissue exposure
to radiations of low linear energy transfer (LET) fromobservations. for example. on the populations exposed
at Hiroshima to mLxed neutron and gamma radiation.
The greater carcinogenicity of neutrons than of gamma
radiation per unit absorbed dose, as shown in various
experimental studies in animals, prevents any simple
inference of the frequency of tumour induction per unitof energy absorbed (but see paragraphs 48 to 61). It has
indeed been suggested (94) that certain types ofmalignancy may be preferentially induced by radiationof high LET.
27. Even in the analysis of effects of medical exposure
to low-LET radiation there may be difficulties in
estimating the likely absorbed dose, for example in thelung, resulting from known skin exposure with specified
field size and position. The absorbed dose in bone fromradiation of low energy may also be particularly difficult
to estimate with confidence.

D. SUITABILITY OF DOSE LEVELAND DOSE DISTRIBUTION
28. Valuable information has been derived fromepidemiological studies of patients previously treated forankylosing spondylitis by local irradiation of affectedparts of the spine. These studies show an increase incancer in certain organs that are likely to have beenheavily irradiated as a result of their frequent inclusionin the direct beam. These increases, or at least thosefollowing single courses of therapy, can potentially be
used to evaluate the sensitivity of these organs, once
estimates are made of the dose they will have received
and if due allowance can be made for the likely normal
incidence of different forms of cancer in this condition.
29. Estimates have also been made of the frequency
with which leukaemia is induced by this treatment.
These estimates have then been related to the mean
absorbed dose to the bone marrow by averaging,throughout the total mass of the marrow. the dosedelivered to the fractions of marrow irradiated in thevarious treatments (see paragraphs 78-80 and 83-84).
Such estimates of leukaemia induction per unit dose as
averaged over the whole marrow are not unduly
discrepant with those derived from conditions of more orless uniform marrow irradiation. It must be recognized,
however, that these conditions involve an entirely
non-uniform exposure of the tissue at risk and that. on
biological grounds, there is ample evidence that theprotection of a small volume of marrow from irradiation
may allow '·recolonization" of irradiated marrow byunirradiated marrow cells, and that this is of importanceto continued marrow function, at least following highlocal exposures.
30. These difficulties may, however. be more apparent
than real if carcinogenesis is related to events induced byradiation in single cells or small groups of cells without
significant reaction between affected and unaffected
cells. To the extent that this is true, we are concernedwith the number of cells involved and with the estimateddose to each. In this way it may be valid to use
365

observations in which, for example, part of the gut orpart of the total skin area has been irradiated to derive
estimates for the carcinogenic effect of irradiating thewhole gut or the whole skin.
31. It may be noted that a gross non-uniformity of theirradiation of cells of an organ will always occur withalpha radiation, since even a uniform concentration ofan alpha emitting nuclide is likely to involve a highdeposition of energy in a few cells and no deposition in
the many cells through which no alpha track passes,
unless the nuclide is present at very high activities.
32. If data are being analysed on the basis of anassumed linearity between dose and frequency of effect,
the arithmetic mean dose throughout the population ofcells at risk will in any case form the appropriate index
with which the tumour incidence should be compared.
If, however, the range of doses to which cells are
exposed exceeds that over which a linearity of thedose-effect relationship can be assumed to apply, thenthe mean dose over the tissue as a whole can at best be
only an approximation to the relevant parameter (seeAnnex I, chapter III, section B).
33. For many forms of tumour induction in animals,
there is evidence (Annex I, paras. 140.154) that, foruniform irradiation of various tissues, the number oftumours induced increases to a maximum (often atabsorbed doses of the order .of a few hundred rad ormore) and then decreases, presumably as the cell-killing
effect of the radiation predominates over the tumourinducing effect. (The maximum yield per unit absorbed
dose occurs at a somewhat lower dose.) It follows fromthis. firstly, that for highly non-uniform radiation,
estimates based on mean tissue dose may overestimate
the risk of non-uniform irradiation and, secondly, that
estimates based on uniform ·high doses may underestimate the risk per rad of uniform low doses. The
paucity or absence of thyroid cancers following theradioiodine therapy of hyperthyroidism, for example, isthus not necessarily in conflict with the relatively
frequent induction of thyroid cancers by moderate or
low doses. The absence of any consistent increase inleukaemia following the radium treatment of cancer ofthe cervix uteri has similarly been attributed to theeffect of cell killing in the parts of the bone marrow
which are most heavily irradiated (see paragraph 82).
34. It follows also that, at very high doses (e.g., several
thousand rad) the number of tumours induced per unit
dose may be lower than that at lower doses (e.g. a few
hundred ~ad). Moreover, there is now abundantevidence in animals, and some evidence in man, that thedose-effect relationship at these lower doses is
non-linear, at least for certain tumours (Annex I,
paras. 30 and I I 2). Indeed, it has been suggested ontheoretical and microdosimetric grounds, that thetumour-inducing effect of radiation is likely to be
represented substantially by the sum of a linear term in
dose corresponding to the consequences of single events
due to ionization tracks passing through sensitive cellstructures. and of a quadratic term in ( dose )2
corresponding to damage due to two events (125. 157).
It must be emphasized therefore that the frequency oftumours induced per unit absorbed dose at a given dose366

level applies strictly only at that dose level, and that thelikely frequency per rad at low dose levels of a few rador less, which are of most concern in radiation protection, cannot be assumed to be equal to the frequency
observed per unit absorbed dose at higher levels.
Similarly, the frequency observed in populations
exposed at different doses cannot be taken as thatapplicable at the mean dose, unless the dose range within
the group is small. These considerations apply
particularly to radiation of low LET.
35. If the carcinogenic effects of radiation are in fact
attributable only to the sum of one- and two-event
processes, with a decrease of effectiveness at very highdoses due to cell death and dependent on similar
contributions, the relationship of frequency of effect E
to absorbed dose D has been described by

E = (aD+bD2) e-lcD+dD11
At very low doses, the effect per unit dose E/D tends
towards a. For moderate doses, this ratio would be given
approximately by

E/D = a [I + (b/a) DJ [l - (c + dD) DJ
The value of (c + dD)D is likely to be small for all valuesof D which are substantially below that at which the
maximum induction of tumours occurs. On this basis theyield per unit absorbed dose at low doses is likely to beoverestimated by that at rather higher doses by thefactor 1 + (b/a)D).
36. Data on the genetic. effects of low-LET radiationin the mouse and on the induction of chromosome
aberrations in several mammalian species including man
which have been analysed in this way suggest values ofb/a in the range 0.01-0.03 (20), and it has beensuggested that similar values may apply for carcinogenesis. If this is so, it would indicate that estimates ofcarcinogenic effects per rad derived at doses of 100 radof low-LET radiation could only overestimate thefrequency of effects per rad at low dose by a factor of
between 2 and 4.

E. SUITABILITY OF COMPARISONPOPULATIONS
37. The excess incidence of malignant disease in an
irradiated population can be reliably estimated only bycomparison with a control population which is similar in
all respects except that it has not been equally
irradiated, and this condition is seldom fully achievable.
38. In the important studies on late effects ofradiation in patients after radiotherapy the problem isparticularly difficult, since it is usually hard to establish
and follow up a control group of patients, with the samedisease and of the same severity, but untreated byradiotherapy, since the selection of patients for suchtreatment usually correlates with the stage or severity ofthe disease. Yet. it is difficult to be sure that some formof malignant disease may not be slightly increased inincidence in patients with the disease being treated. The
radiation exposure itself may be unlikely to produce
more than a small increase of this sort. so that spurious
results may be caused if comparisons are made with theincidence of malignant disease in a sample of the general
population, matched only for age and sex. If the excess
incidence in the irradiated. compared with the general,
population correlates with the radiation dose received,
and if this dose does not correlate with the severity (ortype) of disease treated, the comparison may be valid. It
may also be valid when the disease treated is one such as
ringworm of the scalp, which appears very unlikely to be
associated with increased malignancy, at least of tissues
other than the skin, but here controls by unirradiatedpatients with ringworm have in fact been possible.
39. In the treated ankylosing spondylitics, it has been
pointed out that the excess incidence of cancer of thecolon cannot be regarded as evidence of radiationinduction of this form of malignancy, since ankylosing
spondylitis is known to be associated with ulcerative
colitis and the incidence of cancer of the colon isincreased in patients with ulcerative colitis. In addition,
little was originally known of any association between
either the disease itself, or the drugs used in control of
its symptoms, and the incidence of other malignancies,
except that in an initial survey (37) one case ofleukaemia occurred in a thousand patients withankylosing spondylitis who were not treated byradiotherapy. Further data have, however, now beenobtained (120) showing no increased mortality fromleukaemia, cancer of the colon or other malignancies ascompared with that in the general population, in 1021
patients with ankylosing spondylitis followed during amean period of 8.5 years, and who had not been given
x-ray therapy. Similarly, the raised incidence of cancerof the breast in patients irradiated for acute post partum
mastitis could only be attributed reliably to theradiation if it was known that there is no increase insuch cancers in untreated patients with this form of
mastitis. It is particularly valuable therefore that asurvey has now been made (138) on the breast cancer
incidence in such untreated patients (see paragraph 176).
The increased incidence of thyroid cancer in children
following neck irradiation for enlargement of thethymus was similarly regarded as possibly being due tosome effect of thymic malfunction, associated both withthe enlargement that was being treated, and with afailure of the immune reactions to a developing cancer,
so that cancer incidence might be increased in suchpatients. It was only when it was found that theincreased thyroid cancer incidence was associated withneck irradiation for a variety of other conditions ininfancy that it could be asserted that the radiation was
likely to be responsible for the excess. In the same way,leukaemia is known to occur in patients withpolycythaemia vera whether treated with 3 2 P or not.
Control series of untreated polycythaemic patients are
only valid if the duration of the disease when untreatedwith 3 2 P is as long as when it is so treated. In general.
the 3 2 P treatment is effective in prolonging life andmay, therefore, be apparently associated with a higher
incidence of leukaemia purely because the patients sotreated live long enough to allow the development ofwhat may be a natural sequel of prolonged polycythaemia.
40. A further example of the hazards of using thegeneral population as a comparison group for patientswith a particular disease treated by radiation is given byfollow-up studies of hyperthyroid patients ( 128) treatedwith radioactive iodine. The incidence of leukaemia wasfound to be slightly higher in the group of patients sotreated than in members of the general population of thesame age and sex. Fortunately, however. a control series
had been studied of patients with the same condition
treated by surgery in which a similar slight excess ofleukaemia was found. It would have been hard to
predict. and perhaps even to suppose, that leukaemia
would be increased in frequency in hyperthyroid
patients, and particularly in hyperthyroid patients who
had been cured of their disease by adequate treatment,
and the excess might have been used as a basis forradiation risk estimation if the appropriate control series
had not been studied.
41. In the very important epidemiological studies of
the incidence of cancer in A-bomb survivors in
Hiroshima and Nagasaki, the establishment of an
appropriate control group has always presented difficulties. In mortality studies, the general mortality rates
at appropriate age and sex in the Japanese population asa whole have been used, but are subject to criticism inseveral respects. Firstly, living conditions in the twocities were very obviously difficult for a long period
after the explosions, and may have involved factors
which might influence mortality rates even for malignant
disease. Secondly, the populations exposed weredepleted of men of military age, and particularly thoseof this age and in good health; and, while the difference
in sex distribution could be adjusted, the adjustment
would not necessarily be accurate if based on statistics
for the whole of Japan, even if these were confined to
the years at issue, since the distribution may well havebeen different in urban and rural areas. Thirdly, andparticularly in regard to carcinoma of the bronchus, it is
known that the incidence of this condition differs inurban and rural communities so that comparisons
between the survivors in the two cities and those forJapan as a whole are not necessarily valid. Moreover, it is
known that the mortality from tumours of the lung inJapan rose considerably between 1967 and 1972 (from12 .9 10 -s to 17 .0 10-s per year). The use of the 1967
values (97) as controls for estimating more recent
radiation induction of lung tumours in Hiroshima andNagasaki may therefore overestimate this induction. The
use of the mortality in those exposed at 0-9 rad may
therefore be preferable. In various estimates made in thisreport, both bases of comparison are shown, eventhough the small numbers of death occurring in the
0-9 rad _group may considerably reduce the accuracy of
estimates based upon comparison with this group (seeparagraph 45).
42. In addition, the immediate mortality at the timeof the explosions must necessarily have been selective tosome extent, involving those in different states of healthto different degrees, and this in itself may haveinfluenced the mortality rates for different conditions
amongst the survivors. Moreover, those surviving in thehigh exposure groups are likely not only to have been
subjected to a more powerful selection of this type atthe time of the explosions. but in addition may wellhave had other injuries, ailments or difficulties in living
conditions which may have correlated strongly with themagnitude of the exposure that they received. or withthe position in the city at which these exposures werereceived.
367

F. FURTHER FACTORS AFFECTING THE
PRECISION OF RISK ESTIMATES
43. Even when populations irradiated at known doseare followed over sufficiently long periods of time, withfull ascertainment of resulting malignancies and with anadequate control group for comparison. several otherfactors will affect the precision of the resulting estimate.
The size of the exposed population is of great
importance for detecting an excess of most types oftumour following irradiation. Since the incidence ofmany types of tumours following radiation appears to bein the range of 5-20 per million per rad, radiationinduced tumours will usually not occur in more than,say 1 per cent of those exposed. Such an excess may bereadily detectable in an exposed population of a few
hundreds if the type of tumour induced occurs rarely inthe absence of radiation. If, however, a small frequency
of induced tumours has to be distinguished statisticallyfrom a large number of similar tumours occurring
naturally, populations of many thousands may need to
be studied.

remembered that probabilities cannot necessarily bederived from values of the standard error on theassumption of a symmetrical distribution.
47. In quoting the amount by which an observed
number of cases (e.g. of deaths from a disease) exceeds
the expected number, the size of the excess may be
negative, or one of the confidence limits with which it isestimated may be so. In such cases the excess is notedwith its negative value, or is quoted simply as being
negative (with the abbreviation "neg."). Thus forexample, for an observed number of 3 that has 90%
Poisson confidence limits of 0.8 and 7 .8 and an expected
number of 2.2, the excess would be expressed as 0.8(-l.4-5.6)or0.8(neg.-5.6), and rates derived from suchan excess are quoted similarly. Since so many estimatesin this Annex are necessarily based on small excesses ofnumbers observed over those expected, it is irnp~rtant toindicate in this way the accuracy of the stated excess orexcess rate on statistical grounds and the confidencewith which it can be asserted even to be positive.

44.

The statistical uncertainties involved in estimates
based on small numbers of tumours are inc1eased if theincidence in the comparison population itself involves
small numbers of tumours also.
45. For example, it has been emphasized (para. 41)
that the incidence of malignant disease in the irradiatedsurvivors at Hiroshima and Nagasaki cannot necessarilybe estimated accurately by comparison with the generalmortality rates for Japan as a whole. The same applies
with equal emphasis for morbidity rates, particularly
since the populations of Hiroshima and Nagasaki arelikely to have been under much closer medical
surveillance for the particular purposes of the healthstudy than other populations. For these reasons
therefore, the incidence of malignant disease in the
exposed groups has often been compared with theincidence, either in residents of the two cities who were
not in the cities at the time of the explosion, or ingroups exposed only to radiation at doses of 0-9 rad.
When such comparisons are made however, the incidenceof diseases in the control groups may be subject tosubstantial statistical uncertainty in view of the small
numbers of tumours occurring in these groups. The
estimate of risk based on these comparison groups may,therefore, be more valid than when the comparison iswith the Japanese health statistics as a whole, but may
be so imprecise that this advantage is lost.
46. Throughout the following sections, attempts havebeen made to indicate the statistical reliability of theestimates and rates quoted, usually by stating the 90%
confidence limits involved, as determined by the Poisson
distributions depending upon the number of cases
observed. Thus. whenever an estimate is followed by astatement of two alternative values within parentheses,
for example "51 (26-88) 10- 6 " it is implied that the
expectation 51 10- 6 has 90% confidence limits of
26 10-6 and 88 10-6 • These values give only a minimum
estimate of the confidence zones if other sources oferror affect the estimate. Where several such sources ofrandom error can be evaluated and where standard errorsof a mean value are quoted in consequence, it must be
368

G. WEIGHTING FACTORS FOR NEUTRONS
48. For neutrons and for alpha radiation, estimates ofrisk per unit absorbed dose cannot be used in any direct
way for estimating risk per unit absorbed dose fromradiations of low LET for two reasons. Firstly,
radiations of high LET are known to be more harmful
than those of low LET per unit absorbed dose, and theRBE, or ratio of absorbed dose~ causing a given
frequency of effect, may vary for different types ofeffect. Moreover, even for a given type of effect andquality of radiation, the RBE is likely to vary with thedose levels at which the comparison is made or with thefrequency of effects (76, 125).
49. There are considerable difficulties therefore in
expressing the carcinogenic risks observed in A-bon:bsurvivors in any form which is applicable to radiation in
general. In Hiroshima in particular, a substantial
proportion (23-35 per cent in the different dosage
groups) of the estimated kerma (tissue kerma in free air,
T65 estimates) is attributable to neutrons.
50. In Nagasaki this percentage is much lower, lessthan 2 per cent in all dose groups. In principle, it would
be possible to obtain approximate risk estimates for
low-LET radiation for various forms of malignancy fromthe mortality data in Nagasaki. In fact, however, manyof the estimates from this city are of low statisticalreliability, those from Hiroshima being determined withconsiderably greater accuracy.
51 . For leukaemia, however, relatively accurate risk
estimates can lie made for several dose groups in eachcity. In this case, therefore, it is possible to compare therelative effectiveness of neutrons and gamma radiation inthese dose groups in inducing leukaemia, if it is assumed
that a given absorbed dose of high-LET radiation was
equally effective in each city, and that the same applies
to equal absorbed doses of low-LET radiation. For thiscomparison two steps are required. Firstly, an estimate

must be made of the mean absorbed doses of high- andlow-LET radiation in bone marrow resulting from theneutron and gamma radiation in each city and for eachgroup examined. For bone marrow, values for the ratio
mean absorbed dose/mean kerma are under investigation(71). Preliminary estimates however (70) indicate thatthe ratio for gamma radiation is likely to be about 0.55.
For neutrons, the corresponding ratio is estimated as
0.26 for the absorbed dose of high-LET radiation (fromprotons induced by neutron capture or by recoil) withan additional 0.07 by induced gamma radiation. 2
52. As the second step, a biological weighting factor W
for the effectiveness of high- relative to low-LET
radiation in inducing leukaemia can be derived byequating the induction rates-in excess cases perperson-year per unit absorbed dose-in the two cities,
giving the component of absorbed dose due to high-LET
radiation in each city the same weighting factor.

53. Thus, if the mean absorbed doses in marrow fromgamma radiation and from neutron-induced protons in agiven dose (kerma) group are D(H.r) and D(H.p) for
Hiroshima, and D(N.r) and D(N.p) for Nagasaki. thevalue of W for this dose group may be derived from theequation
M (H.obs)- M (H.exp)------------'--=
P(H) [D(H.y)+ WD(H-p)]
Iv! (N.obs) - 1W (N.exp)
P(N) [D(N-y)+ WD(N-p)]where M( .. .) represents the number of deaths fromleukaemia observed (obs) or expected (exp) in
Hiroshima (H) or Nagasaki (N), and .P(H) and .P(N) are
the populations exposed in the relevant dose groups inHiroshima and Nagasaki.
54. For example, in those exposed at over 200 rad(kerma) the mean absorbed doses in marrow of low- andhigh-LET radiation can be estimated as 155 and24.4 rad, respectively, in Hiroshima and 181 and 1.4 radin Nagasaki. The number of deaths from leukaemia inthis d.:ire group in Hiroshima was 28 as compared with
1.3 expected on the basis of the 0-9 rad group. thecorresponding values being 15 and 1.2 in Nagasaki. The
number of persons was 1301 in Hiroshima (the average
number of survivors during the period of survey) and
1191 in Nagasaki. For this kerma group therefore

28 - 1.3
15 - 1.2=-------1301 (155 + 24.4 W)
1191 (181 + 1.4 W)
whence W = 7 .6.

55. Estimates of W can be derived in the same way forlower dose groups considered separately, but are very
imprecise. with the standard error (SE) of sampling
approaching or exceeding the expected value itself. The
values of such a weighting factor can, however. be
estimated with reasonable confidence for the (over• A recent study by Hashizume et al. (53a) estimates thatfor bone marrow the ratio of mean absorbed dose to mean
kerma would be about 0.65. For neutrons. the ratios would be
0.25 for proton induction, and 0.10 for gamma radiationinduction by neutrons. The use of these ratios would lower thevalues of the weighting factors given in paragraph 55 by about
10 per cent.

lapping) groups of till those exposed at over 100 rad,over 50 rad, or over 10 rad. On this basis, the values are
as follows:
Kenna group (rad)Weighting factor W.
by comparison with:
0-9 rad group
SE
Japanese National
Statistics
SE

>200

>100

>50

>IO

7.6
±4.2

11.4
±5.2

14.4
±6.6

19.3
±9.4

7.3
±4.1

10.6
±4.7

13.0
±5.5

15.8
±6.6

56. These values clearly suggest an increase ineffectiveness of high- relative to low-LET radiation inleukaemia induction as progressively lower dose levels
are included {also see Annex I, paragraph 176). As
stated, however, no adequate estimate can be made of
the value of W at lower doses, owing to the uncertainty
in risk estimates in these dose groups that results fromthe small excess of observed over expected cases. Thus.
for example, the estimate of W for those exposed at100-199 rad kerma ( using comparison with the 0-9 radgroup) is 47, with the standard error about 67.
57. These estimates are based on the mortality fromleukaemia in the two cities in members of the Life Span
Study, for whom the kerma has been estimated.
Substantially larger numbers of deaths from this disease
have been recorded in the Leukaemia Registry, butvalues of the kerma are not known for many of these
individuals. If approximate kerma estimates are made forthis larger population, however, on the basis of the
distribution of the whole A-bomb-exposed population in
1950, the excess mortality from leukaemia in this groupis more nearly proportional to estimated kerma in bothcities {13). On this basis the variation of W with kerma
might therefore be considerably reduced.
58. The values quoted in paragraph 55 can however beused to obtain tentative risk estimates for the inductionof leukaemia by low-LET radiation over the stated dose
ranges in the two cities. 3 Thus, in table 4, in addition toestimates of excess mortality rate per rad kerma, rates
are quoted also per unit of weighted absorbed dose. inwhich the high-LET component of the tissue dose isweighted by the value appropriate to the dose groupconsidered.
59. For malignancies other than leukaemia. the risk
estimates, in particular for Nagasaki, are too uncertain toallow any adequate values to be derived for separate
weighting factors appropriate to each malignancy. In
previous reports. risk rates have been quoted per radkerma without an estimated allowance for the neutroncomponent of the exposure. The reports of the joint
3This comparison should correctly be made at equal
weighted absorbed dose, rather than at equal kerma. When suchcomparisons are made, estimates of Ware somewhat lower in thehigh dose range with values of 5.4, 7.8 and 14.2 at weighted
absorbed doses of 190, 150 and 90 rad respectively. The
necessity for averaging doses and leukaemia rates over wide doseintervals in this analysis also introduces errors, to the extent thatthe low-LET dose-effect relationship departs from a simple linear
proportionality between dose and effect. These errors prove not
to be large, however, when calculated on the basis ~f likell'estimates for the factors, discussed in paragraph 35, w~1ch ~ay
determine linear and quadratic components in such re!auonslups.

369

Atomic Bomb Casualty Commission (ABCC)-Japanese
National Institute of Health (JNIH) surveys also givedose ranges in rad (kerma) but refer in some instances to"RBE dose estimates in rem" (e.g., reference 67,
table 5), using the RBE of 5 which Ishimaru et al. (63)note as being applicable for neutrons in leukaemogenesis.
60. In the absence of other estimates for theeffectiveness of neutrons in inducing malignancies inman, and since the estimates of leukaemia mortality now
yield weighting factors for different dose groups asshown in paragraph 55, these weighting factors havebeen used in later chapters to derive risk estimates forother malignancies, in addition to those quoted per rad(kerma). The use of this procedure is not intended to
imply that. the RBE for neutrons in inducing malignantchange is necessarily the same at a given dose for all
types of malignancy. It is of interest however that theinduction rates in the two cities for a range ofmalignancies for which approximate risk estimates canbe made, do appear to be statistically consistent with theuse of the same weighting factors for all types. The
intention in using these factors for other malignancies isthus solely in order to derive from the important
observations in Hiroshima, risk estimates that may be
more applicable to low-LET radiation than those derived
directly from kerma, or absorbed dose. having large
components of high-LET radiation. For this purpose it
appears preferable to use factors which reflect a dose
dependent RBE and which are based on other humancarcinogenic data observed within the same dose groups,
than to apply a constant value for RBE derived fromquite different sources.
61. In the case of the breast and the thyroid, estimateshave been published (9, 53) for the ratios of absorbed
dose D to kerma K. both for gamma radiation (r) andfor neutrons (n) as inducing proton (p) or gamma (r)radiation in tissues. Mean values for various modes ofirradiation are as follows:
BreastThyroid

D"Y/K-yDp/Kn

D"Y/Kn

0.80
0.76

0.55
0.33

0.045
0.10

These ratios have been used in deriving risk rates for theweighted absorbed doses.
62. For evaluating the risks of alpha radiation, either
in bone sarcoma induction by radium or lung carcinoma
by daughter products of radon, no comparable biologicalbasis is available for estimating any RBE. or weighting
factor. that should be applied to the high-LET radiationof tissues in these cases. Risk rates are quoted, therefore.
per rad of alpha radiation and require to be interpreted
in the light of other evidence as to the likely RBE foralphas at the dose levels concerned.

II. LEUKAEMIA
A. LEUKAEMIA IN A-BOMB SURVIVORS
63. The seventh report on mortality data in the
JNIH-ABCC Life Span Study (97) included information
on deaths in exposed populations to the end of 1972,
and indicated that the annual frequency of deaths fromleukaemia had returned to about the level observed in
the unexposed or only lightly exposed comparison
populations (table 2 and fig. III). During the three-year
period 1970-1972, only 3 deaths occurred in the groups
exposed at known doses greater than 10 rad, as
compared with 2.7 expected by comparison with the
0.9 rad group, and with 2.1 expected on the basis of

TABLE 2. EXCESS MORTALITY FROM LEUKAEMIA IN HIROSHIMA AND NAGASAKI BY PERIOD
Dose groups 10->200 rad T65
Males and females, all ages

Period

Man
rad
year

Ex•
Ob·
served peered

ExcessExcess rate(JO') (JO"' y-• rad"')Period

Man
rad
year

ObExserved pected

HIROSHIMA

ExcessNAGASAKI

Compared with 0-9 rad group

Compared with 0-9 rad group

1950-1954
1955-1959
1960-1964
1965-19691970-1972

16
22
12
11
3

2.9
5.5
1.5
2.7
1.5

13.1 (6.9-21.6)
16.5 (9.0-26.3)
10.5 (5.3-18.0)
8.3 (3.2-15.8)
1.5 (neg.-6.8)

5.0
5.6
5.2
4.9
2.7

2.6 (1.4-4.4)
3.0 (1.6-4. 7)
2.0 (l.0-3.4)
1.7 (0.7-3.2)
0.5 (neg.-2.5)

1950-1954
1955-1959
1960-1964
1965-19691970-1972

8
5
4
3
0

6.5 (2.2-13.2)
3.9 (0. 7-9.6)
0.7
3.3 (0.5-8.7)
2.6 0.4 (neg.-6.0)
1.2 -1.2 (neg.-3. 2)

1950-1972

64

14.2

49.8 (36. 7-65.1) 23.4

2.1 (1.7-2.7)

1950-1972

20

7.1

Compared with Japanese National Statistics
1950-1954
1955-1959
1960-1964
1965-19691970-1972

as
2.0
b
2.3
a ove 2.6
1.5

1950-1972

9.6

1.1

14.9 (8.9-23.2)
3.0 (1.8-4.7)
20.0 (12.7-29.2) as
3.6 (2.3-5.3)
9.7 (4.6-17.1) b
1.9 (0.9-3.3)
8.4 (3.6-15.6) a ove 1.7 (0.7-3.2)
1.5 (neg.-6.3)
0.5 (neg.-2.3)
54.4 (41.8-69.2)

2.0 (1.5-2.5)

Source: Reference 97.
Note: The 90% confidence limits are indicated in parentheses.

370

Excess rate

1(JO') (10" 6 y-• rad· 1

1.5
1.1

3.7 2.0 (0. 7-4.0)
3.7 1.1 (0.2-2.6)
3.5 0.9 (0.1-2.5)
3.4 0.1 (neg.-1.8)
1.9 -0.6 (neg.-1. 7)

12.9 (5.4-22.7) 16.2

1.3 (0. 7-2.1)

Compared with Japanese National Statistics
1950-1954
0.6 7.4 (3.4-13.8)
2.3 (l .0-4.2)
1955-1959 as
0.7 1 4.3 (l.3-9.8) as
1.2 (0.4-2.6)
1960-1964 above 1.1 2.9 (0.3-8.1) above 0.8 (0.4-2.3)
1965-1969
1.1
1.9 (neg.-6.7)
0.6 (neg.-2.0)
1970-1972
0.6 -0.6 (neg.-2.4)-0.3 (neg.-1.2)
I 950-1972

4.1 15.9 (9.1-25.0)

1.0 (0.3-1.9)

last 3 years of the 22.25 years of the survey appears tohave been only about 1.5 per cent of the total excess
leukaemia mortality.

Japanese National Statistics. While these differences are
not significant, it is noted that a small significant excess
was still present in the two subgroups that had
previously shown the highest frequencies. Thus. in
Hiroshima in the groups exposed at 100-200 rad and atover 200 rad, 2 and 1 deaths occurred during this latest
period as compared with 0.2 and 0.1 expected on thebasis of the 0.9 rad group or of Japanese National
Statistics. With this expectation, 3 or more deaths would
occur by chance with a probability of only 0.0035,
although the testing of these two subgroups selectively
because they showed higher incidences must somewhat
increase the probability of this difference being
fortuitous. While, therefore, some mortality may havebeen persisting, the contribution to deaths during the

64. As shown in table 2, the annual death rate per man
rad rose somewhat from the first (1950-1954) to thesecond (1955-1959) five-year period of survey, then fell
progressively. Ignoring any cases that may have arisen
prior to October 1950, the mean interval from radiation
exposure until death from leukaemia has been 13.7 years(with median 12.5 years). as judged from the annual
incidence rates. If this mean interval is determined forexcess deaths of those exposed in each dose group(table 3), no relationship between interval to death andsize of dose is evident.

TABLE 3. MEAN INTERVAL FROM EXPOSURE TO DEATH FROM LEUKAEMIA 1950.1972 IN
HIROSHIMA AND NAGASAKI
Males and females, all ages
(Years)

Dose group (T65 kerma)
Population
Hiroshima
Excess deaths
Mean interval
SE 0
Ndgasaki
Excess deaths
Mean interval
SEa
Hiroshima and Nagasaki
Mean interval
SEa

0-9

10-49

50-99

100-199

>200

All

12.0
10.1
±0.9

10.8
15.8
± 1.2

5.5
12.5
±3.6

11.0
15.0
± 2.0

27.2
14.1
± 1.1

66.5
13.7
±0.6

4.7
19.1
±4.5

0.0

(neg.)

2.3
10.2
± 1.8

14.3
13.8
± 1.6

20.6
13.8
±2.1

12.6
± 1.4

15.8
± 1.2

(12.5)(± 3.6)

14.1
± 1.8

14.0
±0.9

±0.6

13.7

Source: Reference 97.
asE = standard error. The values of standard error are based on the number of deaths from leukaemia in the different groups.

65. lchimaru et al. (61) show the number of cases ofacute and chronic leukaemia with onset in each year
from 1947 to 1971 including all confirmed cases in the
ABCC Leukaemia Registry. For those who had received
a kerma of 100 rad or over, the mean interval between
exposure and onset (mean latency) of leukaemia was asfollows (in years):
Type ofleukaemia

All
cases

Excesscases'l

SDb

SE

Acute
Chronic

11.8
11.l
11.6

11.5
11.0
11.4

5.9
6.4
6.0

0.9
1.7
0.8

All

Approximate
median latency

11

9
10

0

As compared with onsets in unexposed groups.
bSD = standard deviation.

Since these values are based on the onset of individual
cases, and since the numbers of persons in the fixedsample was decreasing slowly with time, the meanintervals based upon incidence rates WQuld be slightly
longer. Excess numbers of cases in the group exposed at
1-99 rad are too small for analysis of latency.

66. As judged by recorded month of onset, there
appear to be no significant differences in latency
between different types of acute leukaemia, althoughthat for acute moncytic is slightly shorter than the
average for other acute types, as seen from these data
(years):Type of acuteleukaemia

Number of
cases

Mean
latencySD

SE

Granulocytic
Stem cell
Lymphatic
Monocytic
All

19
5
15
7

12.4
13.2
10.8
9.2
11.5

4.9
6.1
6.9
3.8
5.9

1.1

67. Clear evidence is now obtained, however, of avariation in latency with age at exposure, at least for
acute leukaemias and possibly also for the chronic(granulocytic) type induced. From the recorded monthand year of onset of leukaemia between October 1950
and December 1971 in those who had received a kerma
of I 00 rad or more in either city, the following meanlatencies are determined:

Acute leukaemias
Age atexposure(years)Number
of
cases

Mean
latency(years)

SD

<15
15-29
30-44
;;.,45

11
15

9.4
11.0
14.7
15.2

3.3
5.3
6.4
4.2

10
7

2.7
1.8
1,4
0.9

Chronic leukaemia

SE

Number·
of
cases

Mean
latency(years)

1.0
1.4
2.0
1.6

5
4
4
1

9.3
11.3
12.4
12.6

SD

SE

0.8
9.1
9.1

0.4
4.6
4.6
371

w

-.J

N

TAD LE 4.

EXCESS MORTALITY FROM LEUKAEMIA IN IIIROSIIIMA AND NAGASAKI, 1950-1972
Males and females, all ages

Dose group(rad kerma)

Observed

Expected

ExcessExcess rate
per unitkerma(Jo-• rad-')

Excess rate
per unit
weighted
absorbed dose(10" 6 rad" 1 )Dose group(rad kerma)

Observed

Expected

ExcessExcess rate
per unitkerma(10-• rad_,)

Excess rate
per unit
weighted
absorbed dose(10" 6 rad_,)NAGASAKIHIROSHIMA
Compared with 0-9 rad group

Compared with 0-9 rad group61 (41-84)

10-49
50-99
100-199
>200

2
0
3
15

3.5
1.2
1.2
1.2

-1.5 (neg.-3.3)-1.2 (neg.-1.9)
1.8 (neg.-6. 7)
13.8 (8.0-24.4)-22 (neg.-47)-15 (neg.-24)
11 (neg.-41)
35 (20-52)

61 (35-91)

55 (40-73)

47 (34-63)

>100

18

2.4

15.6 (9.2-23.5)

28 (16-44)

48 (28-76)

42.0 (31.3-54.9)

50 (37-65)

38 (28-50)

> 50

18

3.6

14.4 (8.0-23. l)

22 (12-36)

38 (20-61)

49.8 (36.7-65.1)

47 (35-61)

31 (22-39)

> 10

20

7.1

12.9 (6.1-22.0)

18 (6-33)

30 (10-55)

10-49
50-99
100-199
>200

17
7
12
28

9.2
2.2
1.5
1.3

7.8 (1.6-16.8)
4.8 (1.1-11.0)
10.5 (5.4-17.9)
26.7 (18.6-37.1)

37 (5-80)
29 (7-67)
51 (26-88)
57 (39-79)

>100

40

2.8

37 .2 (27 .2-49.5)

> 50

47

5.0

> 10

64

14.2

Compared with Japanese National Statistics

Compared with Japanese National Statistics

10-49
50-99
100-199
>200

17
7
12
28

6.2
1.5
1.0
0.9

10.8 (4.6-19.3)
5.5 (1.8-11. 7)
11.0 (5.9-18.4)
27.1 (19.0-37.5)

52 (22-92)
33 (11-71)
54 (29-90)
57 (40-79)

>100

40

1.9

38.1 (28.3-50.2)

> 50

47

3.4

> 10

64

9.6

62 (43-86)

10-49
50-99
100-199
>200

2
0
3
15

2.0
0.7
0.7
0.7

0.0 (ncg.-4.3)-0.7 (ncg.•2.3)
2.3 (0.1-7.1)
14.3 (8.5-22.4)

0 (neg.-62)-9 (neg.-29)
14 (1-43)
36 (21-56)

63 (37-98)

56 (52-74)

50 (35-67)

>100

18

1.4

16.6 (10.2-25.3)

29 (18-45)

50 (31-78)

43.6 (32.9-56.5)

52 (39-67)

42 (32-54)

> 50

18

2.1

15.9 (9.5-24.6)

25 (15-38)

42 (25-64)

54.4 (41.8-69.2)

52 (40-66)

38 (29-48)

> 10

20

4.1

15.9 (9.1-25.0)

22 (13-35)

37 (22-59)

Source: Reference 97.
Natl,: The 90% confidence limits are indicated in parentheses.

68. The effect of age at exposure on the frequency
with which leukaemia has been induced in Hiroshima
and Nagasaki is now clearly shown (14) by a study ofthe number of excess deaths per million person-year-radin different age groups. As estimated by the number ofdeaths from leukaemia from October 1950 to September
1974 in the Adult Health Study Populations exposed at
Hiroshima and Nagasaki, the induction rate is highest in
the groups aged 0-10 years and over 50 years at
exposure.
withexcessmortalityratesof
3.2 (2.8-3.6) 10-6 and 3.4 (2.8-4.1) 10-6 y- 1 rad- 1
respectively. The rate is lowest in those who were aged
10 to 20, with a value of 1.0(0.7-1.2) 10- 6 y- 1 rad- 1
and intermediate for age groups 20-35 and 35-50 years
at exposure, with values of about 1.9 (1.5-2.2) 10-6 y- 1
rad- 1 in each group. These differences in mortality rate,
as estimated in the period up to 29 years from exposure.
are not clearly attributable to differences in latency withage, since excess deaths have been occurring in all age
groups in a comparable way since the beginning of theperiod surveyed (i.e., from 5 years from exposure).
69. The mortality from leukaemia in Hiroshima andNagasaki is not reported separately for the two sexes incurrent Jl\TJH-ABCC Life Span Studies but the appendix
of the latest review of tI,e ABCC Leukaemia Registrydata (61) records the sex of patients developing any
form of this disease. Of 57 cases with onset from 1950
to 1971 in people estimated to have received a kerma of
100 rad or more, 32 occurred in males and 25 infemales. From Report 7 of the Life Span Study {97) the
number of person years at risk during this period appears
to have been about 47 370 in males and 61 390 infemales (the Registry study uses total person-years
which are about 7 per cent higher but does not quotevalues separately for the two sexes). On this basis, theleukaemia incidence is somewhat higher in males than infemales. It is of some interest, however, that theincidence of acute leukaemias in this dose group appears
to be equal in the two sexes, while that of chronic(granulocytic) leukaemia is considerably higher in the
male:
Males

Females

Type ofleukaemia

Incidence(JQ-4 y·lj

Cases

Incidence(Jo-• y·•1

Cases

Acute
Chronic

4.2 (2.8-6.1)
2.5 (1.5-4.1)

20
12

3.7 {2.6-5 .3)
0.3 (0.1-1.0)

23
2

All

6.8 ( 4.9-9 .1)

32

4.1 (2.8-5.7)

25

However, the numbers involved are small and the age
structure of the male and female populations differedappreciably, with a relative deficiency of males aged
20-35 and a slight relative preponderance of males at ages
over 35.
70. The natural annual incidence rate of leukaemia inJapan, as judged by cancer registry data (35) issomewhat lower in females than in males, with values of
2.7 and 3.7 10- 5 y- 1 in females for age standardized
populations in two Japanese registries, as compared with
4.4 and 4.3 10-s y- 1 in males. It is ratherlower than inregistries in many other countries {which have mean
rates for 58 other registries of4.4 and 6.8 10- 5 y- 1 infemales and males). The incidence rates in members of
the Master Sample exposed at less than 5 rad at
Hiroshima and Nagasaki were 3.1 and 5.7 10-s y- 1 ,respectively. The incidence rate of chronic lymphatic
leukaemia in this group was only 0.1 10-s y- 1 (2.7 percent of all cases) as compared with a mean of 1.2 10-s
y- 1 (22 per cent of all cases) in 22 registries in othercountries reporting leukaemia by type (35).

71.

During the total period 1950-1972, the number ofdeaths from leukaemia in the Life Span Study Group in
Hiroshima (97), at known kerma of over 10 rad
exceeded the number expected on the basis of the 0-9
rad group by about 50 (with 90% confidence limits 37
and 65). The corresponding excess for Nagasaki was 13{6-22). Expressed as rates per million exposed and perunit kerma, these excesses correspond to 47 {37-65)
10- 6 rad - 1 and 18 ( 6-33) 10-6 rad -i ; and table 4 gives
rates for the different (kerma) dose groups comparedwith both the 0-9 rad group and the Japanese National
Statistics.

72.

The rates are given also for all those exposed atover 10, 50, 100 and 200 rad. For these groups, table 4
gives estimates also of the induction rate per rad(weighted) absorbed dose, using the weighting factors
for neutrons derived above in paragraph 55. Theseestimates assume the ratios of absorbed dose to kerma
for bone marrow of 0.55 and 0.26 for gamma andneutron radiation, respectively, as discussed in p;rragraph
51. The distribution of mean numbers exposed, andneutron component of kerma, for each dose group is
given in table 5.

TABLE 5. ESTIMATED KERMA AND NUMBERS EXPOSED IN LIFE SPAN STUDY DOSEGROUPS

Males and females, all ages, 1950-1972
Hiroshima

Nagasaki

Dose group
(rad)

Mean
kerma
(rad)

Percent
fromneutrons

Mean
number of
persons},leankerma(rad)Percenrfrom
neutrons,'r[eannumber of
persons

10-49
50-99
100-199
>200

21.9
70.2
138.6
363.2

20
19
22
26

9 533
2 350
1 473
1 301

21.0
70.5
145.7
334.7

0.0
0.3
1.0
1.7

3 302
1 120
1 127
1191

Source: Reference 97.

373

73. In the eighth report on mortality data in the Life
Span Study (14), the excess mortality rate per unit
kerma from leukaemia in the 24·year period 1950-1974
has been

56 (51-61)10- 6 rad- 1 in Hiroshima,
35 (29-41) I O"6 rad-, in Nagasaki, and

46 (42-50)10- 6 rad- 1 in both cities combined,
these rates being estimated from the slopes of( variance-weighted) regression lines of mortality rate
upon kerma. They correspond closely with the excess
rates for the period 1950-1972 as based on comparison
between the > 200 rad group and rates in the 0-9 radgroup, as would be expected if(a)no substantial excess mortality has occurredin 1972-74;(b) the regression line is influenced subs tan·
tially by the large numbers in the 0-9 rad group and thelarge excess in the > 200 rad group. The additional
deaths from leukaemia in 1972-74 have in fact been 6 inthose exposed at 10 rad or over in both cities, ascompared with about 3.7 expected on the basis of the
0-9 rad group (see paragraph 240). The previous excess
for 1950-72 was 63 deaths.
74. The types of leukaemia that had developed inmembers of the ABCC Master Sample exposed at S rador over at Hiroshima and Nagasaki differed significantly
from the types occurring in the groups who wererelatively unexposed (at Jess than 5 rad), according to
the report of Ishimaru et al. (63), analysing theincidence of leukaemia from October 1950 toSeptember 1966. The types of leukaemia occurring
between October 1950 and December 1971 are now
reported by Ichimaru et al. (61). Their data show
differences in relative frequency of the different types inthose exposed to radiation in the two cities, butcorresponding differences are also seen between the''control" groups for these cities. Thus, no differences
are seen, either in Hiroshima or in Nagasaki between therelative frequencies in those exposed at less than 1 rad,and in those who were not in the city at the time of thebomb.
A comparison of relative frequencies in < l radgroup and the National Institute of Cancer (NIC) groupshows the following:( a) For all specified types of leukaemia:
Hiroshima, x2 = 3.4, 5 degrees of freedom. .
.
(d.f.), n~t sir~ficant;Nagasaki, x - 8.2, 5 d.f., not s1gn1ficant,(b) For specified types and groups of acute andchronic unspecified types:
Hiroshima, x2 = 3.8, 7 d.f., not significant:Nagasaki, x2 = 9.8, 7 d.f., not significant.
Comparing the combined control series for Hiroshima
with that for Nagasaki, however, there appears to be aclear difference in relative frequencies:{a) For all specified types, x2 = 24.8, 5 d.f.,

P<0.001:.

(b) For specified and unspecified groups,
x2 = 29.5, 7 d.f.,P<0.001.
The difference is due mainly to a relative excess of acutelymphatic and chronic granulocytic types in Hiroshima
and of acute granulocytic and chronic lymphatic types
in Nagasaki.
374

75. When the groups which were heavily exposed(at orover 100 rad kerma) in the two cities are compared,
there is some indication of a significant difference inrelative frequency of types of leukaemia (with x2 = 8.0,
4 d.f., P = 0.09 comparing specified types and x2 = 8.3,
5 d.f., P = 0.15 including unspecified groups), the main
contribution to the difference being again a relative
excess of chronic granulocytic leukaemia in Hiroshima
and of acute granulocytic leukaemia in Nagasaki. The
difference is much clearer when the incidence in all
those exposed at over 1 rad is compared in the two cities(x2 =17.4, 4 d.f., P<0.005 and x2 =17.l, 5 d.f.,
P = 0.005), the main difference again being due to a
relative excess in Hiroshima of the chronic, and in
Nagasaki of the acute granulocytic types.
76. Since, however, this difference is also evident
between the control series for the two cities, a differencein the types of leukaemia induced by radiation in thesecities· can only be established by estimating thefrequencies of excess cases of different types in eachcity. In each city, the leukaemia rate in those who were
unexposed was about 12 per cent of that in those who
were exposed at or over 1 rad. Part of thedifference between the types of leukaemia observed inthose exposed at Hiroshima and at Nagasaki may
therefore merely reflect the similar differences observed
between the control series in the two cities.

B. LEUKAEMIAINPOPULATIONSINMARSHALL ISLANDS IRRADIATED

THE

FROM

FALLOUT

77. Leukaemia has developed and has proved fatal in
one inhabitant of the Marshall Islands who was exposed
to radiation from fallout in 1954. The leukaemia was of
the acute myelogenous (promyelocytic) type (26). Quite
clearly the occurrence of one case might be due tochance rather than to radiation. In a population
estimated to have received about 11 870 man rad of
exposure, however, if the expectation of leukaemia was,for example, 20 cases per million per rad, the chance of0, 1 and over l cases occurring would be 0.82, 0.16 and0.02. No excess incidence of other forms of malignancy,
apart from that of the thyroid (see paragraphs 108-111)
has been pbserved.

C. LEUKAEMIA FOLLOWING PELVICIRRADIATION
78. Following x-radiation of the pelvis in the treatmentof metropathia haemorrhagica, Smith and Doll (142)observed an excess death rate from leukaemia of 16.3
per l 0 5 woman-years at risk, during the period of 5 ormore years after treatment. Since the mean marrow dose
was 134 rad, this rate corresponds to 1.22
(0.25-2.8)10- 6 rad- 1 y- 1 . Since the mean period of
follow-up from the time of treatment was 19.0 years,
and since no excess was observed in the first 5 years. theestimated leukaemia risk to 19 years in women becomes
17 (3-36)10~ rad-, at this dose level.
79. The 7 cases of leukaemia (2.33 expected) werediagnosed at 11.0 (± 2.1 SE) years after exposure anddeath occurred at 11.6 (± 2.0 SE) years after exposure.

Correcting for the decreasing number of patient years at
risk gives mean intervals of 12.4 and 12.9 years todiagnosis and to death, values which clearly are notdiscrepant with those observed in the leukaemia registry
and in the mortality data from Hiroshima and Nagasaki.
80. Brinkley and Haybittle (18) made a follow-up of
277 women for a mean period of 16.1 years after an
x-ray induced menopause involving a mean pelvic doseof about 735 rad. No deaths from leukaemia wereobserved, but only 0.24 were expected on the basis ofnormal incidence at the ages concerned, and only afurther 0.83 cases would have been expected if theinduction rate per woman-year and per rad found by
Smith and Doll had applied.
81. Alderson and Jackson (2) followed up 2049
patients of whom 15 per cent were treated with radiumand 85 per cent with x rays in the therapy ofmenorrhagia. No deaths from leukaemia were observed
during the first 5 years but 4 occurred subsequently ascompared with 1.09 expected. Risk estimates are
difficult to obtain owing to the non-uniform pelvic
irradiation from radium. Dickson (32) observed nosignificant increase in leukaemia in 4010 women treatedwith radium for benign uterine haemorrhage, but lessthan 50 per cent of the patients were adequately traced
and this negative finding is therefore of doubtful
significance.
82. A number of studies, which are reviewed by Smith
and Doll (142) show no significant increase in leukaemia
following pelvic irradiation for carcinoma of the cervix,
in many cases by radium. It was, however, suggested by
Hutchinson (60) that the negative findings in thesestudies are due to the much higher doses given intreatment of cervical cancer than those used for
metropathia, so that considerable cell killing is likely totake place in the areas of pelvic marrow which areirradiated.
D. LEUKAEMIA FOLLOWING TREATMENT OF
ANKYLOSING SPONDYLITIS BY X-IRRADIATION
83. In a survey of patients who had received one or morecourses of radiotherapy for ankylosing spondylitis,
Court Brown and Doll (29) observed an excess mortali~
rate from leukaemia and aplastic anaemia of 4.2 1oduring an average period of 9.7 years in patients fully
followed up. and 4.7 10-3 in a rather longer but lesscomplete follow-up for an average of 11.4 years. Since
10 years appears to be about the median interval
between irradiation and death from radiation induced
leukaemia, a total induction in the region of 9 10-3
cases might be expected. It was likely that an average
dose of about 880 rad was delivered to 40 per cent of
the bone marrow. If this can be regarded as equivalent toan average dose of 350 rad, the total induction rate perunit absorbed dose is estimated as 25 10- 6 rad- 1 , thenumber of excess cases observed determining 90%
confidence limits of (20-31) 10-6 rad- 1 • The meaninterval in years from irradiation to death had been as
follows:
Follow-up

Complete to 1960
Incomplete to 1963

By deaths

By death rates

6.2 ±0.5 (SE)6.6 ±0.5 (SE)

8.6
7.9

84. In a further survey of the patients who hadreceived only one course of radiotherapy (36), an excess
of 31-6.5 = 24.5 (I 5.9-35.3) deaths from leukaemia wereobserved in 14 109 patients followed for a mean periodof 9.5 years. This survey covered about 134 OOO
person-years at risk, 11 900 of them being within the
period starting 17 .5 years after treatment during which
no further excess deaths from leukaemia occurred(I observed, 0.96 expected). With an estimated mean
marrow dose of 321 rad, this excess corresponds to anannual risk of 0.57 10-6 y- 1 racl- 1 over the period ofsurvey, this rate having been 0.78 10- 6 y- 1 rad -lduring the first 6 years and 0.49 1o- 6 y- 1 rad - 1 during
the subsequent period, until the time at which excess
deaths ceased to occur. The total risk is 5 .4 10-6 rad - 1
as estimated from the whole group, which was studied
for a mean period of9.5 years. This value, however, is anunderestimate of the true expectation because decreasing numbers were at risk during the periods when
leukaemia incidence may have been maximal, since
many patients were withdrawn from survey when theyreceived a second course of treatment. A more valid risk
estimate may be derived, however, by summing theexcess mortality rates, rather than the number of deaths,
at successive time intervals after exposure, as if a cohortof patients were being followed without withdrawals
from survey except as a result of death. When this isdone the total risk until 20 years, when excess leukaemia
deaths had ceased to occur, is 11.4 (7.5-16.4) 10-6
rad -l . 4 The mean interval from irradiation to deathfrom leukaemia was 6.6 ± 0.9 (SE) years, or 7.4 years as
based on excess leukaemia rate per person-year at thedifferent time intervals after exposure. These intervals,
and those noted in paragraph 83, are thus clearly shorter
than those observed in Hiroshima and Nagasaki.

E. LEUKAEMIA FOLLOWING OTHER
RADIOLOGICAL PROCEDURES
85. An increased incidence of leukaemia has been
observed in the various series of patients followed up
after the use of Thorotrast as a diagnostic .contrast
medium (see paragraphs 283 ff.). As shown in table 6, a
total excess of 53.7 cases has occurred in series including
4594 subjects followed for a mean period of 27 years
after receiving a mean dose of 26 ml of Thorotrast. Risk
estimation from these data is subject to considerable
uncertainties in respect to irradiation of already deadcells, or to any possible chemical carcinogenic action ofthorium oxide, as discussed in paragraph 283. Subject tothese reservations, the induction rate from the absorbed
dose delivered to the end of the period of follow-up
would be 33 (24-39) 10-6 rad -i of alpha radiation.
Since the thorium remains in the tissues and continues
to irradiate the bone marrow, however, much of this• An additional 5 patients died with leukaemia recordedon the death certificate, although not as the primary cause ~fdeath; and :or 2 patients, death was recorded as due to aplast1c
anaemia but, on review, it was considered t~at a more
appropriate diagnosis would have been of leu~emia. If these. 7
patients are included with those recorded.as dying of leu.kae?1~·
and if 3 further patients are excluded m whom leukaemia IS
known to have been present at the time of treatment, t:ie _total
excess leukaemia mortality rate per unit absorbed dose within 20
6years from treatment becomes 13.5 (9-20) 10- rad_,.

375

TABLE 6. LEUKAEMIA FOLLOWING THOROTRAST INJECTION
Dose to bone marrow(rad)Reference

141
42
69
72
96

Country

Follow-up
period(years)Dose(ml)

A tendoffollow-up

10 years fromend offollow-up

Numberofsubjects

Observed

Expected

Portugal
Denmark
United States
Germany,
Fed. Rep. of
Japan

30
28
10

26
23
24

387
322
120

258
207
0

1 231
756
724

20
11
3

0
(3.7)
0

30
30

30
16

444
271

296
189

1 750
133

25
1

2.4
0.2

Mean

27

26

353

221
4 594

60

6.3

Total

radiation is likely to be "wasted" in the sense that it isdelivered after leukaemia may have been induced. If amean latency of 10 years is assumed for leukaemia, andthe dose estimated for the period of 10 years less thanthe mean duration of survey, the rate would be 53( 41-67) 10-6 rad- 1 of alpha radiation.
86. A small excess incidence of leukaemia occurred ina series of 2872 children who had had scalp irradiation
for tinea capitis, but only a very tentative risk estimate
can be made from these data. The cranial marrow dose
was estimated (131) as 385 rad, but the proportion of
the active marrow which is in the cranium of a child isuncertain. Atkinson (8a) has estimated that 7 per cent of
the active bone marrow of children is in the skull. and on
this basis the mean marrow dose may have been in theregion of 30 rad. The excess leukaemia incidence was of
4.7 (1.0-10.9) cases, the confidence limits ignoring
variability in estimation of the control rates. These
values give a risk estimate of 50 (10-130) 10-6 rad- 1 ,but there are obviously considerable uncertainties, apartfrom the statistical imprecision in this estimate.
87. No additional information has become available
since the Committee's 1972 report on the possible
induction of leukaemia by 32 P as used in the treatmentof polycythemia vera. As noted in that report (Annex H,
para. 85) it remains difficult to derive valid radiation risk
estimates from study of the sequels of this treatment.
The position is further complicated by the evidence thatthe frequency of subsequent acute leukaemia is notdirectly related to the amount of 32 P administered. andvaries according to the size of the spleen at the time oftreatment (21).
88. No further data have been published on thefollow-up of hyperthyroid patients treated with 131 I or
by surgery (1972 report, Annex H, para. 78). Since theinitial survey of hyperthyroid patients continued for amean period of only about 10 years, terminating in
mid-1967, a further study might be informative, but theestimated mean marrow dose, of only about 10 rad,makes it doubtful whether useful results would beobtained. In the series of patients treated for thyroid
cancer at high dose levels with 131 I (1972 report, Annex
H, para. 73), no further cases of leukaemia havedeveloped despite a further 9 years of follow-up of thisseries (118).
376

Cases of leukaemia
and anaplastic
anaemia

89. Additional studies have been made of the
exposures likely to have been received by radiologists inthe course of their occupation (49) but no further
evidence has been obtained from which corresponding
risk rates are derived.

F. SUMMARY

90. Leukaemia is thus induced by radiation with amean latency to diagnosis of about 10 years. Estimatesof the mean or median interval from exposure to death,under widely different conditions of irradiation, varyfrom about 8 to 13 years. These mean intervals areprobably about half those which apply for other cancers.
They do not appear to differ considerably for different
types of leukaemia. They do, however, vary with age at
exposure, estimates from Hiroshima and Nagasaki
increasing from 9 to 15 years with increasing age at thetime of exposure; and the latency is short after pre-natal
exposure. The mean latency does not appear to varywith dose in a consistent manner, and the increased
incidence after exposure appears to have almost ceased
after about 30 years.
91. All acute forms, and the chronic granulocytic typeof leukaemia are induced, the former types predominating. No evidence has yet appeared indicating thatchronic lymphatic leukaemia is induced by radiation.
92. The frequency of induction per unit dose increases
with age from early adult life, but is also relatively highfollowing exposure in childhood, and perhaps also inutero (see chapter VIII). There is no clear evidence of adifference in induction rate in the two sexes.
93. There are no reliable bases for determining directly
the frequency with which leukaemia is induced in theadult at absorbed doses of low-LET radiation of lessthan about 100 rad. The total deaths from leukaemia inthe Life Span Study 1950-1972 in those estimated tohave been exposed at 0-9 rad were recorded (97) as
higher than those in people who were not in the cities(P = 0.065) and were also higher than expected on thebasis of Japanese National Statistics (P = 0.004), butneither comparison allows estimates of any precision.

94. The mortality rates for leukaemia in Hiroshima inkerma ranges of I O to 50 rad and higher allow induction
rates to be estimated. but here the neutron componentof the dose complicates the interpretation of theestimates. For Nagasaki. the estimates for several dosegroups are too imprecise to be useful. Here however.
estimates derived from the inclusive groups of all over
200 rad, over 100 rad etc. are based on adequate
numbers. These estimates (table 4) suggest clearly thatthe frequency of leukaemia induction per unit kerma
decreases with decreasing kerma, and hence withdecreasing absorbed dose. As the inclusive dose groups
are widened to include a progressively greater contri·
bution from those exposed at lower dose, the rate perunit kerma falls from 35 10- 6 rad- 1 at mean kerma
330 rad, to 18 10- 6 rad- 1 at mean kerma 100 rad, therate per unit absorbed dose in this group being 33 1o- 6
rad -i at mean dose about 55 rad. This decrease of effectper rad with decreasing dose is perhaps to be expected
for the predominantly low-LET radiation and suggests avalue of about 30 10-6 rad- 1 as an upper limit for the
likely effectiveness of low absorbed doses of low-LET
radiation.
95. This inference would be consistent with estimatesderived above for the rates, per million per rad, of 25
and of 11 following x ray treatment of ankylosing
spondylitis, and of 17 after pelvic x-irradiation. The
tentative estimates of 50-55 rad -i of alpha radiationfrom thorotrast deposits and of 50 (10-130) following
treatment of tinea in children are not inconsistent.
96. An estimate in the range (15-25) 10- 6 rad- 1
might thus be taken for the induction rate for low-LET
radiation in a population of all ages, probably with asomewhat higher rate in the young and in the elderly,
and lower in early adult life. It must be emphasized,
however. that this estimate is derived predominantly
from rates observed following absorbed doses of over
100 rad. While the rate per unit dose from doses of a few
rads is unlikely to be higher than this value, it might besubstantially lower.

III. THYROID CANCER
97. The Committee's previous reports have shown the
thyroid gland to be an organ of high sensitivity forradiation carcinogenesis. Indeed,· considering that themass of the gland is typically about 20 g, much of whichis cell-free colloid, the sensitivity per cell is likely to beconsiderably higher than for most other types of tissue.
98. At the same time, the malignant tumours induced
have consistently been of a histologically well-differentiated type which usually develops only slowly andwhich can often be completely removed by operation or
successfully treated with radioiodine even if metastasized. For this reason the Committee has previously
quoted risks in terms of morbidity rather than ofmortality. It will, however, be necessary to assess thelikely contribution to fatal cancers as well as to cancer
induction, from thyroid irradiation (paras. 148 and149).

99. In its previous reports, the Committee has
reviewed information indicating the induction of thyroid
cancer by radiation in Japanese A-bomb survivors, inresidents of Marshall Islands exposed to radioactive
fallout. in patients therapeutically irradiated fromexternal sources, and in children treated for hyperthyroidism with radioiodine.

A. THYROID CANCER IN A-BOMB
SURVIVORS
100. From the report of Wood et al. (163) it wasevident that thyroid cancer had been induced byradiation in members of the Adult Health Study Sample
of Hiroshima and Nagasaki. It was clear that the rate ofinduction was greater in females than in males, and thesex ratio of affected females to males was 2.2 in thegroup exposed at distances to 1400 m. The rates of
induction were much higher in those who were exposed
proximally than in those distally exposed as examinedin females, the number of male cases being too small forstatistical tests. For females of all ages combined, thegroup exposed within 1400 m had a rate of 2.5 times ashigh as that for those exposed at distances greater than3000 m.
I O1.. The rates were also expressed in terms of estimatesof kerma at different ranges, but it was difficult toderive values for the annual incidences per unit kerma
since available records were only of the total number ofcases diagnosed at examination about 20 years after
exposure. With assumptions as to the mean dosecorresponding to the stated dose ranges, however, theCommittee made tentative estimates of induction rates
corresponding to between 10-20 cases per million per
rad for males. and 20-40 for females, for kermas in therange 25-200 rad. The variation of induction rate withage at the time of exposure was not clear from the datathen available.
102. Since the last report of the Committee, a further
detailed study has been published ( 109) of thyroid
cancers diagnosed between 13 and 26 years after
exposure in members of the Adult Health Study
population. This examination clarifies further the greater
induction rate in females, the histological type oftumour induced, the rate of induction per unit absorbed
dose and, to some extent, the variation of induction ratewith age at the time of exposure. Of the 74 thyroid
cancers recorded in the population studied only 40 werediagnosed during life (see paragraph 104). The other 34
were found first at autopsy and were neither detectedduring life, nor judged to have been detectable bynormal clinical examination. They were usually small
and of the papillary sclerosing type, although sometimes
showing metastases to local lymph nodes. The study by
Sampson et al. (130) of tumours of this type wasdiscussed in the Committee's 1972 report. where it wasnoted that the frequency of these tumours was increased
by about 23 per cent in autopsies in females receiving
kermas of over 50 rad. The high • prevalence inunirradiated subjects, however, in about 16 per cent of
autopsies, was regarded as casting doubt on the clinicalimportance of these tumours. Indeed. Woolner (164) has
reported a study of 140 cases of occult papillary377

carcinoma of the thyroid observed during a 30-year
period and regards the presence of these tumours as
having no effect on mortality.
103. The autopsy findings of Parker et al. ( 109) rely on
routine autopsy methods, rather than on serial sectionsof the thyroid, and the authors consequently report alower incidence of such ''clinically silent" tumours in
the unirradiated group (receiving kermas of less thanI rad). The observed frequencies at autopsy were 1.3
and 1.1 per ten thousand person-years of observation inmales and females respectively, tumours of this type
having been detected in about 0.15 per cent of
autopsies. Two thirds of these tumou,s were of thepapillary sclerosing type, the remainder being either
papillary or follicular. As in the study by Sampson et al.
(130), there was a significant increase in the frequencyof these '·clinically silent" tumours in females who hadreceived 50 rad or more, but no such increase was
detectible in males. The numbers of tumours detected
only at autopsy in the low-dose (less than 1 rad andnot-in-city) and high-dose (greater than 50 rad) groups
appear to have been as follows:
Low-dose group

High-dose group

Male

FemaleMale

Female

0
0

0
4

1
0

3
0

5

3

1

8

Person years (10 ) 38

63

20

23

Tumours:
Papillary
Follicular
Sclerosing
papillary3

indicating an increase in incidence rate for papillary andfor sclerosing papillary tumours in females.
104. The remaining 40 thyroid cancers had been
diagnosed clinically during the course of the Adult
Health Study. Of these, 9 occurred in persons who hadreceived less than 1 rad. Six cases, with 3.9 expected,
occurred in those expos~d to between 1 and 49 rad. A
further 25 cases ( 4.5 expected) occurred in those
exposed to 50 rad or more and the analysis in the reportis based essentially upon this more heavily exposedgroup. Comparing this group with those receiving lessthan 1 rad or not in the city at the time of the bomb,
the excess of cases diagnosed clinically corresponds to arate of2.2 (0.7-5.0) per 10 OOO person-years in the male,and 5.0 (2.9-7.9) in the female. The mean dose for the
exposed group is not stated, but appears, from the
distribution of person-years at risk in the three exposuregroups quoted, to have been about 200 rad kerma. If so,and since observations covered thirteen years, the total
excess incidence for the period 13-26 years fromexposure corresponds to rates of 14 (5-31) 10- 6 and33 (19-52) 10- 6 per rad kerma in males and females,
respectively. The rates per rad absorbed dose would be
20 {6-44) 10-6 and 47 (27-73) 10-6 , assuming ratios ofabsorbed dose to kerma as in paragraph 59 for gamma
radiation and neutrons: or of 11 (3-24) 10-6 and24 {14-38) 1CJ" 6 per rad of absorbed dose weighted
according to the weighting factors for neutrons given inparagraph 55. The rates for both cities combined would
be 37 10- 6 and 19 10- 6 per rad weighted absorbed
dose.
378

105. The relationship between excess incidence and age
at the time of exposure could not be examined in males,
since too few cases were observed. In females, the ratioof the incidence in those exposed at over 50 rad to thatin the group with minimal exposure was noted as being
greater in those younger than 20 at the time of exposure
than in older age groups. The relative risk is difficult tointerpret, however, in view of the few cases occurring in
the unexposed group, in three of the four age groups
only one case having been observed. The absoluteincrease, therefore, appears to be a more reliable index
of tumour induction, and was probably, although notnecessarily, higher in those aged less than 10 years at thetime of exposure than in the other three age groups.
Thus, the excess numbers of cases per 10 OOO personyears in the four age groups. as compared with theincidences observed in the unexposed group. were
14.2 (5.0-32.7), 4.9 (1.9-10.3). 3.6 (1.4-6.9), and
5.4 (0-16.2) in those aged less than 10 years,
10-19 years, 20-49 years, and 50 years and over,respectively. The observed occurrence of 4 cases infemales aged 10 years or less at the time of exposure
would only have been equalled with a chance of P = 0.04
if the rate of induction at this age were equal to theaverage of rates at all other stages. A fall of induction
rate D, with age A is also of probable significance(r = -0.85. P = 0.08, the data being fitted by theequation D = 11.6 - 0.22A). The suggestion that thegland in childhood may have several times the sensitivityof the adult gland thus continues to support the earlier
indication from study of the same subjects (130) in
which the percentage incidence of thyroid cancers inthose exposed at less than 1400 m was I.I ± 0.62 inthose aged less than 10 at the time of exposure, ascompared with 0.22 ± 0.13 in those aged 20 or over. The
excess incidence in those aged between 10 ·and 20 had anintermediate value of 0.83 ± 0.29.
106. Of the 40 tumours diagnosed clinically, histological examination of 34 tumours in high and low dose
ranges showed that papillary and follicular cancers both
had higher incidences per person-year in the high-dosegroup, of 50 rad or over, than in the group who were notin the cities or who received less than 1 rad, clearlysignificant increases occurring in females. The number ofclinical cancers were as follows:

Tumours:
Papillary
Follicular
Sclerosing
papillary
Person years (10 3 )Low-dose group

High-dose group

Male

FemaleMale

Female

1
0

6

2

4
1

12
7

0
38

0
63

0
20

32

As in previous series of radiation-induced thyroid
cancers, no anaplastic or medullary tumours wereobserved (see paragraph 138). The absence of anaplastic
cancers is of importance, since these are rapidly growing
and commonly inoperable tumours. The absence of
medullary carcinomas may suggest that the parafollicular
cells of the thyroid are less sensitive to tumour induction
than are follicular cells, but this difference may arise
merely because fewer parafollicular cells are present in
the thyroid and at risk. Only one of the 40 clinicallydiagnosed cancers had caused death at the time of thereport.

....
107. Tumour registry data for the period 1959-1970(14) show incidence rates of thyroid cancer per unit
kerma of about 10 (5-15) 10 - 6 rad -i for Hiroshima and11 (5-17) 10- 6 rad- 1 for Nagasaki. These would correspond to rates per unit absorbed dose of about
14 (7-20) 10- 6 rad- 1 , and 14 (6-23) l0- 6 rad- 1 , withequal rates in the two cities. The rates per unit weighted
absorbed dose would however differ substantially in
Hiroshima and Nagasaki, with values of about 4 (2-6)
and 13 (6-20) 10-6 rad- 1 , respectively.

B. THYROID CANCER IN POPULATIONS IN THE
MARSHALL ISLANDS EXPOSED TO THYROIDIRRADIATION FROM FALLOUT
108. The Committee's 1972 report described thedevelopment of 4 thyroid cancers in residents of certainof the Marshall Islands who had been exposed in 1954 to
fallout (25), both by external radiation and by ingestionof radioiodine.
109. By September 1976. 3 further thyroid cancers had
developed and the total incidence at that timecorresponded to 7 such tumours in 243 subjects exposed
to both external and internal radiation (27). To within
22 years from exposure, therefore, the diagnosed
incidence rate per unit absorbed dose was
145 (70-270) 10-6 rad- 1 (table 7).
TABLE 7. INCIDENCE OF THYROID CANCER IN MAR·SHALL ISLANDS POPULATIONSAge atexposure(years)Estimated
Number collective dose Numberofto thyroidofsubjects (man rad)cancers

Rate per unit
absorbed dose(lo·• rad·•,in utero
<10
10-18
>18

4
83
34
122

595
25 3157 980
14 64502
2
30 (0-5000)
80 (15-250)
250 (45-790)
205 (55·535)

Total
exposedUnexposed

243
504

48 53570145 (70-270)

C. THYROID CANCER IN PATIENTS THERAPEUTICALLY IRRADIATED FROM EXTERNALSOURCES112. Since the Committee's last review of this subject inits 1972 report, further information has become
available on the carcinogenic effect of radiation of the
thyroid in infancy and in childhood. The earliest reports
had been of radiotherapy given for supposed enlargement of the thymus, and the possibility could not be
excluded that some abnormality of the thymus, forexample in relation to immune mechanisms. was in itself
determining an increased incidence of subsequent
thyroid carcinoma, since control series did not include
children with a corresponding thyrnic enlargement (seeAnnex I, paragraph 59).
113. Subsequent evidence. extensively reviewed by
Lindsay and Chaikoff (80) however, made it clear thatthyroid cancers were developing after irradiation for awide variety of clinical conditions in infancy orchildhood, so that the development of the cancers could
not be attributed simply to pre-existing thyrnic
abnormality. Indeed, it seems likely in retrospect thatmost of the thymus glands irradiated for a supposed
enlargement may in fact have been normal.

114. The prospective study of Pifer et al. {112) was
described in the Committee's 1964 report, which also
noted that the analysis by Toyooka et al. ( 153)
indicated that 29 of 34 thyroid tumours (malignant andbenign) had developed in 472 children treated by
combined anterior and posterior radiation fields,
whereas only 5 tumours developed in 2111 children
treated by anterior fields only.
ll5. A further report of this study was published in1967 (56), when 2876 children had been followed forthe mean period of 16.5 years, during which 19 thyroid
carcinomas had been diagnosed as compared with only
0.14 expected. Since the mean absorbed dose to thethyroid was about 160 rad with the field size ordinarily
used, this incidence corresponded to a mean rate ofabout 40 10- 6 rad- 1 •Source: Reference 27.

110. These data neither support nor exclude a greater
sensitivity in childhood, the induction rates per unit
absorbed dose in those aged less than 10 years and in
those aged more than 18 years at exposure being 80 and
205 10- 6 rad- 1 • Both estimates, however, have wide
confidence limits and are consistent with the averagerate for all ages (table 7).
111. All the cancers have occurred in females (27),indicating a significantly higher induction rate than inmales:
7 cancers in 130 females exposed, rate 5.4(2.5-10.2) per cent
0 cancers in 113 males exposed, rate 0.0 (0.0-2.7)
per cent
No cancers were observed in 504 subjects who were
unexposed. and no data are available on the relative
frequency of naturally occurring thyroid cancers in thetwo sexes in this population.

116. In reviewing these and other series of irradiations
involving the thyroid in infancy or childhoo-d, Dolphin(38) in 1968 suggested that the frequency of tumours
observed by various authors after different periods offollow-up could be corrected to allow for tumours whichmight develop subsequently. This correction was madeon the basis of information on an observed distributionof latent periods between irradiation and the diagnosisof thyroid cancers. On this basis he inferred that the6
ultimate incidence would be of about I 00 10- rad -i
following mean doses of a few hundred rads delivered ininfancy.
117. In I 968. Hempelmann (57) reported further on
the series previously described by Pifer et al. ( 112),
extending the mean period of follow-up to abo~t
25 years and reporting the diagnosis of further t_hyro.1dcancers in the "high-risk subgroup C" involving i_rradiation by both anterior and posterior fields ~1th anestimated mean thyroid dose of 335 rad. In this groupthe excess incidence rate of thyroid cance~6 per ;:,~rut
absorbed dose corresponded to about 130 IO rad as·;379:.

'T'.,/·:I_·7'..i:,..'_.
•

Ill

.

~t:r,
lo

diagnosed within an average of 25 years following
irradiation. Several surveys, however, indicate much
lower incidences. For example, Janower and Miettinen(68) found evidence (by postal questionnaires) of only
2 thyroid cancers, as compared with 0.4 expected on
the basis of control populations, in 466 subjects
irradiated in infacy or childhood at a mean thyroid
exposure of about 400 R, surveyed at 30 years after
exposure. These values correspond to a risk of only
10 (0-30) 10-6 rad -i .
118. A further report by Hempelmann et al. (58) has
modified the general applicability of the risk estimatesderived from the high-risk subgroup C. It is now
suggested that much of the increased risk in this group,
as compared with th~ other groups studied, is likely tohave been due to a higher induction rate per unit
absorbed dose in Jewish than in non-Jewish children,and to the fact that a large proportion of children in
subgroup C were Jewish.
119. Table 8 gives separate estimates of these risks. The
somewhat higher rates observed for each racial categoryin subgroup C as compared with other groups is thought
likely to be due to the closer surveillance of children
from subgroup C and probably also to the longer meanfollow-up of this group (31 years) than for others(23.5 years). The dose-effect relationship for thyroid
cancers was consistent with, but not necessarily
diagnostic of, a linear function (although that for benign
tumours appeared not to be). For the dose range andfollow-up times involved, these data indicate mean risk
estimates of about 160 10- 6 rad- 1 and 50 10-6 rad- 1
for Jews and non-Jews in the United States of America
irradiated in childhood. This difference may, of course,
be due to cultural or environmental circumstances, forexample, influencing diet or surveillance, rather than to
any genetically determined racial factor. Hempelmann
refers to reports (103, 133) indicating a somewhat
higher mortality from spontaneous thyroid cancer inJews than in non-Jews in New York City. Israeli Cancer
Registry data (35) show no increased incidence for Jews
born in Israel but moderate increases for Jews born
elsewhere, as compared with registries from othercountries, and particularly if the unusually high values
from the 5 Hawaiian registries are excluded (table 9).

TABLES. THYROID CANCER FOLLOWING X-RAY EXPOSURE IN CHILDHOOD
Exposure
group

Racialorigin"Subgroup C"

Non-Jewish
JewishNon-Jewish
JewishNon-Jewish
JewishOther groups
All groups

Number ofcancers

Number of
subjects

Mean dose
(rad}

Rate
110·• (man radr'J

4
9
9
2
13
11

136
125
2 506
105
2 642
230

388
410
87
153
102
293

76 (26-174)
176 (92-306)
41 (22-72)
124 (22-392)
48 (28-76)
163 (92-270)

Source: Reference 58.

TABLE 9. THYROID CANCER REGISTRATION
Persons of all ages
(Annual rate per 100 OOO)
ActualRegistryAge-standardized

Males

Females

Males

Females

1.6

4.1

1.8

4.2

Israeli
All Jews
Jews born in:
IsraelAfrica or Asia
Europe orUnited States
Non-Jews

0.2
1.8

1.0
5.2

0.3
1.6

2.0
4.6

3.2
0.9

6.6
1.2

2.0
1.2

4.0
2.0

55 other registries
Mean
±SD

1.1
± 1.0

3.2
± 3.1

1.2
± 1.1

3.4
±3.2

50 other registries'l
Mean
±SD

0.8
±0.5

2.5
± 1.3

o.s
±0.6

2.6
± 1.4

Source: Reference 35.
aThe 55 registries just above less the 5 Hawaiian registries.

380

120. The frequency with which thyroid cancer wasdiagnosed in irradiated females was 2.3 times that inmales. This difference was significant and arose mainly
owing to a 5-fold difference in frequency in subjects
aged 15-29 at the time of diagnosis, the frequencies
being equal in the two sexes for those younger or older
than these ages. The ratio of2.3 was considerably lower
than that for "naturally occurring'' cancer of the thyroidin the two sexes in the same district. No relationship was
found between latency and size of dose.
121. A significant excess was observed of 4.7 (1.0-10.9)
cases of leukaemia but no estimate of mean marrow doseis available. With regard to other tissues within theradiation field, it may be noted that no malignant
tumours of the salivary glands are now regarded ashaving occurred, the four salivary tumours noted
previously now being regarded as benign mixed tumoursof these glands. Only one cancer of breast, diagnosed
since completion of the main survey, has occurred.
122. Observations published by Modan et al. (92) in1974 suggest that thyroid cancer may be induced byirradiation in childhood (at ages less than 15) at verymuch lower absorbed doses. They report a follow-up for
12 to 23 years of I O 902 children irradiated for
ringworm of the scalp and subsequently reported as
showing an incidence of thyroid cancer in excess of thatobserved in control populations. One such population
was of an equal number of controls matched for age,sex. country of origin and date of immigration into
Israel. The second control group consisted of siblings
who had not been irradiated and who were within
5 years of age of the irradiated child.
123. The development of thyroid cancers was ascer·
tained in part by reference to a central tumour registry,
which was regarded as having 95-per-cent completenessof ascertainment, but which had only been in operation
since 1960. Since the irradiations were carried out
between 1949 and 1960, this check was supplemented
by examination of death certificates, and review of
hospital records in the event of deaths involving
malignancies or suspicions of malignancies. In bothmethods of ascertainment, the investigator was unawareof whether the name sought was that of an irradiated ora control subject. By these means, twelve thyroid
cancers were shown to have developed, as against 2.0
expected on the basis of the rates observed in the twocontrol series. It was emphasized that this frequency of
induction represents an underestimate since ascertainment may not have been complete during the initialperiod of 0.11 years after irradiation. The minimum
induction rate is thus 0.09 (0.04-0.16) per cent.
124. Careful estimates were made ( 159) of the absorbed
dose expected in the thyroid. A ''phantom" wasirradiated in conditions similar to those used originally,
with 5 scalp fields at 350 R per field. The absorbed dose
was estimated to vary somewhat in different parts of the
thyroid gland from 6.2 to 7.4 rad with an average value
taken as 6.5 rad. It is of very considerable interest thaton this basis the incidence rate is in close agreement withthat observed by Hempelmann following much higher
mean doses, Modan's (minimum) estimate for a periodof 13-24 years from irradiation being 140 (70-240)
10- 6 rad- 1 , but for an estimated mean dose of a few
rads only. It is to be noted that this high risk derives (asin paragraph 118) from data on the irradiation of Jewish
children.
125. During irradiation, the neck, face and parts of thehead were shielded with lead-rubber sheeting. It is clear
however, and is emphasized by the authors. that theestimate of dose depends critically on the assumptionthat the children maintained a constant position during
irradiation and did not move so that the thyroid cameinto the primary field. Since these fields involved an air
exposure (focus/skin distance of 25-30 cm) of
350-400 R per field, such errors in alignment would only
require to have occurred during radiation of. forexample. 5 per cent of fields (and each child wasirradiated with 5 fields) for the mean thyroid dose tohave been 3 times as high as estimated. Modan has infact repeated the thyroid dose estimation ( 160) using avariety of different head positions simulated on thephantom. and with different filtrations (0-1 mm ofaluminium). With air doses of 350-400 R to the scalp,
the maximum range of estimates for either thyroid lobe
was 4-1 7 rad; but the average value (8 .8 rad) differedlittle from the original best estimate of 6.5 rad. It
remains apparent therefore. that malignant thyroid
tumours may be induced by quite low doses fromexternal irradiation in children, and that the rate ofinduction per unit absorbed dose may be comparablewith that following mean doses higher by a factor of 50
or so. It may be noted however that in a smaller series of2215 children irradiated at comparable doses for thesame condition (139), six thyroid tumours developed, of
which all were classed as benign and none malignant,after a mean follow-up period of 20.5 years.
126. The induction of tumours of brain, salivary glandand possibly skin in this series is dealt with inappropriate sections (see paragraphs 254, 257 and 294).
127. It should be noted that, despite the -evidence forthe carcinogenic effect of radiation on the thyroid in
infancy and in childhood, no excess of thyroid cancers
has been observed by Stewart ( I 52) or by McMahon(83) to result from irradiation in utero. Both thesestudies. however, were of mortality, in contrast to thoseof Hempelmann (58) and Modan (92) which recorded
morbidity. The slow progress and low mortality ofradiation induced thyroid cancers could therefore
account for this difference in findings.
128. Reference has already been made to the longlatency between irradiation and clinical diagnosis ofmany malignant tumours, including those of the thyroid.
The occurrence of the small occult sclerosing papillary
thyroid cancers. found in high frequency at autopsies on
subjects without evidence of thyroid disease during life,
in itself shows that tumours with histological charactersof malignancy and with metastases to lymph nodes may
not develop to a clinically diagnosable state during the
lifetime of the subject.
129. Even for clinically significant thyroid cancers, themean latency appears to be long. Prospective determinations of this mean latency are liable to be truncated byinadequate periods of observation. Retrospective determinations may be affected by the fact that thymus
irradiation in infancy was practised only over a limited
period of time so that estimates, which have been basedlargely on resulting tumours developing during childhood, tend to be dependent upon the date of the survey.
De Groot and Paloyan (30) however, record a mean ageof 20.3 years in 20 patients presenting with thyroid
cancer whose glands had · received absorbed doses.
probably in the region of 500.900 rad, when thesepatients had a mean age of 7.4 years.
130. Moreover, the available evidence suggests that thelatency increases with age at the time of irradiation.
Raventos and Winship (122) indicate a rise in meanlatency from 10 to about 17 years following irradiation
in infancy or during adolescence respectively. Greene( 48) obtained similar results in 59 subjects developing
thyroid carcinoma, with mean latencies of 9.8 ± 0.7(S.E.). 12.4 ± 2.3, and 19.0 ± 3.2 years following
irradiation at ages of less than I year, 1-17 years andover 17 years respectively. Analysis (118) of a numberof separate publications also suggests a latency (L) risingwith age at irradiation ( A) until adult life, according to
the equation L = 9.4 + 0.27A.
381

131-. Parker et al. ( 109) point out that new cases
continue to be detected in the Adult Health Study
population and that 25 new cases have been ascertainedin the 5-year period since June 1966 (i.e. at 21-26 years
after exposure) as compared with 49 in the previous
8-year period. It is of some significance however, that
this ascertainment largely involves cases only detected at
autopsy. For clinically ascertained cases, only 6 havebeen detected in this 5-year period as compared with 34
in the previous 8 years. If the ascertainment truly
reflects the rate of new clinical presentations during thecorresponding periods, this may suggest some reductionin the incidence of new cases with time.
132. This point is of great importance for estimating
the total expected development of tumours during thewhole lifetime of irradiated subjects. A report ofconsiderable interest in this connection is that of
Refetoff et al. (123). These authors describe the findings
on examination and at operation on patients who had
been irradiated for a variety of reasons (commonly for
tonsillar and thymic enlargement) in childhood and who
had come for examination only because they were awareof the possible consequences of thyroid irradiation, andnot because of any abnormality detected clinically or bythemselves. Of 100 patients so examined, operation wasrecommended in 18 patients who had either discrete
thyroid nodules, diffuse enlargement of the gland or
abnormal consistency in the absence of raised thyroid
autoantibodies. Operation was performed in 15 of thesepatients, a total extracapsular thyroidectomy being
carried out. In 7 cases thyroid carcinomas were found, 5
being shown to be invasive, while 5 were multifocal incharacter. Four of the glands removed were multinodular, I was diffusely enlarged and 1 showed a single
nodule on palpation, so that none of these tumours
appear to have been of the occult sclerosing papillary
type. All were either papillary, follicular of mixed incharacter.
133. The mean age at irradiation was 4.7 ± 5.2 (SD)years and the mean interval since irradiation was
24.4 ± 5.2 years. The estimated dose to the thyroid
varied with the reasons for irradiation, but had an
average throughout the whole group of about 750 rad. It
is of considerable interest that this incidence of thyroid
cancer, undetected clinically at 24 years after irradiation, in 7 per cent of subjects corresponds to a rate of
9 5 (45-17 5) 1o- 6 rad -t , which is close to estimates ofthe frequency with which such tumours are diagnosed
clinically at intervals of up to about 20 years following
irradiation in childhood or infancy, as in the series
reported by Pifer, Hempelmann and others. If all thetumours detected by Refetoff and his colleagues would
have become diagnosable clinically during the lives ofthese , subjects, these observations would appear to
confirm that a median latency for clinical detection of
thyroid cancer following irradiation in infancy may beof the order of 25 years.
134. Similar observations are reported by Arnold et al.
(8) on 1452 persons with a history of x-ray therapy to
the neck for benign disease 18-35 years previously. In
21 per cent. clinical or imaging studies indicated thepossibility of abnormality and 193 were explored
surgically. Thyroid malignancy was found in 56 of these,382

the tumours being of the occult papillary type, ofdiameter less than 1.5 cm, in 40 (1 I with metastases tonodes), larger papillary tumours being present in 11 (4with nodal metastases) and follicular cancers in theremaining 5 (2 with nodal metastases). These observations do not allow risk estimation, since the originalradiation exposures are not known and since the persons
examined may have been subject to some selection. The
detection of such tumours in 4 per cent of irradiatedsubjects, with I .I per cent of other than the sclerosing
papillary type, at 2 or 3 decades after irradiation,
however, supports both the high incidence and the slow
progress of such induced tumours. Becker et al. (12)report similar findings in adults who had been irradiatedin infancy or childhood, and who were operated upon
because of scintigraphic abnormalities at a mean time of
25 years after irradiation. Of 15 operated. 8 were foundto have thyroid cancers.
135. Favus et al. (45) also examined during 1974, 1056
subjects who had had radiation therapy during the 1940s
and 1950s and who were examined in order to detect
any resulting abnormality, and not because of any
symptoms or known evidence of thyroid disease. If
palpable or scintigraphic abnormalities were found,
operation was suggested and the findings at operation
were known in 182 of the 270 subjects in whom thisadvice was given, a total of 60 thyroid cancers being
found. Of these, 15 were microscopic in size, 6 were lessthan 5 mm in diameter and 39 were larger. Capsularinvasion was noted in 12, blood vessel invasion in 5, andlymph node involvement in 17. Of the tumours larger
than 5 mm in diameter, 10 were papillary and 27 wereof mixed papillary and follicular structure, only 2 being
follicular.
136. The thyroid dose could be most reliably estimatedin a group of 859 subjects who had had x-irradiation of
the tonsil or nasopharynx only. Their mean age at
exposure was 5.4 years, and at examination 32.8 years.
The mean dose to the thyroid was estimated at 725 rad,and 57 thyroid cancers were found in this group,
corresponding to a risk of 85 (65-105) 10-6 rad- 1 at
this dose level. the rate for cancers greater than 5 mmdiameter being about two thirds this value and the rate
in an unirradiated population being small. Three cancers
occurred in the remaining subjects with an estimated
42 600 man rad to the thyroid giving a similar total risk,of 70 (20-185) 10- 6 rad -t after a slightly shorter
period, of 26 years since irradiation at a mean age of
6.7 years. Taking account of the fact that histologicalfindings were known in only two thirds of those subjects
for whom surgery was recommended, the authors
estimate an annual risk of 4.5 10-6 y- 1 rad -t for thegroup receiving tonsillar and nasopharyngeal irradiation
only, and emphasize that this may be an underestimateof the final risk. If no bias was introduced in the actual
selection for surgery of those for whom it wasrecommended on clinical or scintigraphic evidence. therisk by 27.4 years would be 125 (100-155) 10- 6 rad- 1 ,with microscopic tumours forming about 25 per cent.
and tumours larger than 5 mm forming about 65 percent of this total.
137. Paloyan et al. (I 08) report the histological findingsin 38 thyroid cancers found at operation upon 70

subjects who had nodular thyroids and had had
irradiation to the neck in childhood:
13 were papillary (7 in males, 6 in females), 6 having
nodal metastases but none with remote metastases
8 were follicular (4 in males, 4 in females), 3 with nodal,and 2 with remote metastases
17 were of mixed oapillary and follicular structure (9 inmales and 8 in females), 11 with nodal and 2 withremote metastases.
138. These histological findings are characteristic ofmost reports of radiation induced thyroid cancer, and no
excess of anaplastic or medullary cancers has been
identified. Only two anaplastic tumours appear to havebeen reported as following radiation exposure, one being
diagnosed 6 years after external irradiation in infancy{140), and the other following radioiodine treatment(10). In both cases the previous irradiation may perhaps
have been fortuitous, but it still cannot be excluded thatthe types of tumour that develop are those characteristic
at the age at which they are diagnosed, since themajority of irradiations studied have been in childhood,and tumours arising in early adult life are rarely
anaplastic. One case of a probable fibrosarcoma of the
thyroid after irradiation has been noted by Hernpelm·ann(see paragraph 148).

D. THYROIDCANCERINPATIENTSTREATED WITH 1 3 1 I
139. The Committee reported in 1964 (154) that athyroid carcinoma of low grade malignancy had
developed in a child treated for hyperthyroidism with131
I but noted that, apart from this instance, noassociation had been reported between this treatment
and the development of thyroid cancer.
140. In a recent study, Safa et al. (129) have followed
87 patients treated in 1949 with 1 1 I for hyper·
thyroidism at ages of between 3 and 18 years. During
the period of follow-up, 5-25 years (with mean
12.3 years), no deaths and no cancers were observed inthese patients. The authors refer to a total of sevenreports, including their own, in which such patients havebeen followed clinically for average periods of about
10 years, and in which 2 cases of cancer had developed
among the total of 273 patients reported. Theyemphasize the need for continued and longer periods offollow-up and indeed, if the mean latent period for thedevelopment of thyroid cancer following irradiation inchildhood is in fact 20-25 years, this estimate must betreated with reserve. It does, however, tend to exclude ahigh rate of induction following high doses in childr~n.
It remains uncertain whether this is attributable to theover-active state of the irradiated gland in hyperthyroidism or to the high absorbed doses used in thistreatment, probably of the order of several thousands ofrad, with which substantial cell killing must be
associated. It is in fact noted that hypothyroidism
developed in 40 per cent of the children treated in thisseries, and in 48 per cent in the six other series noted.
Since clinical hypothyroidism ordinarily develops only
when the thyroid function. as measured by its

radioiodine uptake, has fallen to below about 5 per centof normal, it is to be presumed that considerable cellkilling or inhibition must have taken place in thesepatients.
141. In adults no excess of thyroid cancer has been
observed following the radioiodine treatment ofhyperthyroidism in a large series of patients followed foran average time of about 10 years (33). Isolated
instances are reported in which such a cancer has
followed radioiodine treatment in an adult (87), 11 suchcases are noted in one review {90). In view of the verylarge numbers of patients who have been treated in thisway, however, with a predominance of females in thehigher age groups at which thyroid cancer incidence isnormally greatest, the numbers at present reported do
not suggest any excess above a chance expectation. On
the basis of the age and sex distribution of patients being
treated for hyperthyroidism with radioiodine, an
incidence of 44, and a mortality of 16, cases per million
patient-years were estimated to be likely to occur bychance among these patients (114) if the normal
incidence of thyroid cancer is the same in hyperthyroid
patients as in the general population. Since the total
experience from this treatment is likely considerably
to exceed 1 million patient-years, the present evidence
appears to exclude any substantial cancer induction byirradiation at these high doses in adults also. It is,however, important to note that the period of
follow-up of many patients is still relatively short, sincethese treatments were only started 35 years ago and only
became common within the last 25 years. Moreover, theactivity ordinarily administered has been reduced within
the last 10-15 years and it will remain important toconfirm that no increased cancer incidence occurs
following this use of the rather lower absorbed doses,
now commonly in the region of about 4000 rad.

E. SUMMARY
142. In summary, therefore, it is evident that thyroid
cancers are induced by radiation at absorbed doses ofover 100 rad and probably even at less than 10 rad. The
induction rate per unit absorbed dose appears to be
somewhat higher in females than in males, and isprobably also rather higher in infants and children thanin adults. The mortality from radiation-induced thyroid
cancers is, however, low, at least during the first 20 years
after irradiation, so that although the thyroid shows ahigh rate for radiation induction of malignancies, it has arelatively low rate for induction of fatal malignancies.
143. The cancers induced are ordinarily of papillary or
follicular type; anaplastic or medullary thyroid cancers
have not been reported. The frequency of small occult
sclerosing papillary tumours is increased by radiation,
but these appear to have little or no effect clinically or
on mortality.
144. The induction rate per unit absorbed dose infemales has been found to be between 2 and 2.5 times
that in males in surveys in which this point has been
examined. Thus, a ratio of 2.3 is derived from the data383

of Parker et al. (para. 104) for clinically diagnosabletumours. and also from those of Hempelmann et al.
(para. 120). In the Marshall Island populations, Conard
et al. (para. 111) observe rates of 5 .4 {2.5-10.2) per centin females, and 0.0 (0.0-2.7) per cent in males.
145. None of the studies of therapeutic irradiation
involving the thyroid give evidence on an effect of age at
exposure on cancer induction rate, since adequategroups of people irradiated at different ages have notbeen equally followed up. However, the findings ofParker et al. in Hiroshima and Nagasaki described inparagraph 103 indicate an apparent dependence upon
age at exposure, for tumours diagnosed clinically
13-26 years subsequently. The mean rate of detection
per ten thousand person-years of survey of those aged
less than 10 at exposure was 4.1 ± 2.1 times that for
those aged 20 or over at exposure, considering males andfemales together. The ratio in males could not be
determined with adequate accuracy, but that in females
was 3.7 ± 2.2. The rate for the males and females who
were exposed at age 10-20 is perhaps slightly higher{1.6 ± 0.8 times) than in those who were aged 20 orover. It must be recognized, however, that these
inferences as to a variation of induction rate with age at
exposure, depend critically upon the assumption thatthe latent period between irradiation and detection of atumour does not in itself depend upon age at irradiation.
The observations recorded in paragraph 130 suggest thatin fact the mean latency may increase with increasing
age at exposure, and this effect might explain thepresent apparent difference in induction rates atdifferent ages.
146. On the other hand, the induction rates observed in
the irradiated Marshall Islands population {para. 110) do
not support this indication of an age effect. those aged

less than 10 at exposure having only 0.4 times theinduction rate per unit absorbed dose of those aged over
18. The confidence limits of these estimates are,however, too wide to exclude the possibility of some age
effect in the direction observed in Hiroshima andNagasaki. In the Marshall Islands populations the thyroid
doses tended to be considerably higher in children thanin adults owing to the greater concentrations of ingested
radioiodine in the smaller glands of children. A lower
induction rate might perhaps therefore be associatedwith doses causing substantial cell killing, and cases of
impainnent of thyroid function were in fact observed inseveral of these children.
147. In the populations studied, estimated induction
rates until about 25 years have mainly been in the range
50-150 10-6 rad- 1 (table JO). The rates in Hiroshima
and Nagasaki are, however, conspicuously lower, withvalues of 37 10-6 rad- 1 absorbed dose on the data ofParker et al. {109) or 14 10-6 rad- 1 on those of theTumor Registry (14). The lower rates in these cities
involve some ascertainments by autopsy but depend also
on repeated clinical examinations in the Adult Health
Survey, so should truly reflect morbidity and not only
mortality. It is to be noted that the incidence rates ofclinically diagnosed thyroid cancer in the reference
populations (those not in the cities, or exposed at lessthan 1 rad) appear to be substantially higher. at least infemales, than in other Japanese, or other national,
tumour registries ( table 11 ). These relatively high rates
for unirradiated populations in Hiroshima and Nagasaki
may well reflect the close surveillance in the Adult
Health Survey; if so, they should apply equally in the
exposed and the unexposed groups. Moreover, theestimated induction rates would only be increased byabout 20 per cent even if the control rates were taken as
zero. There appears, therefore, to be no obvious

TABLE 10. THYROID CANCER-INCIDENCE RISK ESTIMATES

Text
reference

Population
Studied

Period of study(years since
irradiation)

Type ofradiation

13-26

Dose (rad}Risk in periodof study(per unit ofabsorbed dose)

Rangeoo·• raa·•,Gamma and neutron

about 200 S0->200(kerma)14-25

Gamma and neutron

Marshall Islands(47% male)
Infants andchildren

To 22

Internal andexternal (low-LET)Radiotherapy
to neck

200

byregression,0->20027-115037 (23-54);
19 (12-28),
weighted dose
14 (7-20)
14 (6-23)

119

63%<100
29%>200

135-136

Mainly children

To 27 (mean)

Radiotherapy
to neck

725±185

132-133

Children180-1 500

ChildrenRadiotherapy
to neck
Radiotherapy
to scalp725

122-125

Operations at 24(mean)To about 18 (mean)(para.)

102-106

107

108-111114-120

384

Hiroshima andNagasaki(38% male)
Hiroshima
Nagasaki

To 24 (mean)

Mean

6.5

4-17
(estimated)

145 (70-270)
48 (28-76),
non-Jewish;
163 (92-270),
Jewish85 (65-105).
operated cases;
125 (100-155),
inferred, all cases
95 (45-175)
140 (70-240)

TABLE 11. THYROID CANCER INCIDENCE
Persons of all ages
{Annual rate per JOO OOO)
Males

Hiroshima and Nagasaki .
Unirradiated (clinical diagnoses)
Japanese registries
Miyagi prefecture
Okayama prefecture

Females

2.7 (0.1-12.5)

12.6 (6.3-22.8)

Unco"ected
0.7
1.3

Corrected 0
0.8
1.1

Unco"ected
2.0
3.8

Co"ecred 0
2.0
3.3

I.I ::: 1.0

1.2 ± 1.2

3.0 ± 3.1

3.4 ± 3.3

0.9 ± 0.6

0.9 ± 0.6

2.4 ± 1.3

2.6 ± 1.4

58 other registries

Mean± SD
53 other registriesb

Mean± SD

Source: Reference 35.
corrected to population of standard age.
bExcluding s Hawaiian registries (see paragraph 119}.

0

explanation for the apparent difference between
induction rates estimated for these cities and from othersources. The tumour registry data, and the rates
observed in unirradiated populations in Hiroshima andNagasaki, tend to exclude a low rate of spontaneous
thyroid cancer as a possible explanation for the low
induction rate (table 11 ), although Parker et al. quote
one report (132) as indicating a low mortality rate forthis malignancy in Japan.

I 48. Few radiation-induced thyroid cancers arereported to have caused death. De Groot and Paloyan(30) record that one patient, out of 20 with thyroid
cancers following childhood irradiation, had died duringa (mean) period of about 22 years from irradiation,although 4 had post-operative recurrences of the disease.
Parker et al. (109) note 6 deaths within 26 years of
exposure at Hiroshima and Nagasaki in their 40 patients
whose thyroid cancer was diagnosed clinically, bu! only
one of these deaths was attributable to the cancer.
Wilson et al. (162) record 2 deaths from the cancer
amongst 58 patients with thyroid malignancies following
neck irradiation, occurring within 23 years of exposure.
Six of their patients, however, had Jung metastases andone had bone metastases. Hempelmann (58) observed nodeaths during a mean follow-up of 24 years on 24
patients with apparently radiation-induced thyroid
cancer. One other irradiated patient was said to havedied subsequently from a fibrosarcoma of the thyroid.
but histological confirmation was not obtained.
149. These four reports, therefore, enumerate 4 deaths(or S, including the fibrosarcoma) occurring in 142
subjects with apparently radiation-induced thyroid
cancer, indicating a fatality rate of about 3 per centwithin a mean period of 24 years from irradiation.

1SO. If, ignoring the lower values from Japan, the riskof induction is taken as 50-1 SO 10- 6 rad -i within about
25 years of irradiation (table 10), with equal numbers tobe detected subsequently (para. 132), the lifetime risk ofa fatal induced thyroid cancer should be of the order of
5-15 10-6 rad- 1 , assuming a 3-per-cent fatality risk per
25 years, both for the earlier and for the later developing
tumours. Such estimates are necessarily tentative butreflect the apparently high frequency and low mortalityof radiation-induced thyroid cancer.

IV. BREAST CANCER
A. BREAST CANCER IN A-BOMB SURVIVORS
151. The study of Wanebo et al. (158) of theoccurrence of breast cancer in A-bomb survivors in
Hiroshima and Nagasaki was described in the Committee ·s 1972 report. In view of the low mortality of mostforms of breast cancer during the early years after
diagnosis, Wanebo et al. examined the incidence of thisdisease in members of the morbidity sample of the
JNIH-ABCC Adult Health Study, and based theirevidence on findings at the 6-month health examinations
made on this group. This clinical evidence was
supplemented by records of local tumour registries,
surgical pathology diagnoses, autopsy diagnoses anddeath certificates. As compared with incidence rates
observed in groups exposed to 0-9 rad or not in the city •at the time of the bomb explosion, a significant excess
of cases was found in the exposed groups, the relativerisk increasing with the estimated kerma. The total
excess was 11.6 (15 observed compared with 3.4
expected) in females exposed at known doses in excess
of 10 rad. If, as suggested by the numbers in each dosage
group, the mean dose _was in the region of 130 rad, an
induction rate of 24 (12-40) 10-6 rad- 1 can be inferred(table 12).
152. While this excess was noted as being statisticallysignificant, it was emphasized that part of the excess
might possibly be due to factors other than theradiation, since parity, duration of lactations andfrequency of married status were not equal in the
exposed and comparison groups and these factors are
known to affect breast cancer incidence (85). However,
Wanebo eL al. ( 158) found no differences in marital
status, parity or length of lactation among the 16
women with, and 7819 women without, breast cancer
who answered a questionnaire on these points. The
average period of lactation in 10 fertile patients withbreast cancer who had lactated was shorter than inwomen without breast cancer (36 months comparedwith SO months), but most of this difference was
explainable by the fact that there were fewer children in
the breast-cancer group. No relationship was foundbetween the frequency of any of these epidemiologicalfactors and radiation dose.
385

TABLE 12. INCIDENCE AND MORTALITY FROM BREAST CANCER IN HIROSHIMA AND
NAGASAKI COMBINED
Females, all ages
Dose
group
(rad)

Ob-

Man
rod

Excess rate
r10·• rad- 1)

servedEx·peered10-39
40-89
90-199
>200

4
2
4
5

1.14
0.77
0.72
0.76

INCIDENCE 1958-1966
2.9 (0.2-8.1)
0.023
128 (44-358)
1.2 (neg.-5.5)
24 (neg.-108)
0.051
3.3 (0.6-8.5)"30 (5·77)
0.110
4.2 (1.2-9.7)
14 (4-78)
0.294

Total

15

3.39

11.6 (5.9-19.7)

Excess

(JO')

0.478

Induction rate(cases or deaths
per thousand
persons exposed)

2.3 (0.2-6.4)
1.5 (neg.-6.9)
4.1 (0.7-10.6)
4.9 (1.4-10.3)

24 (12-41)

3.1 (1.6-5.3)

INCIDENCE 1950-1972'

Compared with 0-9 rad group
10-49
19
15.2
6
4.0
50-99
100-199
8
2.5
4
2.3
>200

Total

37

24.0

3.8 (neg.-13.4)
2.0 (neg.·7.9)
5.5 (1.5-11.9)
1.7 (neg.-6.9)

0.172
0.150
0.205
0.480

22 (neg.-78)
13 (neg.-51)
27 (7·59)
4 (neg.-14)

0.5 (neg.-1.8)
0.9 (neg.-3.9)
3.8 (1.0-8.2)
1.2 (neg.-4.9)

13.0 (3.1-25.1)

1.011

13 (3-25)

1.0 (0.2-1.9)

as
above

41 (2-93)
19 (neg.-58)
29 (10-60)
5 (neg.-15)

0.9 (0.1-2.0)
1.3 (neg.-4.0)
4.1 (l.4-8.5)
1.6 (neg.-5.4)

1.011

18 (9-30)

1.4 (0. 7-2.3)

Compared with Japanese National Statistics
7.0 (0.4-15.9)
10-49
12.0
2.8 (neg.-8.6)
as
3.2
50-99
above
6.0 (2.0-12.4)
2.0
100-199
2.2 (neg.-7.4)
1.8
>200

Total

37

19.0

18.0 (8.6-29.6)

Sources: References 97, 158.
Note: The 90% confidence limits are indicated in parentheses.

153. No further data have been published on the statusof the exposed populations in respect of these factors.
Examination of the mortality experience in the Life
Span Study (97), however, now indicates a significant
excess also of deaths from breast cancer occurring inthese survivors.

1154. For females of all ages and from both cities, thedeaths from breast cancer observed from 1950 to 1972
in groups at known doses greater than l O rad totalled
37. The number expected, on the basis of the 0-9 radgroup, was 24: as compared with Japanese National
Statistics, 19. From evidence as to the mean doses
within these groups, the excess mortality corresponds torates per unit kerma of 19 ( 6-35) 10-6 rad -l in
Hiroshima compared with Japanese National Statistics,
and 16 (4-34) 10-6 rad- 1 in Nagasaki. Table 13 gives
the mean rates for the different dose groups. The
corresponding rates per unit absorbed dose (seeparagraph 61) for those exposed at 10 rad or over would
be 26 (8-48) 10- 6 rad -i for Hiroshima and 20(5-42) 10-6 rad- 1 for Nagasaki. with close agreement
between the two cities. The rates would, however, differ
substantially if expressed per unit weighted absorbed
dose (using weighting factors as in paragrafh 55), withvalues of 6 (2-11) and 17 ( 4-37) 10- rad -l in
Hiroshima and Nagasaki, respectively. Similar rates apply
for higher dose groups in Hiroshima but somewhat lower
ones in Nagasaki. While mortality rates per unit kerma of
10-20 deaths per million per rad are consistent with amorbidity rate of 24 (I 2-41) cases per million per rad,the consistency must be due in part to overlap in theinformation on which each estimate depends. Thus themorbidity study made use of data from deathcertificates and autopsy data. and the mortality study
386

included deaths occurring up to 1972, and so will haveincorporated records of patients alive in 1966 when themorbidity study terminated.
155. Both in the study of excess morbidity (158) and inthat of excess mortality (97) from breast cancer (fig. I),
the excess rate per unit kerma in the lowest dose groups
considered (I 0-39 or 10-49) is higher than the average,
whereas that in the highest dose group ( > 200 rad) islower than the average rate per unit kerma (table 12). It
is difficult to interpret this observation (see Annex I,
paragraphs 140-151 ). which is of uncertain significancestatistically, and the agreement of the two reports on
this point may be due in large part to their study of thesame population. When the rate of induction in various
dose groups ( cases or deaths occurring per I OOO
exposed) is considered in relation to the mean received
in each group, there is no clear indication of a kerma
giving a maximum yield of tumours (fig. I), since the fallat kerma above 200 rad is statistically not significant. In
the mortality studies the total yield falls as the mean
kerma rises from 140 to 350 rad in the two highest dosegroups, but the estimate in the highest group depends
upon only 4 deaths as compared with 2.3 or 1.8
expected. and the significance of this fall is very
doubtful.
156. The mortality data suggest that the frequency withwhich breast cancer has been induced by radiation at
Hiroshima and Nagasaki depends considerably upon age
at the time of exposure. No deaths from breast cancer
had occurred by the end of 1972 in those who were lessthan 10 years of age at the time of the bomb. of whom
2757 (as at October I, 1950) had been exposed at
known doses of 10 rad or more. Few deaths in excess of

--TABLE 13. EXCESS MORTALITY FROM BREAST CANCER IN HIROSHIMA A.c\il) NAGASAKI,
1950-1972
Females, all ages
(Compared "'Hh Japanese National Statistics}
Dose group(radkemuz)Ob·
servedExpeered

ExceSJ

Excess rate
per unit kerma
r10·• rad.,,

Excess rate per unit
absorbed dose

10-49
50-99
100-199
>200

13
4
6
3

9.5
2.4
1.3
1.1

HIROSHIMA
3.5 (neg.-10.2)
1.6 (neg.-6.8)
4.7 (1.3-10.5}
1.9 (neg.-6. 7)

27 (neg.-78)
15 (neg.-65)
39 (11-87}
7 (neg.-25}

9 (neg.-34}

>100

9

2.4

6.6 (2.3-13.3)

17 (6-34)

22 (8-45)

> 50

13

4.8

8.2 (2.9-15.9}

17 (6-32)

23 (8-43)

> 10

26

14.3

11.7 (3.9-21.8)

19 (6-35}

25 (8-47)

10-49
50-99
100-199
>200

6
2
2
1

2.5
0.8
0.7
0.7

NAGASAKI
3.5 (0.1-9.3}
1.2 (neg.-5.5}
1.3 (neg.-5.6)
0.3 (neg.-4.0)

86 (2-228)
26 (neg.-121)
14 (neg.62)
1 (neg.-19)

1 (neg.-23)

>100

3

1.4

1.6 (negAi.4)

5 (neg.-21)

6 (neg.-26)

> 50

5

2.2

2.8 (neg.-8.3)

8 (neg.-24)

10 (neg.-30)

> 10

11

4.7

6.3 (1.5-13.5)

16 (4-34)

20 (5-42)(lo-• rat1· 11

Source: Reference 97.
Note: The 90% confidence limits are indicated in parentheses.

expectation had occurred in those aged 20 or over, mostof the excess occurring in those who were 10-19 years
old at the time of the bomb explosion. The following
data refers to exposures at or greater than I O rad kerma:

Age group

Personyears
1950-1972

0-9 years
10-19 years>20 years

49 74064 253174 319288 312All

Death frombreast cancer
Expected

Total excess
per unitkerma(Jo·• rad"')

27

0.4
23.7

0 (neg.-19)
34 {18-59)
6 (neg.-23)

37

24.1

13 (3-34)

Observed

010157. In view of the small number of deaths that haveresulted from breast cancer, it is difficult to make any
reliable estimate of induction rates, except for age
10-19. Table 14 shows that, for most dose groups, theestimates are non-significant or negative and, even where
significant, have wide confidence limits. For those who
were aged 20-34, only 2 out of 7 dose groups indicate
apparently significant induction, at rates likely to lie
between 1 and 40 10- 6 rad- 1 ; for ages at or over 50, the100-199 rad group gives a value of 155 (17-457) 10- 6
rad -i , all others being negative or non-significant; andno group gives a significant result for those aged 35-49.
It can only be stated, therefore, that exposures have

TABLE 14. EXCESS MORTALITY FROM BREAST CANCER IN HIROSHIMA AND NAGASAKI, 1950-1972
Females, all ages, dose ;> 10 rad(Compared "'ith mortality in 0-9 rad group)(Deaths per million per rad kerma)
Total cases
10-19

20-34

35-49

>SO

>20

">10

10-49
50-99
100-199
>200
>100
> 50
> 10

141 (51-305)
94 (24-250)
neg
13 (2-40)
9 (1-28)
19 (7-41)
34 (18-59)

neg
27 (ns)26 (ns)I O (ns)
15 (1-28)
17 (2-42)
IO (ns)neg
neg
37 (ns)neg
4 (ns)neg
neg

9 (ns)neg
neg
neg
155 (17-457)48 (13-103}neg
neg
47 (ns)14 (2-33)
18 (ng)9 (ns)
16 (ns)
6 (ns)

Total cases:
Observed
Expected
Excess

10
0.4

8
5.3
ns

12
12.6
neg

7
5.8
ns

27
23.7
ns

37
24.1

98

81

72

61

74

81

Mean kerma (rad)> l 0-rad groups

26 (ns)16 (ns)31 (8-66}
4 (ns)
12 (4-25)
13 (4-25)
15 (4-87)

Observed Expected Excess

19
6
8
4
12
18
37

15.4
4.0
2.5
2.2
4.7
8.7
24.1

ns
ns
ns

Source: Reference 97.
Note:
neg = estimated excess negative.
ns = excess not significant (at P = 0.05).

387

MORBIDITY

C 10-6rad- 1

·O·
120

.

.
100

..

80 >-

8

.
60

6

40

4

I

..
~
20

.J

2

0

0

~t

r-

..

..

MORTALITY
D 10-6rad- 1

100

200

300

rad

100

200

300

rad

Figure I. Variation of breast cancer induction rate with T6S kerma (Hiroshima and Nagasaki. females. all ages, periods as in Table 12)
Excess rates as compared with 0-9 rad group
Upper diagrams-morbidity (158), excess cases (C) induced
Lower diagrams-mortality (97), excess fatal cases (D) induced
Left diagrams-excess cases or deaths per million man rad
Right diagrams-excess cases per thousand persons(Ranges indicate 90% confidence limits)388

induced breast cancer. fatal within 29 years in those who
were aged 10-19, probably also at a low rate in those
who were older, but not, or not yet, in those who wereyounger.
158. It has, however, been emphasized (13) thatmortality is far inferior to incidence as an indication ofradiation induction of breast cancer and that, whereas
the annual excess mortality rates in Hiroshima andNagasaki in 1950-1974 were 0.43 and 0.26 10- 6 y- 1
rad -i . the excess incidence rate during the period
1950-1969 was about 1.5 10- 6 y- 1 rad- 1 in both cities.
The incidence of breast cancer in A-bomb survivors has
now been reviewed (88) in considerable depth and detailusing numerous sources to ascertain the frequency withwhich breast cancer has occurred in members of the Life
Span Study during this period.
159. This report makes a full analysis of(a) The frequency with which breast cancer is
induced in females of each of five age groups (0-9, 10-19,
20-34, 35-49, ;;;i. SO):(b) the distribution in time since exposure (andtherefore also in age) with which induced cancers aredetectable in each age group:(c) the way in which the frequency of induced
breast cancers increases with estimated kerma or
absorbed dose in breast tissue.

l160. In the exposed group as a whole, the breast cancer
incidence started to increase above expectation within
10, but probably not within S, years of exposure. In
women of different ages at exposure, however. thesubsequent time course of the detection of breast
cancers differed. In those who had been less than 10
years old, no breast cancers had been detected (by1969). In those who had been 10-19, few werediagnosed prior to 1960, but in 1965-1969 an ecesss was
detectable at an annual rate which exceeded thatobserved in those who had been older at the time of thebombs. These differences in time course prevent any
simple comparison of the way in which ultimate total
risk may vary with age. For example, it is not yet known
whether those exposed at age 0-9 will show a large
excess when they reach the age at which hormonal orother influences determine a full expression of "latent"cancers, or will show only a minimal excess because only
few breast cells haJ developed, and were exposed toradiation, at the time of the bomb explosion.
161. For breast cancers detected in the period surveyed,
however, of 5-24 years after exposure, the annual risk
per unit kerma of inducing breast cancer varied with age
as follows:
Annual incidence

I
I
I

Age atexposure(years)

Cases

Person years10•

per unit kerma,
estimate ± SD
r10-~ y·• rad"')

0-9
10-19
20-34
35-49
;;;i,50;;;i,10

1
38
76
76
40
230

0.198
0.250
0.292
0.252
0.115
0.909

2.4 ± 0.8
2.1 ± 0.8
0.6±0.8
1.4 ± 1.7
1.9 ± 0.45

0the incidence rates being determined by estimated slopesof maximum likelihood regression of annual incidence
onkerma.

162. The variation of incidence with dose, for all those
aged 10 years or more. was consistent with a linear
relationship. It is of considerable interest that the slopeof this regression was closely similar in the two cities.
despite the difference in neutron component of theradiation. Thus, the risk estimates per unit kerma for all
aged 10 or over were 1.8 ± 0.6 and 2.0 ± 0.7 10- 6 y- 1
rad- 1 in Hiroshima and Nagasaki; or, when the
populations were standardized with regard to age
distribution, were 1.90 10-6 y- 1 rad- 1 in Hiroshima
and 1.88 10- 6 y- 1 rad-, in Nagasaki. The corresponding rates per unit absorbed dose would be
2.6 10- y- 1 rad- 1 in Hiroshima and 2.4 10-6 y- 1
rad- 1 in Nagasaki.
163. The mean latency after which induced cancers
were detected did not vary with dose, SO per cent of all
tumours diagnosed between 1950 and 1969 being
detected by about 18 years from exposure in each age
group (0 to 9, 10 to 99 and~ 100 rad, for women lessthan 30 years old at the time of exposure).
164. Wanebo et al. {158) report that the histologicaltypes of tumours occurring in subjects who had been
exposed in Hiroshima and Nagasaki at over 60 rad (T65
kerma estimate) were similar to those occurring in those
who were exposed at lower dose. Of 12 cancers from theformer· group. 11 were duct carcinomas, one was acomedo carcinoma, and all were of infiltrating character.
In the latter group also, all were infiltrating, 8 being
ductal, one a comedo type and one an infiltrating colloid
carcinoma. A more recent survey (74) confirms thisindication that types of breast cancers are induced inabout the proportions in which they occur "spontaneously" in the same population, the great majority
being infiltrating ductal carcinomas. This type represented 85, 85 and 76 per cent of cancers examined inunirradiated persons (at O rad, or not in the cities), in
those exposed at 1-99 rad, and in those exposed at
100 rad or over respectively. The tumour had remained
intraductal, and therefore presumably of good prognosis,
in 13, 9 and 21 per cent in these groups. Other types ofcancer represented only a small proportion of eachseries. (The total series was of 225 cancers classified
histologically, with 118, 74 and 33 from the threegroups). Yoshizawa and Kusama (168) have surveyed anumber of published series of radiation-induced breast
cancers and note that most such cases are reported as ofductal origin.

B. BREAST CANCER FOLLOWING EXPOSURE
IN DIAGNOSTIC RADIOLOGY
165. The occurrence of breast cancer in patients treatedfor pulmonary tuberculosis by artificial pneumothorax
was reported by Mackenzie in I 965 (82) to be in excess
of expectation, and this excess was regarded as probably
attributable to the large number of fluoroscopic
examinations required to control the lung collapse.
Breast irradiation will have been substantial, since
Mackenzie's patients conunonly faced towards the x-ray
tube rather than towards the screen during the389

fluoroscopies. Myrden and Hiltz (99) extended thissurvey, and reported 22 cases of breast cancer in 300
patients treated with pneumothorax (7 .3 per cent) and
four cases in 483 patients not so treated (0.8 per cent).
The annual incidence in the pneumothorax treatedpatients was about 6.5 tiines that in the general female
population of Nova Scotia, but that in the tuberculous
patients untreated by pneumothorax did not differ
significantly from this general rate. There was commonly
an agreement between the side on which the carcinoma
developed and that on which the pneumothorax, when
unilateral, was established.
166. In its 1972 report the Committee discussed
estimates of the dose likely to have been delivered tobreast tissue and concluded that it may have been in therange 4-20 rad per examination. On the basis of thisestimate, and of the number of examinations involved,
which commonly exceeded I 00, it was concluded thatthe observed excess of 20 cases in 300 treated patientswould correspond to a rate of (20-120) 10-6 cases per
rad as diagnosed in the 20 years following initial
exposure with 90% confidence limits of (15-160) 10-6
rad- 1 • Myrden and Quinlan (100) state that a further
follow-up which now extends for 22-32 years, of 326
patients with pneumothorax shows 32 breast cancers tohave developed (as compared with 22 in the group in1967). A control group of 535 patients with pulmonary
tuberculosis but without pneumothorax or multiple
fluoroscopies have shown seven breast cancers comparedwith four in 1967. Without correcting for thepatient-year total of surviving patients, the excess cancer
incidence rate appears now to be of (30-140) 1o- 6
rad -i on the dosimetric basis assumed in the last reportof the Committee, with confidence limits (20-200) 10- 6
rad -i. This estimate may be low since it is uncorrected
for the death of 104 of the original 326 patients, and thefailure to trace 18 others. Brown (19) has used thefrequency with which the tumour and the pneumothorax were on the same or on different sides of thebody, to estimate the dose that is likely to have beendelivered to the breast on the side opposite to thepneumothorax. By this method he obtains a factor of
1.5 by which he considers that the estimate of risk perunit absorbed dose to the breast (on the side of thepneumothorax) should be increased, to determine therisk for equal irradiation of both breasts.
167. The additional 10 cancers have developed inpatients who were aged 20 to 39 at fluoroscopy andcrude incidences suggest a rather lower induction rate inthose over 30 at the time of exposure:
Age(years)Patients(initial
number)0-19
20-29;;;,3059
181
86

Breastcancers

Incidence

623

10 (4-20)
13 (9-18)
4 ( 1-9)3

169. The excess breast cancer incidence started toappear 15 years after the exposures and was continuing
at 40 years from exposure. The risk incrpased withestimated dose in a way consistent with a linear
dose-effect relationship. For the whole group, the meandose to breast was estimated as 150 rad assuming
a 15-s exposure yielding a 1.5-rad dose to breast
per fluoroscopy. This implied a total risk during
the
26.8
year
periodoffollow-up of(41-23.3)/(1047x 150) = 113 (50-190) 10-6 rad- 1 • The
authors estimate an annual risk rate of 6.2(2.8-10.7) 10-6 y- 1 rad- 1 by comparison with New
York State health statistics (or 5.6 relative to thecomparison group of patients). A rate of 2.9 10- 6 y- 1
rad -i is obtained by fitting a linear regression to all
data, or 8.2 if this analysis is confined to doses of lessthan 300 rad. For doses less than 100 rad an increased
risk was observed but was not statistically significant.
However, the relationship between excess rate andestimated absorbed dose in the breast was consistent
with linearity over the whole range of doses used,although some reduction of risk is suggested by the data
at high doses (corresponding to over 150 fluoroscopies).
170. Most of the observed excess, 10.7 (4.9-18.8) cases,
occurred in 341 women who were younger than 20(although older than 13) at the time of the exposure.
The remainder, 7.0 (-0.8-17.1) cases, was observed in
706 women of 20 or older at exposure. who were
followed up for a mean time (26.9 years) comparablewith that for those aged under 20 (26.4 years). The total
excess rate during these periods of time taking account of
the estimated mean breast dose at each age (I 7a) is
162 (74-285) 10- 6 rad- 1 for those who were under 20
and 78 (-8-189) 10- 6 rad- 1 for those who were 20 orover. The wide 90% confidence zones clearly preventany determination of risk rates at higher ages than 20(although the excess rate is just significant for ages
20-29. at 108 (11-297) 10-6 rad 1 ). They do, however,appear to indicate that the rates are highest in those
exposed in adolescence. For all cases, the mean interval
between exposure and diagnosis of a breast cancer was
24.4 years. Allowing for the expected incidence at
different periods, the mean latency for induced cases is
estimated as about 27 years.

(%)

The cancers have proved fatal in 14 of the 32
fluoroscoped patients, and in 3 of the 7 others.
168. Boice and Monson (17) have reported a significant
excess of breast cancer (41 observed and 23.3 expected)
in 1047 women who had had an average of 102
390

fluoroscopies during pneumothorax or pneumoperitoneum treatment and who were followed up for a mean
period of 26.8 years. Just over half of the total personyears at risk were in the period of 15-45 years after
exposure. No excess occurred {15 observed, 14.1
expected) in 717 women from the same sanatoriums
who had not had such treatment for their tuberculosis.

171. The authors emphasize the substantial uncertainties in estimating retrospectively the doses to thebreast. From questions to patients and physicians it was
concluded that the patient faced the tube in about one
quarter of all the examinations. Interviews with physicians
led to the acceptance of a mean exposure time of
15 s, and to the conclusion that 69 per cent ofphysicians had worked with the fluoroscope shutters
open so that both breasts were exposed to radiation:
81 per cent always also scanned the opposite Jung.

Estimates of dose. and thus of risk. are therefore morenearly applicable per patient than per single breast: andit was in fact found that the cancer was on the same side
as the pneumothorax in 17 cases, and on the opposite
side in 12.
172. As noted in the 1972 report of the Committee(Annex H. para. 120), the high incidence of breast
cancer in the series reviewed by Myrden and Hiltz (99)
may have resulted from the procedure adopted, with thepatient facing the x-ray tube so that breast tissue
received high doses. Similar frequencies have not been
observed in several other series. in which the same
position was not used, or if mortality rather thanmorbidity was studied, as in the report of Kitabatake etal. (78). Here 568 patients, who had received an averageof 75 pneumothorax refills between 1941 and 1961,
were reviewed in 1975. No deaths had resulted either
from breast cancer (0.4 expected) or from lung cancer( 1.6 expected).
173. Similarly Delarue et al. (31) found no increased
incidence of breast cancer in patients followed for aminimum of 20 years. and who had had multiple
fluoroscopies in the supine position (i.e. with backtowards the x-ray tube and receiving 17 rad per
examination, whereas the prone position would have
involved 308 rad per examination). Six breast cancers
had developed in 269 fluoroscoped patients as comparedwith 8 "in 260 patients who had not been fluoroscoped.
174. It is of interest that Janower and Miettinen (68)report the occurrence of 3 breast cancers in 466
individuals who were irradiated for thymic enlargement
during childhood or infancy. No estimate is given for thedose to breast tissue but that to the thymus was about
400 R and the anterior radiation field used in 92 percent of cases was planned to extend down from the levelof the suprastemal notch. with a maximum conediameter of 12.7 cm. Two breast cancers were recorded
in 2604 unirradiated controls, the period of follow-up(from irradiation to the date of the postal questionnaire)
being 30 years. On the basis of the control series, theprobability of 3 or more breast cancers occurring in the
exposed group would be 0.006-but this estimate is notstrictly valid since the incidence of breast cancers is
tested for statistical significance because it is raised. If
breast tissue received the same exposure as the thymus, aof(3-0.4)/( 466 X 400),orriskestimate
14 (2-40) 10-6 R- 1 , is obtained. The risk per rad cannot
be derived with confidence, but is unlikely to be higher
by a factor of more than 1.25.

C. BREAST CANCER FOLLOWINGRADIOTHERAPY TO THE BREAST
175. Mettler et al. (91) reported 13 confirmed cases ofbreast cancer occurring among 606 patients treated for
acute post-partum mastitis by radiation to the breast
area. The mean exposure of the irradiated breast was
346 R. Only one breast was irradiated in many cases.

and the mean exposure of breast tissues as a whole wasestimated at about 210 R. This incidence. which wasobserved during follow-up periods of 10-25 years, wasclearly in excess of that (5.9 cases) expected in a general
female population at the same ages. No data wereavailable however of the incidence of breast cancer
following post-partum mastitis untreated by radiation. If
radiation were. however. the sole factor responsible, theexcess would correspond to an induction rate of55 (15-115) 10- 6 rad -t to all breast tissue.
176. An important further study (138) on this group ofpatients has now been reported, in which it was possible
to examine the incidence of breast cancer in two groupsof patients who had had post-partum mastitis-which
had been treated by x-ray therapy in one group but notin the other. The incidence was examined also in further
control groups consisting of sisters of members of eachof these groups. This procedure is of value in controlling,
not only against possible differences in breast cancer
jncidence for genetic reasons in different families, but·also against any such differences in different localities
since the irradiated patients were mainly from one town
and the unirradiated patients from another. All
diagnoses were confirmed histologically.
177. The dose to the irradiated breast was commonly ina range corresponding to an exposure of 100-400 R in
air, and the mean absorbed dose was estimated as
377 rad to this breast. The average dose to both breasts
was estimated as 247 rad per treatment.
178. The breast cancer incidence in irradiated womenstarted to exceed that expected on the basis of thecontrol groups at 12-15 years after irradiation. Thereafter, new cases appeared annually in excess of the
expectation in 0.27 per cent of exposed subjects. Therewas some suggestion of a decrease in latency withincreasing exposure, but this was of uncertain
significance. The time intervals until detection of 25 percent of excess cases (percentage of all cases diagnosed by
30 years, determined by_ life-table methods). with 80%
confidence zones were:{R}

Interval to 25% of cases(years)50-199200-400
400-1 100

20.5 (17.7-22.0)
19.4 (13.0-21.6)
13.9 (8.5-16.7)

Dose group

179. The relationship between relative risk and mean
exposure to both breasts remained closely consistent
with linearity until a mean exposure of 234 R (group200-229 R). The relative risk at the highest exposure, at
401 R (group 300-550 R), however, was lower than thatat 234 R, with a value about 0.57 (0.31-1.03, 80%
confidence zone) of that expected if the linear regression
had continued. This indication of a maximum yield ofcancer at a mean absorbed dose in the region of 300 rad
is not as clearly established in other human epidemiological findings (but see figures I and II) but iscommonly demonstrable for cancers in animals (seeAnnex I). The dose-effect relationship ~r estimateddose to single breasts (rather than mean dose to both391

breasts) does not show as clear an initial linearity, but
the relative risk again reaches maximal values of 3.53 (at264 R) and 3.55 {at 452 R) and then falls to 2.29 (at733 R) .

.,180. No excess of cancers was detected within 10 yearsof irradiation, and life-table methods were used to derive
the subsequent annual risk of cancer induction until
34 years from irradiation, the population (571 women)
having been followed up over a mean period of
25.2 years. The estimated annual rate in the whole
exposed group during this 24-year period was
8.3 10-6 y- 1 R- 1 where the value for the exposure istaken as the mean value for both breasts. In a separate
analysis, the annual risk from irradiating one breast wasestimated to be 5.0·10- 6 y- 1 R- 1 • Over 80 per cent of
the total number of cancers induced would be diagnosed
only after 20 years following exposure.
181. The risk of cancer induction was somewhat greaterin those exposed at an age of over 30 than in those who
were younger:
Age atexposure(years)Number ofsubiects

Induction rate
(JO"' y- 1 R" 1)

15-29
~30

397
173

7.3
12.0

182. In the period of survey, 7 of the 37 breast cancers
occurring· in the exposed group had proved fatal,
as had 8 of 34 cancers in the comparison groups. The
time intervals between irradiation and death, andbetween detection of the cancer and death. were notreported. but the figures indicate a mortality risk frombreast cancer within a mean period of 25 years fromexposure which is about one fifth the incidence risk
during the same period. This unusually low fraction ofbreast cancers proving to be fatal (see paragraph 18) is
likely to be due to the short average period of follow-up
since many of the cancers were only recently diagnosed,
and to the fact that most of the women treated were in
the younger age groups at the time of exposure.
183. It is of interest that the risk per unit exposure
proved to be about equal following treatments given in I
or 2 fractions (mean total exposure 143 R. risk
8.3 10- 6 y- 1 R- 1 ) or in 3 or more fractions (mean total
exposure 235 R, risk 9.6 10- 6 y- 1 R- 1 ), suggesting that
increasing the number of fractions does not reduce the
carcinogenic effect of the total dose given, although here
the exposure per fraction does not appear to havediffered greatly in the two groups. The risks per unit
dose are unlikely to be higher than those quoted per
roentgen by factors of more than 1.1.
184. This study is of particular value in presenting
adequate controls for any increased incidence of breast
cancer following acute post-partum mastitis per se, as
well as tending to exclude genetic or geographical bias.
since the two groups of patients with mastitis and theirsibling controls were drawn from different parts of New
York State. It appears to determine the observed
carcinogenic effect as being due to radiation, although,392

as the authors note. the effect of radiation on inflamed
and lactating breast might differ quantitatively from thaton normal breast tissue.
185. Anotl1er prolonged follow-up study (11) has been
made of patients who had had x-ray treatment of breast
conditions. and in whom an increased incidence ofbreast cancer was detected subsequently. Radiotherapy
was given to 1115 women in the period 1927-1957 at
the Radiumhemrriet in Stockholm for benign diseases ofthe breast, mainly for fibroadenomatosis, but for acutemastitis in 120 cases and for chronic mastitis in 49. In
most instances only one breast was irradiated, the meandose to this breast being relatively high. about 845 rad.
In 1023 of these patients, who were followed up for amean period of 31.5 years, 115 cancers occurred in theirradiated breasts. and 20 in unirradiated breasts. atperiods of over 5 years after irradiation. From Swedish
breast-cancer incidence data (available since 1970). theexpected number in each breast having regard to the agesof patients at risk would have been 19.9; or, since
14 per cent of patients had irradiation to both breasts,
28.7 per irradiated breast.
186. The excess in unirradiated breasts is not
significant. That in irradiated breasts corresponds to arisk rate of (115-28. 7)/(1168 X 845) = 87 10" 6 rad- 1
per breast to 31.5 years or about 175 10- 6 rad- 1 per
patient if both breasts had been irradiated.
187. Excluding 9 cancers which were detected within 6
years of treatment, the mean latency from irradiation todiagnosis was 23.6 years. The distribution of latencies(uncorrected for a presumably diminishing number of
person-years at risk during later periods) was shown by
the observation that 13 per cent of cancers developed at
6-14 years from irradiation. 38 per cent at I 5-23 years,
34 per cent at 24-32 years and 15 per cent at over 32
years. The mean latent period decreased somewhat withincreasing dose:
Dose group(rad)Latencymean± SE
(years)1-499
500-999
I 000-1 499
1 500-3 999

25.8 ± 1.4
25.5 ± 1.2
21.6± 1.9
19.3 ± 1.4

However. the mean administered dose increased
markedly with age at the time of treatment (from
420 rad at age 10-29, to 770 rad at age 30-49 and960 rad at age 50 or over), and it is uncertain whether
the mean period of follow-up varied with age at
exposure, or whether latency varies with this age per se.
Either factor. or the increased death rate of older
patients from other causes. might possibly be responsible
for the apparent relationship between latency and dose.
A small apparent reduction in mean latency with age at
exposure (from 26 years following irradiation at ages lessthan 30, to 22 years for greater ages) may well be due tothe confounding of dose size with age.
J88. The authors show that the numbers of cancers
induced per rad and per breast vary markedly with age at

exposure in a manner similar to that seen in otherstudies. with apparently higher incidence rates following
exposure at ages less than 30:
Breast cancers

Age at· Number
irradiation of(years}breasts

Observed

Expeered

Excess rate
per breast(10- 6 rad"'}

10-19
20-29
30-39
40-49
;;;.,50

28
205
333
31 I
119

2
31
28
20
7

0.25
3.4
8.3
8.9
3.1

219 (18-757)
308 (212-429)
89 (52-136)
40 (16-73)
34 (1-88)

All

996

--

88
24.0
90 (69-114)
These values relate to the total excess numbers ofcancers detected, and indicate an increased sensitivity ofthe breast to cancer induction at younger ages, unlessthe periods of follow-up varied so markedly with age
that the reduction at greater ages merely reflects a lower
ascertainment of induced tumours. This appears mostimprobable in view of the magnitude of the reduction inrate.
D. SUMMARY

189. In summary, therefore, it is clear that breast
cancers may be induced with relatively high frequency
by radiation, particularly in adolescence and early adultlife. The cancer is of the type arising initially from ductcells. but is commonly found to be infiltrating breast
tissue. Cases start to appear in excess of normal
expectation within 10 years of irradiation, and new cases
continue to appear for over 30 years more, the meanlatency probably being in the region of 25 years.
190. Three bases can be used for estimating the
carcinogenic risk of breast irradiation in women:
namely, from the Japanese Life Span Study, fromsequels of repeated fluoroscopy. and following radiotherapy to the breast. From Hiroshima and Nagasaki
mortality records, the risk rate per rad kerma for
1950-1972 was about 0.6 10- 6 per year, or 13 10- 6
during the whole period by comparison with the 0-9 radgroup. or 19 10- 6 as compared with Japanese National
Statistics. The rates per rad for 1950-1974 as determinedby regression analysis over all dose groups were 0.43 and0.26 10- 6 y- 1 rad- 1 for Hiroshima and Nagasaki.
respectively, or 0.36 for the two cities combined.
191. On incidence data, however, the mean annual rate
per unit kerma for 1950-1969 was 1.9 10- 6 y- 1 rad- 1
for those aged 10 or over at exposure. of
1.5 10- 6 y- 1 rad- 1 for the whole exposed population,
giving an average incidence rate over the period of about
30 10- 6 rad- 1 for all ages. This incidence rate, of 3 or 4
times the mortality rate in the same period, appears
consistent with a rather slow course and high cure rate
for breast cancer of the types induced (see paragraph 18
and reference 40).
192. The risk rates inferred from studies following
radiological procedures, however, are considerably
higher. After multiple fluoroscopic examinations, one
study {para. 168 ff.) gives an annual rate of
6.2 10- 0 y- 1 rad- 1 for those patients surviving 10 years
after the examination. and about 4 (2-7) 10- 6 y- 1
rad- 1 for the whole series (with an incidence rate perunit absorbed dose of about 110 (50-190) 10- 6 rad- 1
during the mean follow-up of 27 years). It is likely thatmuch of the estimated breast dose applied bilaterally. but
rates for uniform irradiation of both breasts might besomewhat higher. The dose estimates must however be
regarded as highly uncertain owing to lack of direct
evidence as to the duration of the fluoroscopies.
193. In another study (para. 165). dose estimates arealso quite uncertain. but an annual rate in the region of{1-7) 10- 6 y- 1 rad- 1 is suggested (with an integral
effect of (20-50) 10- 6 rad- 1 over the 22-32 year periodof present follow-up). The rates in this study should
probably be increased by about 50 per cent to apply forbilateral breast irradiation.
194. Following radiotherapy, a survey (para. 176 ff.)
with detailed control studies yielded an estimated annual
incidence rate of 8.3 10- 6 y- 1 R- 1. for bilateral breast
irradiation (implying a total incidence rate of
210 10-6 R- 1 in the 25-year mean period of follow-up).
Analysis based on single-breast exposure gave thesomewhat higher annual rate of 10 10- 6 y- 1 R - 1 • The
further study following irradiation for various benign
breast conditions (para. 185) yielded a rate of about
2.8 10- 6 y- 1 rad- 1 for single-breast exposure (corresponding to a total risk for bilateral exposure of
175 10-6 rad- 1 during the mean period of 31.5 years
follow-up).
195. There is thus a substantial discrepancy between
the induction rates estimated for the Japanese
populations and those for patients exposed toeither diagnostic or therapeutic radiological procedures.
Although surveyed over comparable periods of time,
25-30 years after exposure, the Japanese incidence rates
per unit kerma for those older than l Oat exposure, havebeen 1.9 10-6 y- 1 rad- 1 or about 2.5 10-6 y-1 rad- 1{absorbed dose). The rates estimated following radiological procedures range from 2 to I 0, with a figure of(6-8) 10- 6 y- 1 rad- 1 being consistent with all of theseseries.
196. Mortality risk rates are estimated at about 0.25 times
the incidence rates in the Japanese Life Span Study. In
one of the surveys after fluoroscopy the mortality rate
was 0.45 times the corresponding incidence rate,
whereas following one radiotherapy series it was 0.2
times the incidence rate. To a period of 25-30 years after
exposure therefore, approximate values for the total risk
rates per unit absorbed dos.e (bilateral absorbed dose) toadults would be of an incidence of about 50 10-6 on
Japanese data, or 200 10- 6 on surveys following
radiological procedures. The corresponding mortality
6
risk rates within this period would be about 10 101
6from the Japanese studies. or about 60 10- rad- fromradiological surveys.
197. Several factors may con tribute to the discrepancy
between these sources of risk estimates. Firstly. thenatural incidence of breast cancer in Jap;m is somewhat
lower than in most other countries, with an averageannual incidence rate in females in 2 Japanese cancer
registries of 11 and 14 10-s y- 1 , as compared with amean value in 41 registries in other countries of 46(SD 23) 10-s y- 1 • This difference in incidence is due
mainly to a lower incidence at older ages in Japan thanelsewhere. This is strikingly demonstrated by estimating
the ratio between the mean incidence rate for age 60-75
to that for age 40-55. In the 2 Japanese registries, this393

ratio is less than l (0.59 and 0.69, and 0.64 for Japanese
populations in Hawaii). In tl;le 41 other registries forwhich the ratio can be derived, the lowest value is 0.97
and the mean is 1.48 (SD 0.24). It is not obvious,
however, how this striking difference would affect theinduction of tumours by radiation or their expression.
198. It must also be recognized that the whole basis of
the dose-and therefore the risk-estimation for thesurveys following fluoroscopy, depends upon theopinion of physicians that the average time that theyspent on pneumothorax fluoroscopies, which in mostcases ceased to be performed many years previously, was
15 s. It is hard to feel sure that this estimate would be
accurate, and easy to imagine that it could be
systematically biased in one direction or the other. 1n
addition, in the studies following radiotherapy, theabnormality of the breast tissue clearly also represents
another source of possible bias since, although it has
now been clearly shown that acute post-partum mastitis
is not followed by any increased breast cancer incidence,
the irradiation of an infected and lactating gland could
possibly be more carcinogenic than that of the normal
gland.
199. It remains clear, however. that the breast is ofrelatively high susceptibility to radiation carcinogenesis,
particularly when exposed during adolescence.

V. LUNG CANCER
200. In the 1972 report the Committee discussed
estimates for lung cancer incidence in survivors of the
A·bomb explosions at Hiroshima and Nagasaki. inuranium miners, in patients irradiated for ankylosing
spondylitis and in certain groups of tuberculous patients
who were likely to have received repeated diagnostic
chest x rays.
A. LUNG CANCER IN A-BOMB SURVIVORS
201. Further information has been published on
mortality from lung cancer in the JNIH-ABCC Life Span
Study (97). During the period 1950-1972, 100 deaths
occurred from malignant neoplasms of trachea, bronchus
and lung (referred to in this section as ··Jung cancer") inthe groups exposed to known doses in excess of 10 rad( table 15). The numbers expected on the basis of themortality experience in the 0-9 rad group are 78.4, sothat the excess is 21.6 (6-40). However, it must be
noted, firstly, that the induction of any cancers in thegroup exposed at 0-9 rad will reduce the estimate of risk
for the higher dose groups, and secondly, that the small
number of deaths occurring in this 0-9 rad group will. in
itself, increase the statistical uncertainty of the control
rate and therefore of the estimate of excess in othergroups.

TABLE 15. EXCESS MORTALITY FROM CANCERS OF THE TRACHEA, BRONCHUS AND
LUNG IN HIROSHIMA A.J."ID NAGASAKI BY DOSE GROUP, 1950-1972
Males and females, all ages
(Compared with 0-9 rad group)

Dose
group

Excess rate
per unitkenna(lo-• rad·')

Excess rate
per thousand
persons

1.5 (0.3-2.9)
1.7 (neg.-5.3)
2.9 (neg.· 7. 7)
2.8 (neg.-7. 7)(rad)Observed

Expected

Excess10-49
50-99
100-199
>200

49
10
8

34.4
9.0
5.8
4.4

14.6 (2.8-28.6)
4.0 (neg.-12.3)
4.2 (neg.-11.3)
3.6 (neg.-10.0)

70 (13-137)
24 (neg.-75)
21 (neg.-56)
8 (neg.-21)

>100

18

10.2

7.8 (1.2-16.7)

12 (2-26)

> 50

31

19.2

11.8 (3.2-22.6)

14 (4-27)

> 10

80

53.6

26.4 (I 0.4-44.6)

25 (1042)(10">)HIROSHIMA

13

NAGASAKI

5

12.4
4.2
4.0
4.2

-5.4 (neg.-1.9)-3.2 (neg.-0.8)
3.2 (neg.-9.4)
0.8 (neg.-6.5)-78 (neg.-27)-41 (neg.-10)
19 (neg.-57)
2 (neg.-17)

12

8.2

3.8 (neg.-11.6)

7 (neg.-21)

> 50

13

12.4

0.8 (neg.-8.3)

1 (neg.-13)

> 10

20

24.8

-4.8 (neg.-6.6)-7 (neg.-9)

10-49
50-99
100-199
>200

7
1
7

>100

Source: Reference 97.
Note: The 90% confidence limits are indicated in parentheses.

394

neg. (neg.-0.5)
neg. (neg.-0.6)
2.8 (neg.-8.4)
O. 7 (neg.-5.5)

202. In Hiroshima, 80 deaths occurred in those exposedat known doses of 10 rad or more, as compared with
53.6 expected on the basis of the 0-9 rad. group,
indicating an excess of 26.4 (10.4-44.6). This excess
corresponds to an induction rate of 25 (10-42)
10- 6 rad -i (kerma). No estimates have been published
for the ratio of absorbed dose in lung to kerma for
gamma and neutron radiation. Table 16, however, showsthat the rates per rad kerma do not differ considerablyfrom those per rad weighted absorbed dose. using
weighting factors as in paragraph 55. and absorbeddose/kerma ratios based either on the Committee ·s
assumption in its 1972 report of the lung as being at a
depth of 4 cm, or on the values quoted for a deep-sitedorgan such as the stomach (53).

TABLE 16. EXCESS MORTALITY FROM LUNG CANCERPER UNIT OF WEIGHTED ABSORBED DOSE,a
HIROSHIMA, 1950-1972
Males and females, all ages
(Compared with rates in 0-9 rad group)

Kerma
group
(rad)

Excess rare
per unir kerma(1rad"')

>200
>100
> 50
> 10

8 (neg.·21)
12 (2·26)
14 (4-27)
25 (10-42)o·'Excess rate per unit weighted
absorbed dose (lo·' rad"')using absorbed dose/kenna ratio
As for 4-cm
depth

As forsromach

7 (neg.·18)
8 (1-16)8 (2·15)
11(4-19)

11 (neg.·28)
14 (2-31)
15 (4-29)
24 (10-40)

aSee paragraph 202.

6

4

2

0 L.L.--....L..--,---<--......,.-----.----L-100

200

300

rad

100

200

300

rad

Figure II. Variation of lung cancer induction rate in Hiroshima with T65 kerma
Excess cancers as compared with 0-9 rad group
Left diagram-excess deaths per million man rad
Right diagram-excess deaths per thousand persons(Ranges indicate 90% confidence limits)

203. The number of deaths observed in Nagasaki are
too few for further detailed analysis. For Hiroshima,
however, the difference between the effectiveness perunit kerma at low doses and at high doses is the same as
was noted in the 1972 report (table 15). Thus, themortality rate per rad falls from 70 (13-13 7) 10- 6 rad-,for those exposed at 10-49 rad, to 8 (neg.-21)
10-6 rad- 1 following exposures at over 200 rad (fig. II).
Similarly, the excess rate per thousand persons exposed
does not continue to rise with increasing mean dose,
although the wide confidence limits of all these values
do not allow the assumption that a maximum mortality
rate for these cancers has been reached at the mean
absorbed doses (of about 200 rad) attained in the higher
exposure groups. When the induction rate in the wholegroup of those exposed at over 10 rad is compared withthat for those exposed only at higher levels (table 16),
the rates per rad thus still differ by a factor of 3 whenbased on kerma, or by a factor of about 2 when basedon weighted absorbed dose, on the assumptions made inparagraph 202. The likelihood of a falling induction ratewith increasing mean absorbed dose is thus not

excluded, but the average rate over a wide dose range
appears to be in the region (10.25) 10- 6 rad- 1 (kerma or
weighted dose).
204. Ishimaru et al. (64) have examined the possibility
that those surviving exposure at high dose might havesmoked more heavily than others. and that the apparent
association of an increased lung cancer mortality withradiation might be due to this. They found no evidence
to support this possibility, or that environmental factors
other than radiation were responsible for the increase.
The smoking history was available in 204 subjects from
Hiroshima and Nagasaki in whom a lung cancer wasverified at autopsy, 61 having been exposed at low
radiation dose and 13 at high dose. The relative risks oflung cancer (in 1323 autopsies) were 8.6 and 3.0 insmokers and non-smokers who had been exposed at over
200 rad (T65 kerma) and 6.2 and 1.0 in smokers andnon-smokers exposed at less than 1 rad. The relative risk
(relative to unirradiated non-smokers and.standardized forsex and age at death) was thus increased by about as muchby radiations whether the subject was a smoker or not.
395

205. The histological character of the '·lung·· cancers
was examined in the same series (24), which included
1700 autopsies on subjects exposed at 1 rad or over
( with 127 at over 200 rad) and 1196 with exposures ofless than 1 rad. The prevalence rate of lung cancer at
autopsy was significantly increased in those who had
been exposed at 200 rad or over, with a rate of 10.2 percent at autopsy as compared with 5.1 per cent in those
exposed at less than 1 rad, and 5.1 per cent also in those
who had not been in the cities at the time of the bomb.
Three types of lung cancer were increased in this highly
exposed group, but the increase was only significant forsmall-cell anaplastic tumours. The excess numbers.
relative to expectation based on the <I rad group. are
however too small to exclude equal increases in othertumour types (table 17). particularly the epidermoid andbronchogenic carcinomas, or even a proportionate
increase.of all types as seen in the control group.
TABLE 17. EXCESS NmIBER OF LUNG CANCERS AT
AUTOPSY(Compared with expected numbers as judged by types observedin the <I rad group)
Kenna group {rad)Epidermoid
Small-cell anaplastic
Bronchogenic
adeno-carcinoma
Bronchio-alveolar
adeno-carcinoma
Large-cell carcinoma
Combined andunclassified
Total

>200

1-199

1.2 (-1.0-6.0)
3.7 (0.7-9.2)

7.6 (-0.8-18.3)-1.8 (-7.3-6.l)

2.0 (-0.6-7.2)-4.0 (-10.9-5.2)

0.0 (-0.6-2.4)
0.0 (-0.3-2.7)

3.1 (-1.7-10.3)-0.9 (-3.1-3.9)

0.6 (-0.4-4.3)-0.3 (-3.3-5.2)

7.5 (2.2-15.2)

3.7 (-10.8-20.4)

Source: Reference 24.
Note: The 90%confidence limits are indicated in parentheses.

206. The number of lung cancers induced, or at least
the number causing deaths within 24 years of the
exposure, appears to depend critically upon the age at
exposure (14). For those who were aged 35 or over, thetotal number of deaths has been increasing about
linearly with time since about 10 years after exposure,that rate of increase being somewhat (about 50 per cent)faster in those who were over 50 than in those aged
35-49. There has, however, been no increase in rate inthose who were aged less than 20, and little, if any, in
subjects aged 20-34 at exposure.
207. The increased mortality in Hiroshima and Nagasaki
over 1950-1972 is slightly. but not significantly, greaterin females than in males (mortality per 1000 persons
exposed at 10 rad or over, as compared with 0-9 radgroup)::Males
0.85 (neg.-2.27)
Females 1.09 (0.37-1.97)(43% were aged 35 or over){38% were aged 35 or over)

B. LUNG CA.NCER IN WORKERSEXPOSED TO HIGH RADON LEVELS
208. In its 1972 report, the Committee discussed theevidence obtained from studies on uranium and otherhard rock miners, of an increased incidence of lung396

cancer associated with the high radon concentrations in
the atmosphere of many mines. It was stated. however,that tile incidence of or mortality from lung cancer ingroups of miners could only be related to the radon
concentrations to which they had been exposed in thecase of those working in the uranium min'es of theColorado Plateau in the United States, where extensive
studies had been made both of the frequency of lungcancer and of the associated radon levels.
209. Since the time of the last report, two further
populations of miners with increased incidence of lungcancer have been described, and the increase related tothe corresponding radon levels. Each of the three major
studies shows a dose-effect relationship between excess
incidence of lung cancer and estimated exposure, thedata being consistent in each case with a linear
relationship between the excess cancer and thecumulative working level rnon ths (WLM) 5 of exposure
to radon.
210. It remains difficult to separate adequately thecontributory effects of radon and of smoking in causing
the cancers, since there are too few non-smoking miners
to form a sufficient control group, but Archer et al. (5)attempt to make a correction for the cigarette-smoking
habits of miners. They find that, among smokers, 15.5
deaths from respiratory cancer should have occurred(among white underground uranium miners) as compared with 58 observed. In non-smokers, 0.5 deaths
should have occurred as compared with 2 observed.
While the proportionate increase in mortality from lungcancers is thus about the same in the two groups. theyemphasize that the sample size of non-smokers is too
small to be certain of this point. They point out.
however, that in the absence of any interaction between
radiation and cigarette smoking, the smoking habits
could account for no more than a 49-per-cent increase inlung cancer rate, so that some interaction between theeffects of radiation and of cigarette smoking appears
probable and is being further investigated.
211. Sevc et al. (136) found that cigarette smokers
formed about 70 per cent of a random sample of 700
uranium miners, and that this was equal to thefrequency in the general
population in Czechoslovakia. They noted that there was no reason to supposethat consumption of cigarettes correlated with radiation
exposure otherwise than through age, and that thecomparison of lung cancer rates in miners with age
standardized general vital statistics therefore permitted
the exclusion of smoking as a major causal factor in theexcess of lung cancers that they observed in miners.

male212. Archer et al. (6) have now shown that the excess
mortality from lung cancer increases about linearly withcumulative WLM in non-smokers, but to an extent which
is only of the order of one eighth that which is observedin miners smoking 20 cigarettes per day.
213. At least in regard to miners who smoke, however.
there are now three estimates of the lung-cancer risk rate
5"Working level" is defined as any combination ofshort-lived radon daughter products in one litre of air that y,ill
result in the ultimate emission of 1.3 I O' MeV of potential alphaenergy. Working level month (WLM) is the exposure to one
working level during 170 hours.

for different exposure levels from radon and two further
estimates are available from other mining groups, givinga mean risk for a stated average exposure.
214. For uranium mines of the Colorado Plateau. thedose-effect relationship is consistent with a linear
regression through zero. The total experience amongst
white underground workers in uranium and other hardrock mines, from July 1950 to September 1968, showed
an excess of 58.3 deaths from lung cancer in a
population equivalent to 37 958 person-years. Assuming
a mean exposure at the midpoints of the various
exposure groups with stated limits, and a mean exposureof 5000 WLM in the group exposed at over 3720 WLM.
the mean exposure would 1;,e of 740 WLM, implying an
excess mortality of 38 10- 6 per WLM during the periodof observation. Average annual rates are about
2.9 10- 6 per WLM year for those who have worked as
miners for over 10 years, or 2.1 10- 6 per WLM year for
the whole group.
215. Studies from uranium mines in Czechoslovakia
showed an excess rate corresponding to 170 1o- 6 deaths
from lung cancer per WLM over an exposure period
varying from 19 to 23 years (135), indicating an annual
rate of about 8 10-6 per WLM year. Most of these
exposures were received prior to improvement ofventilation of mines in about 1958. A further report ona group of these miners who started work in the uranium
mines between 1948 and 1952 and have now been
followed for 21-26 years (136) shows an excess rate of
230 10- 6 per WLM, the dose-effect relationship again
being consistent with a linear regression through zero.
The rate varied with age:
Age at startof mining

Excess rate
and 95% confidence limits(JO·• WLM- 1)

Under 30
30 to 39
Over40140 (100.180)
230 (160.300)
370 (280-460)

All

230 (155-305)

indicating rates per million per WLM year of about 6, 10
and 16 in the three age groups. The authors suggest thatthese rates may be higher than those inferred for the
Colorado miners because of a younger mean age of thelatter at the start of mining. They emphasize that theirown estimates of exposure rely on large numbers (over120 OOO) of measurements of radon concentrations inmines in the period since 1948, with at least 100
determinations per year in each mine, and that theadditional hard-rock exposure of the miners was verysmall.
216. In non-uranium mines in Sweden the excess
mortality shows a linear regression, with slope equivalent
to 3.4 10- 6 excess deaths from lung cancer per
WLM year. For fluorspar mines in Newfoundland themean rate is estimated as 2.2 10- 6 per WLM year. while
for iron mines in the United Kingdom it is 6.0 10- 6 per
WLM year (144).
217. These estimates may be regarded as reasonably
consistent in view of the difficulties and likely
differences in ascenainment of lung cancer, and of

associating radon measurements at certain positions inmines with alpha radiation dose to cells of the bronchial
epithelium, as well as possible differences in smoking
habits, urban or rural residence, typical duration of workin mining, age at starting and other circumstances.
Moreover. it has been shown that differences in risk may
apply to those with long or short total periods of
exposure (135). To the precision required for risk
estimation, however, a rate of 5-10 lung cancers per
million per year and per WLM appears representative ofavailable data.
218. A study of lung cancer in Ontario uranium miners
in the period 1955-1974 (50) records a death rate fromthis malignancy which rises from about 0.3 per cent in
the unexposed subjects to 3.7 per cent in those with180 WLM of cumulated exposure. The authors emphasize, however, that these data cannot properly be used
for risk estimation, owing to the limited total periods ofsurvey (of within 20 years from the start of exposure)and for lack of information on smoking habits. The
survey is of particular value, however, for showing
consistency of the dose effect relationship at low dosewith a linear regression which is taken to exclude any"threshold" greater than 10 WLM. It also indicates that,
although the absolute excess of lung cancers was lower
in those under 35 than over 35 at entry to mining, therelative increase was comparable in the two groups.
219. Several steps are involved in deriving the total riskof lung cancer from estimates of induction per WLM.
Since lung tumours may develop with a long latency
after the relevant exposure. the annual rates of incidence
must be regarded as continuing over long periods oftime. and the mean rates used for calculation of total
mortality must be appropriate for the average of these
periods of time. In the case of the least two of theestimates quoted above, this condition appears to beadequately satisfied. For the Czechoslovak miners, therates correspond to averages over periods of 20 years or
more. If this is regarded as comparable to the medianlatency for tumour development and diagnosis, and thetotal of cancers is doubled to allow for later developing
malignancies, the final figure (of about 450 10- 6 per
WLM) should approximate the total expression of theradiation effect.
220. For the Swedish data also. although mean
exposure times are not stated, the "latencies" observed
from the start of mining to the diagnosis of the tumours
observed. which range up to 40 years and average
26 years, show that the rates derive from populations
with prolonged exposure. The annual rate might thus bemultiplied by 40 (years) to allow for full expression.
giving a total in the region of 140 10- 6 per WLM.
221. The values quoted for miners in the Colorado
Plateau represent rates averaged over somewhat shorter
exposures since. for example, the data of Archer et al.
(5) refer to 3366 miners and 37 958 person-years of
exposure. giving an average exposure of about 10 years.
From information given (81) on the excess deaths andperson-years at risk in the various exposure groups. it
appears that the risk for a given exposure rises with themean period since the start of uranium mining. as shownin table 18. While the mean rate for all periods since397

TABLE 18. MORTALITY IN URANIUM MINING
Period since start of mining (years)

Excess deaths from
respiratory cancer
Person year WLM
product (10 6)
Excess deaths per 1o•person year WLM
90% confidence limits

<..5

>5

>JO

>15

>20

>25

0.6

8.6

20.6

17.6

5.3

5.7

3.4

7.8

7.7

4.3

2.4

2.6

0.2
0.0-1.4

1.1
0.4-2.0

2.7
1.7-4.0

4.0
2.6-6.2

2.2
0.8-4.6

2.2
0.8-4.6

Source: Reference 81.

start of mlllIIlg is 58.3/28.3 = 2.06 deaths per 10 6
person year WLM. that for miners who have worked for
10 years or more is 49.1/17.1 =2.86 per 106 personyear WLM. Or, if the rates for the various intervals areused to estimate the total of all deaths, say to 30 years
from start of exposure, a value of about 70 10- 6 per
WLM is obtained. It is not clear, however, whether theapparent fall in rate after 20 years of exposure issignificant, or what contribution would be made atperiods longer than 30 years.
222. For a full. e.g. 40-year, expression of the total
carcinogenic effect on lung tissue of radon and of its
daughter products, therefore. an incidence of200-450 10-6 per WLM can be regarded as probable.
Since 1 WLM has been estimated as delivering about
1 rad of alpha radiation to bronchial epithelium(Annex B), the risk of exposure to low-LET radiation
would on this basis be in the region of 50 (or from 20 to150) 10-6 rad- 1 if a weighting factor of 5-10 is assumed
for alpha radiation at the high dose levels on which theestimates are based. If estimated in terms of mean lungdose, with 0.5 rad per WLM, the risk per rad would betwice as high. but this criterion seems less appropriate
since the cancers are likely to arise from bronchial
epithelium. It must be recognized, however, that theseestimates depend on very indirect indications of tissue
dose, as derived from air concentrations at monitoringsites in mines and strictly may apply only to miners who
smoke. If smoking has a co-carcinogenic and not simply
an additive carcinogenic effect the same increase cannot
necessarily be assumed for non-smokers. Uncertainties as
to the lung tissue over which dose should be averaged,
the relationship between radon concentration and tissue
dose, and the value of RBE appropriate for Jung
carcinogenesis from moderate doses of alpha radiation
add to the uncertainty of the estimate (ref. 51 andpara. 215).

C. SUMMARY
I. Comparison of estimates
223. There is an apparent discrepancy between the lowmean induction rates in Hiroshima and Nagasaki,
10-25 10- 6 per rad of kerma or of weighted absorbed
dose, and the higher values. 40-180 10-6 per rad, thathave been inferred from the mortality in uranium and398

other miners. There are, however, a number of factorsthat might explain this discrepancy:(a)
The rate per unit kerma is not, and that perunit absorbed dose (weighted according to data on
leukaemia induction) may not be, the relevant basis forrisk estimation. However, even expressing the rates as
per unit absorbed dose {with RBE= 1) would only
increase the Japanese estimates by about 75 per cent;(b) The Hiroshima population was of all ages,
and the carcinogenic effect appears to have been
expressed predominantly in those aged over 35 at
exposure. Since 40 per cent of these populations(exposed at over 10 rad) were over that age, the observed
rates should probably be multiplied by a factor of up to
2.5 to correspond to the rates observed in uranium
miners;(c) The Hiroshima rates are based on information in the period from 5 years to 27 or 29 years fromexposure and, since deaths continue to occur in the
exposed groups, should be increased (perhaps by up to
50 per cent) to correspond to the 40-year period
considered for uranium miners;(d) It has been noted (13) that many deaths
from lung cancer are not identified as such on deathcertificates and that adjustment for such errors would
raise the rates in Hiroshima by about 50 per cent;(e) The induction rate estimated for those
exposedat
I 0-49 radinHiroshimawas
70 (13-137) 10- 6 per rad kerma (table 15), and would
be equivalent to about 120 {23-240) 10- 6 per rad
unweighted absorbed dose. This rate is much greater
then those estimated at higher dose but has wide
confidence limits. It is improbable, however, that thisrate in Hiroshima occurs at a level which corresponds tothose on which the uranium miners mortality are based,since the former was associated with a 0.2-per-centexcess incidence of lung cancer (fig. II). while in thestudies of Sevc et al. (136), the data are consistent withthe higher incidence rate per WLM up to excess
mortalities of 10 per cent:(!)
It might be questioned whether, for the Jung
as for the breast, spontaneous cancer rates in Japan are
unusually low. and that a lower induction rate might bein some way associated. In females the annual rate ofJung cancer registration in two Japanese cancer registries
was 6.0 and 5.2 cases per 100 OOO, as compared with amean rate of 7.6 ± 5.5 (SD) in 54 other registries withcomparable criteria. The annual rate in males was
somewhat lower than that in many other countries. with

age-standardized rates in these registries of 15.6 (in1962-1964) and 15.3 (in 1966), as compared with35.5 ± 19.4 per 100 OOO at comparable periods in theother registries, but Japanese rates have been noted(para. 41) to be increasing;(g) Ishimaru et al. (64) record a history ofcigarette smoking in 52 per cent of a series of 1323
people from Hiroshima and Nagasaki (males andfemales) from whom a smoking history was available,
whereas Sevc records 70 per cent of a random sample ofminers as being cigarette smokers. The difference,
presumably due in part to the proportion of women in
the Japanese populations, might account for some of thediscrepancy in induction rates, but the data of Moriyama
and Kato (97) do not indicate a clear difference ininduction rates in the two sexes in Hiroshima;(h) On the other hand, estimates of the radequivalent of the WLM at the tissues of interest havevaried rather widely and the estimate of 0.5 rad meanlung dose may be too low, or if the dose to bronchial
epithelium (para. 222) were the appropriate value to use,
the risk estimates for miners would be halved;(i)Finally, the values of 5 and 10 taken forRBE (in paragraph 222) for calculation of mortality per
rad of low-LET radiation in miners may be unduly low
at the dose levels involved and an RBE of 20 would
bring these estimates into the range of (20-50) 1o- 6 •However, since these dose levels were associated withhigh incidences of lung cancer, this appears improbable.

2. Conclusions
224. Apart from the findings in Hiroshima and Nagasaki
and in miners, no other sources of information areavailable to confirm the higher or lower value of theinduction rate. In its 1972 report, the Committee noted
the excess of 41.8 deaths from lung cancer among
13 940 patients treated for ankylosing spondylitis(within a mean period of 13 years). A further study ofsuch patients treated with only a single course ofradiotherapy has shown an excess mortality from lungcancer in 0.26 per cent of 14 109 patients followed for amean period of 9.5 years from the time of thetreatment. The excess mortality from lung cancer was
0.46 per cent during the period starting 6 years after thetreatment in 6838 patients (143) who were followed fora further mean period of 11.3 years from this time (36).
No risk estimates can. however. be derived withconfidence. since the mean lung dose will depend
critically upon the position and size of the radiotherapy
fields, and is at present under investigation. The
Committee's 1972 report referred to a tentative estimateof bronchial dose by Dolphin and Marley (39) of 80 rad.
derived by inference from the mean spinal marrow doseof 880 rad. This estimate. if applicable to patients who
had a single course only with estimated mean total
marrow dose of 321 rad, would imply a ri<;k for themean period 6-17 years of 0.0046/80 == 60 10-6 rad- 1 •The mean lung or bronchial dose will, however, depend
critically upon the position and size of the fields used intreatment, and must await a more accurate determination.

225. In view of the unusually short and fatal co4rse oflung cancer, particularly of the anaplastic type(para. 205). the excess incidence of this disease is
Wllikely to differ materially from the mortality. The
incidence rates in Hiroshima and Nagasaki in the period
1959-1970 corresponded to 13 10-6 and 12 10- 6 per
rad kerma respectively. The corresponding rates per unit
absorbed dose of low-LET radiation would be about
20 10- 6 rad- 1 in Nagasaki, and 10, 16 or 25 10- 6 rad- 1
in Hiroshima, according to whether an RBE of 20, 10 or
1 is used for the high-LET component of the absorbed
dose.
226. From the rather discordant sources of information
available, the risk of lung cancer induction by low-LET
radiation would appear to be in the region of
50 10- 6 rad- 1 for exposure at ages greater than about
35. and presumably about half this rate as the averagerisk for exposure of a whole population of all ages.
Further guidance as to this estimate should result fromdetermination of a mean lung dose in the irradiatedspondylitics, since lung cancer incidence is clearly raisedin these patients but not in unirradiated patients withthis disease ( 120).

VI. BONE TUMOURS
227. In its 1972 report. the Committee referred to theabsence of evidence of induction of bone cancer insurvivors at Hiroshima and Nagasaki, where there
appeared to be no excess of diagnoses to I 965 ( 165).
There is still no good basis for estimating the risk ofbone cancer induction by external radiation, except that
results of scalp irradiation for ringworm suggest that it issmall in children. Modan et al. (92) record 2 cancers ofbones of the head (with about 0.5 expected) in 10 902
children. Shore et al. ( 139) record 4 tumours of scalp andjaw, 1 of which was malignant (138), in 2215 irradiatedchildren with none expected. Assuming that the skull
forms about 25 per cent of the total bone mass in children(reference 62, quoting 40 per cent at birth and 15 per centin the adult) and from the dose estimates given for eachsurvey (52, 131, I 59) risks per unit absorbed dose forandbone cancer of 3 (neg.-10) 10- 6 rad- 1
5 (0.2-21) 10- 6 rad- 1 can be derived. In the recent
survey of 14 109 patients irradiated for ankylosing
spondylitis and followed for a mean period of 9.5 years(36), 4 deaths occurred from malignancies arising inheavily irradiated bone areas. Since only I .3 such deaths
were expected, this observation indicates a significant
induction of bone tumours in the adult. No estimate is
yet available for the mean dose to bone from thesetreatments (as distinct from the mean bone marrow doseof 321 rad) so no risk estimate can be derived; and it
could only be very approximate in view of the small
excess number of cancers. Moreover, the distribution of"spontaneous" osteosarcomas in man and probably alsothat of radiation-induced sarcomas, varies in different
bones, and the long bones of the limbs will have been
little exposed in the spondylitis treatments. The excess
mortality, of only 0.02 per cent of patients however.
suggests a low induction rate at least in the spine.
399

228. The Committee also reported on the incidence ofosteosarcomas following intra".enous therapeutic administrations of Peteosthor, a preparation containing
224
Ra. The risk estimates for bone from this source
have been extended in a valuable way by Spiess andMays (146) who have identified the difference in risks
for those who were juveniles (younger than 20) or adults
at the time of treatment. They also show that the risk
appeared to be higher from a given total dose if theadministrations were given over a time span of a year or
more than if given during a short period. i.e. of a few
months only. By June 1970, the average time sincepatients had received their first injections had been
about 22 years for juveniles and 19 for the adults, andsarcomas had developed in 35 of the 208 juveniles forwhom dose and injection span were known, and in 12 of
607 adults (who had in general received lower doses).
229. For juveniles, the estimated risk rises from about
40 10- 6 rad- 1 (mean bone dose) for injections given
during a short span to about 220 10- 6 rad- 1 for longer
time spans. For adults, the risk rises from 30 to
170 10- 6 rad- 1 • In each case the data are consistent
with the risk E (deaths per million per rad) rising fromthe lower to the higher value with an interval
diminishing with a half-period of about 8 months:
For juveniles. E = 40 + 180 (I - e -o.o9m)
For adults,
E = 30 + 140 (1 - e - 0.09m)

cumulative mean bone doses of 700 rad or less. It waspointed out that the number of people studied at doses
4
lower than 700 rad corresponded only to 4.6 10 man
rad and that only 1.8 sarcomas would be expected inthis group. as judged from the incidence at higher doses.
if incidence were linearly proportional to dose.
232. Meanwhile, however, Rowland et al. (127) havenoted that the incidence of osteosarcomas in the groups
studied is better represented by the relationship in which
incidence is proportional to the square of the dose than
to the dose itself, each relationship involving also an
exponential term to correspond with the decreased
incidence at higher doses. The former relationship would
imply an even lower expectation of sarcoma at low
doses. For example, according to the equation given inparagraph 233, the expectation in the group at doses
lower than 700 rad would be only 0.3 sarcomas.
233. The best fit for incidence of sarcomas (/ = fractional incidence) was to the equation

I= 3.9 10-s D2 e- D/4.85 toJ
where D is the total rad dose to bone from exposure to
diagnosis of a tumour. The incidence of carcinomas ( ofparanasal sinuses and mastoid air cells) was adequately
fitted by

I= 3.1 10-s De-D/1.24 io•

where m is the time span in months during which theinjections were given (146).

230. Two points need emphasis with regard to theserisk data. Firstly. since the dose is of alpha radiation (seeAnnex I, paragraph 269), the appropriate risk estimatesfor bone from radiation of low LET might be lower by afactor of 5-20. Secondly, there is now ample evidence
that osteosarcomas arise predominantly from endosteal
cells and that the relevant dose for sarcoma risk
estimation is therefore that to these cells, which lie at a
distance of up to 10 µm from bone surface, rather thanthe mean dose averaged through bone, as used in the risk
estimates quoted. Radium-224 has a short half-life of
3.64 days and its radiation and that of its daughter
products is largely delivered while these radionuclides
are still present on bone surface. This contrasts with thatfrom 22 6 Ra, which becomes distributed throughoutbone during its period of radioactive decay. The dose toendosteal cells from 2 24 Ra is about 9 times that as
averaged throughout bone, whereas that from 226 Ra isabout two thirds the mean bone value (127). The
appropriate risk estimates for sarcoma induction byirradiation of endosteal cells from 2 2 4 Ra in juveniles arethus about 25 10-6 rad- 1 (of alpha radiation) to
endosteal cells for long spans of injection. and20 10-6 rad- 1 in adults. An approximate figure forprolonged bone irradiation from low-LET radiation
would thus probably be in the region of (I -50) 10- 6
rad- 1 •231. In its 1972 report, the Committee discussed thedata available from groups of people with 2 2 6 Ra
burdens and the lack of bone sarcomas at estimated400234. It is of interest that sarcomas have occurredfollowing mean bone doses as low as 90 rad from 2 2 4 Ra,
but only at doses above 1160 rad from 2 2 6 Ra. However,when these limits are expressed as dose to endosteal cells
rather than as mean bone doses, this discrepancy
disappears since sarcomas are seen at endosteal doses
above 810 rad from 2 2 4 Ra and above 760 rad from226
Ra(127).
235. In a review of 261 cases of bone tumour whichwere regarded as having been induced by therapeuticradiation, Yoshizawa et al. (169) note that 50 per centof the induced malignancies were described as
osteosarcomas. 25 per cent as fibrosarcomas and 7 percent as chrondrosarcomas. A further 8.5 per centincluded spindle cell sarcomas and mixed polymorphic
cell sarcomas.

SUMMARY
236. The risk of inducing malignancies of bone by
low-LET radiation thus appears to be low. and in theregion of (2-5) 10- 6 rad- 1 to endosteal cells (table 19)
for absorbed doses of a few hundred to 1500 rad in
locally irradiated bone. Risk estimates for alpharadiation at doses of a few hundred to many thousandrads (table 19) are consistent with a risk of this orderassuming an RBE of about 10. Spiess and Mays foundinduction rates per unit absorbed dose to be about equal
in males and females, and about 30 per cent higher injuveniles than in adults.

TABLE 19. BONE-TUMOUR INCIDENCE RISK ESTIMATES

Reference

Population
studied

Period of study(years since
irradiario11)

92

ChildrenAbout 18

Source ofirradiation

E11dosteal dose (rad)
Mean

Range

Risk i11 period of study
per 1111ir of e11dosteal dose(10" 6 rad"')Radiotherapy
to scalp

about 1ooa

to 1 500

3 (neg.-10)

low LET

about 100a

to 8005 (0.2-21)

low LET

10 OOO1 850± 7 500± l 500

25
20}rugh LET

about 2 OOO

to 30 OOO

9 at 10 radb}high LET
850 at 100 rad

139

Children

20

Radiotherapy
to scalp

146

Juveniles
and adults

About 23'"Ra

41a, 45a

AdultsAbout 35

"

6

Ra

60C

high LETa Assuming 2S per cent of bone to be irradiated at a mean dose of 400 rad.

bBased on quadratic formula (para. 233).
CBased on linear formula (para. 231).

Death rates

VII. OTHER CANCERS
237. While some very approximate indication can begiven for the risk of cancer induction in certain otherorgans by radiation, the total carcinogenic risk cannot
yet be derived by summing the individual contributions
to this risk from every organ. A clearer guide to the sizeof the total risk is obtained by estimating the total
mortality from all forms of malignant disease following
effectively whole-body radiation at known dose levels,for example in the exposed populations of Hiroshima
and Nagasaki, and comparing this with the expected
number of such cancers. With reservations owing to thepartial-body nature of exposure, some estimate can also
be derived from patients treated for ankylosing
spondylitis. In each case, correction has to be applied toallow for tumours that may become diagnosable after
the available period of follow-up, although in somestudies, for example of the effects of foetal irradiation,
the full number of tumours appears to have beenreached.
238. In the case of malignancies resulting fromoccupational exposure of radiologists, this method
cannot be adopted because the exposures are notknown. Here it is possible, however, to record the total
excess of deaths from malignant disease other than
leukaemia, and to compare this total with the excess due
to leukaemia. The ratio is of value, firstly because long
periods of follow-up have occurred since the exposuresthat are likely to have been relevant, and secondly,
because the radiation induction of leukaemia can be
estimated from other sources, so that that for othermalignant diseases can be derived.
239. From the JNIH-ABCC Life Span Study, themortality rates are shown in figure III for successive
periods, both for leukaemia and for all othermalignancies. There is a strong suggestion that the excess
mortality from leukaemia is now ceasing. and a possible
indication that the excess rate from other malignant
disease may have reached its peak. This would, if so, be
consistent with the indications noted above that themedian latency for diagnosis of radiation-induced cancer
may be about 25 years.

10

8

r-

'II
I
I
I

6

.

I

I

I
I

I
I

I

I

I

I

I
I

I
I
I

_J

I

I

I
I

L.

All otherr-t.,malignancies :

I

:
I

2

0 '----1---l'--L.-.lL---..l......-....:t.a=..--L--1945
1955
1965
1975

Figure lll. Variation of death rates from leukaemia and from allother malignancies with time since exposure
Rates, deaths per million man rad during successive periods of
JNIH-ABCC survey
Leukaemia: open circles and hatched columns
All other malignancies: filled circles and dashed columns(Ranges indicate 90% confidence limits)

240. The further increases in the period (of 21 months)
between the 1950-1972 and the 1950-1974 estimates(see table below) are consistent with those indications,
neither the increase in leukaemia nor indeed that inother malignancies being much (or significantly) greaterthan that expected on the basis of the 0-9 rad group. (Ifthis expectation is estimated simply in proportion toperson-years at risk, but without any correction for age
and sex distribution, the 1972-1974 increases forleukaemia and other malignancies became 3.7 and 145.3,
respectively. The corresponding excesses of the ~10 radgroup over the 0-9 rad group are then 6 - 3.7 = 2.3 and
156 - 145.3 = 10.7).
401Hiroshima and Nagasaki
Males and females, all ages
Dose group (rad):

0-9

">10

1950-1972

1950-1974

1972-1974

1950-1974

1950-1974

1972-1974

Person-years ( 10 3 )

1 092

I 166

74

476

522

46

Deaths from:
Leukaemia
Other malignancies

48
2 232

54
2467

6
235

84
1 075

90
1 075

6
156

Ratio

241. Figure IV shows the ratio of excess deaths fromother malignancies to those from leukaemia. The upper
curve. obtained by comparison with Japanese National
Mortality Statistics, may be the more valid, in the sensethat some deaths attributable to malignant disease may
have occurred even in the group exposed at only 0-9 rad.
For example, the mortality ratio for leukaemia was 1.5
even in this group. On the other hand. the 0-9 rad groupis much more comparable with those exposed in themethods of study and ascertainment, as well as in placeof residence.

All other malignancies
3

All leukaemias

2242. It is probable that this ratio of mortality rates may
differ for those exposed in different dose groups, since
the form of the dose-effect relationship is unlikely to be
similar for all forms of malignancy. The precision withwhich the excess number of deaths is determined inlower dosage groups. particularly for solid cancers,
however, is insufficient for this estimation to be madeadequately.
0 ,.___ _ _ _.........___L.--IC_ _~ ' - - - - - - - -

1945

1975

1965

1955

Figure IV. Ratio of numbers of deaths from all othermalignancies other than leukaemia to those from leukaemia
Ratios are of all excess deaths during the period from 1950 until
dates indicatedUpper curve (filled circles): excess deaths as compared withJapanese National Statistics
Lower curve (open circles), excess deaths as compared withfrequencies observed in persons exposed at 0-9 rad

243. In a further report of the Life Span Study
recording mortality data from October 1950 to September 1974 (14), the excess mortality rates are estimatedfrom the slope of the linear regression of deaths perperson-year on estimated dose (T65 kerma). On thisbasis, the relationship between the excess of solidcancers to that of leukaemia is similar to that derived(fig. IV and table 20) by comparison with the rates
observed in th 0-9 rad group, as follows:

Period surveyed

1950-1954

1954-1958

1958-1962

1962-1966

1966-1970

1970-1974

4.06
1.61

2.28
-0.38

1.78
2.35

0.88
2.99

1.13
3.32

0.49
4.19

Cumulative total, October 1950
to September of final year of
period:Leukaemia
Other malignancies

4.06
1.61

6.34
1.23

8.12
3.58

9.00
6.57

10.13
9.89

10.62
14.08

Ratio of cumulative totals.
other malignancies/leukaemia

0.40

0.19

0.44

0.73

0.98

1.33

6

1

Excess rate (10- yLeukaemia
Other malignancies402

rad- 1):TABLE 20. EXCESS MORTALITY FROM LEUKAEMIA AND FROM ALL OTHER CANCERS IN HIROSHIMA AND NAGASAKI BY PERIOD

Dose groups 10->200 rad T65
Males and females, all ages
ALL OTHER CANCERS

LEUKAEMIA

Duration(years)PeriodMan radyear(x 10 6 )Ob·servedEx·
pectedExces.t rate
Excess(lo-• y·• rad· 1
1

Observed

Expected

ExcessExcess raterur• y·• rad·')Ratio
other cancers/
leukaemia
at end of period- - - - - - - - - - - - - - - - - - - Compared with 0-9 rad g r o u p - - - - - - - - - - - - - - - - - -1950-1954
1955-1959
1960-1964
1965-19691970-1972

4.25
5
5
5
3

8.24
9.26
8.77
8.25
4.68

24
27
16
4
3

4.5
7.0
2.2
4.8
2.7

19.5 (J 1.8-29.6)
20.0 (11.6-30.7)
13.8 (7 .6-22.3)
9.2 (3.3-17.5)
0.3 (neg.-5.6)

2.37 (1.43-3.60)
2.16 (1.25-3.31)
1.57 (0.86-2.54
1.12 (0.40-2.13)
0.06 (neg.-1.20)

as above

1.7
2.8
3.3
3.7
2.3

22.3 (14.8-32.1)
24.3 (16.3-34.4)
12.7 (6.7-21.0)
10.3 (4.8-18.2)
0. 7 (neg.-5.5)

2.71 (1.80-3.90)
2.62 (1.76-3.71)
1.45 (0. 76-2.39)
1.25 (0.58-2.21)
0.15 (neg.-1.18)

146
193
258
301
177

126.8
209.0
223.0
268.1
162.0

19.2 (neg.-44.3)-16 (neg.-13.6)
35.0 (4.5-67. 7)
32.9 (neg.-68.1)
15.0 (neg.-42.4)

2.33 (neg.-5.36)-1.73 (neg.-1.47)
3.99 (0.51-7.71)
3.99 (neg.-8.26)
3.21 (neg.-9.06)

0.99 (ncg.-2.22)
U.08 (neg.-1.00)
0. 72 (neg.-1.61)
1.12 (0.14-2.09)
1.37 (0.30-2.44)

17.6 (neg.-39.1)
9.0 (ncg.-33.5)
42.8 (17.0-70.8)
62.6 (34.7-92. 7)
24.0 (2.7-47.5)

2.14 (ncg.-4.75)
0.97 (ncg.-3.62)
4.88 ( 1.94-8.07)
7.59 (4.21-11.24)
5.13 (0.58-10.15)

0.79 (neg.-1.73)
0.57 (neg.·l .24)
1.17 (0.43-1.90)
1.90 (1.09-2.71)
2.22 (1.31-3.13)

Compared with Japa11ese Natio11a/ Statistics

1950-1954
1955-1959
1960-1964
1965-19691970-1972

as ahove

as above

Source: Reference 97.
Note: The 90% confidence limits are indicated in parentheses •

.i,..

0

w

as above

128.4
184.0
215.2
238.4
153.0

244. It has been pointed out (para. 63) that thefrequency with which leukaemia is induced by radiation
varies with age at the time of exposure, with a moderate
rate of induction at age 0-9 years, a lower rate for ages
10-19 and higher rates at greater ages. lt is important tonote that the induction of other malignancies as a wholevaries in a similar manner with age, and that the relative
increase at older ages is greater than for leukaemia. The

current Life Span Study data, therefore, show that theratio of deaths from other malignancies to those fromleukaemia, as occurring in the total period from 5 to
29 years from exposure, differs for different ages at
exposure (see table below). The ratio discussed inparagraph 242 and referred to in the following
paragraphs will therefore depend on the age structure of
the population exposed.

Hiroshima and Nagasaki, 1950-1974
Male and female

Age at exposure (years)().9

Mortality per unit kerma{lo-• rad- 1 ):Leukaemia
Other malignancies
Ratio, other malignancies/
leukaemia

J(J.192().34

35-49

.. so

All

23
76
54
44
(66-85) (17-29) (38-53) (34-53)
33
20
59
74
(25-42) (7-34) (30-68) {16-132)

82
46(66-99)(42-50)153
53(12-295) (35-71)

0.4

1.9

0.9

245. The findings of Doll and Smith (36) on theirradiation of ankylosing spondylitis patients, show asimilar relationship between the induction rate ofcancers, and probably also of leukaemia, and the age at
exposure. Their data refer only to cancers of certain
organs, essentially those in the heavily irradiated parts ofthe body: relatively few treatments were given at ages

1.1

1.7

1.2

below about 20. Their values for excess risk at older
ages, however. show a clear increasing trend with age forcancers of these heavily irradiated sites (xf trend= IS.I)
and for leukaemia (x~ trend = 6.7). The excess rates forcancers at >6 years after treatment and for leukaemia at> 2 years are as follows:
Age at treatment (years)

<25

25-34

35-44

45.54

;,,55

All

Excess rate (1 o- 5 y- '):Cancers
Leukaemia

14
4

34
13

127
19

182
43

339
52

91
90

Ratio, cancers/
leukaemia

4

3

7

4

6

4.7

246. If it is assumed that the median latency for deaths
from malignant disease other than leukaemia is 25 years,
and that the mortality from leukaemia has ceased by thistime, then the final expected ratio of excess deaths fromcancers to those from leukaemia should finally reach
twice the value reached by 25 years. or about 3 on thebasis of the Japanese data (fig. IV).
247. Titis estimate of the ratio can be compared withthe value 4.3 derivable from the mortality studies on
American radiologists, among whom an estimated excess
of 11.3 deaths from leukaemia occurred during theperiod 1935-1958, as compared with an excess of
48.2 deaths from all other cancers (134). For ankylosing
spondylitis. it is difficult to estimate the proportion oforgans sensitive to radiation carcinogenesis which lay
within the radiation fields, as compared with theproportion of marrow in those fields. From thepublication of Court Brown and Doll in 1965 (29),
however. the ratios of excess deaths from all othermalignancies to
those
from
leukaemia were
3.1 ± I.I (S.E.) for patients completely followed up atthat time and 5.5 ± 1.4 for those with incomplete
follow-up. In the further report on patients who hadreceived only one course of treatment (36) and forwhom the relevant time of exposure is therefore
unequivocal, the mean ratio rises to a value of 3.0 by a404

mean time of 13 years and to 3.7 at 25 years from thetime of irradiation. The ratio based on numbers ofdeaths, however, is subject to bias owing to thedecreasing number of patient-years at risk at the longer
intervals after exposure, when leukaemia deaths haveceased to occur but when deaths from induced cancer
continue. If allowance is made for this (by using theratio of cumulant rates rather than of cumulant numbersof deaths). the ratio has a value of 3.6 at 13 years and
5.3 at 25 years. Following pelvic x irradiation for
metropathia haemorrhagica, Smith and Doll (142) havefound a ratio of excess deaths from cancers to thosefrom leukaemia of 3.9 (to a mean of 19 years fromsingle courses of irradiation). Here again, however, theratio will depend on the proportion of marrow and oforgans sensitive to radiation carcinogenesis within thepelvis. In the light of these values, however. andparticularly of the ratios derived from effectively
whole-body irradiation. it appears probable that theultimate total number of deaths from all malignant
disease will be 4-6 times that from leukaemia alone.
248. This estimate might be falsified if, in populations
under study, deaths started to occur from any group of
tumours for which the latency. from exposure to death,
was unusually long. As noted already, it is difficult toestablish mean latencies for any type of solid tumour,because of the very long periods of follow-up required
for full ascertainment. There is some suggestion thattumours of skin, and perhaps also of pharynx andlarynx, may have long latencies, but tl\is is uncertain. It
is clear. however, that some malignant tumours have
exceptionally long mean survival times from diagnosis todeath, and this applies particularly to cancers of the
thyroid of the type induced by radiation. and probably
also to tumours of breast. The high induction rate forsuch cancers by radiation might possibly, therefore,cause a bimodal distribution with time of deaths fromsolid tumours, although the probable low fatality ratefrom these thyroid tumours with adequate treatment
makes this unlikely. For the breast, the data of Wanebo
et al. (158) suggest an induction rate in the Adult HealthStudy population examined between 1958 and 1966
which is several times the mortality recorded in the Life
Span Study by 1972. This ratio, however, could well beconsistent with the fact that many breast tumours may
be fully removed at operation. -There is thus no a priori
reason to expect any large number of deaths from aseparate group of malignant diseases to start to occur,
although the proportion of deaths that are due to breast
cancer and perhaps to thyroid cancer may well rise.

249. In any case, the median latency for fatal induced
cancers in the populations studied at Hiroshima andNagasaki, which had an initial mean age of about 30 at
the time of exposure, could not greatly exceed 25 years,
since the mean expectation of life would in itself start to
exclude a much longer median latency unless the
distribution of latencies was very skewed positively; andit is of interest that that of leukaemia appears to be
negatively skewed.
250. The distribution of malignancies fatal within
27.5 years of exposure at Hiroshima and Nagasaki isshown in table 21. As compared with Japanese National
Statistics, the individual fatal malignancies shown on thisbasis to be significantly increased in frequency were
leukaemia, lung cancer and breast cancer. There was aprobable increase in cancer of digestive organs otherthan the stomach and clear evidence of increase ofcancers not separately listed. Of the total increase indeaths from solid tumours, lung cancers accounted for28 per cent, those of the breast for 11 per cent andthose of digestive organs other than the stomach forabout 18 per cent. Rather over half of all fatal induced
solid tumours therefore probably arose from thesetissues.

TABLE 21. EXCESS MORTALITY FROM ALL CAUSES IN HIROSHThU AND NAGASAKI, 1950-1972
Males and females, all ages

(Values for all exposed at ;;. I Orad; rates are per unit kerma)Compared with 0-9 rad group

Compared with Japanese National Statistics

Cause of death

servedEx·
pectedExcessExcess rate(10" 6 rad" 1)Ex·pectedExcess(JO"' rad- 1)

Leukaemia
All other malignant neoplasms

84
1 075

21.0
987.6

63 (48-80)
87 (24-153)

36 (27-46)
50 (14-87)

13.7
918.8

70 (56-87)
156 (103-212)

40 (32-50)
89 (59-121)

417
261
100
29
37
86
145
Benign or unspecified neoplasms
53
All diseases except neoplasms
3 970

411.8
255.3
76.2
26.0
24.0
77.5
117.0
52.6
3 947.7

5 (-34-47)
3 (-20-28)
3 (-13-20)
6 (-26-39)
13 (3-24)
24 (5-44)
2 (-5-10)
3 (-7-15)
7 (1-14)13 (2-26)
4 (-4-14)
8 (-9-28)
16 (3-30)
28 (6-53)
0.4 (-13-16)
0.2 (-6-8)
22 (-101-148) 13 (-60-88)

Ob-

Cancers of:
StomachOther digestive organs
Trachea, bronchus and Jung
Other respiratory organs
BreastCervLx and uterus
Other malignant neoplasms

Excess rate

-3 (-36-33)-2 (-28-25)
28 (2-56)
16 (1-32)
44 (28-62)
25 (16-36)
12 (4-22)
7 (2-13)
18 (9-30)
10 (5-17)
7 (-8-24)
4 (-5-14)
50 (31-72)
29 (18-41)
10 (-1-24)
6 (-1-14)42.9-622 c-125:_511) -354(-413--294)
4 592
419.6
232.8
56.5
17.2
19.0
79.1
94.6

Source: Reference 97.
Note: The 90% confidence limits are indicated in parentheses.

251. Mortality rates for cancer of the stomach.
oesophagus, urinary organs, and lymphatic and haematopoietic tissues are also significantly increased in exposed
members of the Life Span Study during the period
1950-1974 as discussed below. Table 22 shows theestimated mortalities per unit kerma in this period, andindicates also the total rates for all malignancies.
Although individual estimates are imprecise, it appears
that the types of malignancies listed may account forover 90 per cent of all deaths from malignant disease
that have occurred, and suggests that fatal malignancies
of all other organs, for which increased rates are not yet
detectable, may together contribute only a small
proportion of all fatal radiation-induced malignancies.
This would be consistent with the low induction rate ofbone cancers, and the low fatality rate of thyroid

cancers as discussed above. and with the probably low
rates for other organs. It must be recognised. however.
that some bias towards high estimates for individualtypes of cancer may be introduced. since significant
induction might be suspected if random high, but not
random low, incidences occurred.

252. For a number of these other organs or tissues.
however. radiation has been shown to induce malignant
tumours after moderate doses of a few hundred rads.
While no convincing estimate can be made of the
carcinogenic risk for most of them. it is often possible toshow that the risk is unlikely to be high. The position
can be reviewed briefly with regard to several suchorgans or tissues.
405

TABLE 22. EXCESS MORTALITY FROM MALIGNANCIES IN HIROSHIMA AND NAGASAKI,
1950-1974
Males and females, all ages

(Excess rate per unit kenna, 1

o- rad·')6

Malignancy

Hiroshima

Nagasaki

Both cities

Leukaemia

56(51-61)

35 (29-41)

46 (42-50}

13 (5-21)
19 (3-36)
9 (4-14)4 (neg.-8)
9 (0-18}
4 (neg.-8)
5 (1-8)10 (2-18)
I O(neg.-24)
53 (neg.-11)
10 (neg.-25)-2 (neg.-3)
0.5 (neg.-4)
3 (neg.-13}
2 (neg.-6)
4 (0-9)6 (neg.-17)-9 (neg.-6}
0

8 (3-14}15 (4-27)
5 (1-8)2 (neg.-5}
6 (neg.-13)
3 (0.5-6)
4 (1-7)9 (2-15)3 (neg.-12)
3

7i (51-102)

21 (neg.-4 7)

53 (35-71)

Other (solid) malignancies:
Lung
StomachOesophagus
Large bowel
Other digestive organs
Bladder and urinary organs
Lymphatic and haernatopoietic organs
Breast (females only}
Cervix and uterus (females only)
Residue (by difference)
Total solid malignancies

Source: Life Span Study 1950-1974 (14).
Nore: The 90% confidence limits are indicated in parentheses.

A. BRAIN
253. Although tumours of the brain do not metastasize
and may not therefore be classified as "malignant", they
commonly constitute a hazard to life because of theirsituation in a way- that non-malignant tumours of otherorgans ordinarily do not. For this reason, estimates inthis section (paras. 253-256) are of total brain tumour
induction, where this information is available.
254. Modan et al. (92) record the development of eight
brain tumours (six definite and two probable) during
their follow-up from 12 to 23 years of 10 902 children
irradiated for tinea capitis. Irradiation was by 5 fields tothe scalp, with an estimated dose to brain of
120-140 rad at the surface, and 95-120 at a depth of
2.5 cm. On the basis of two control studies, 1.5 certainor probable tumours would have been expected. This
incidence for a mean dose of, say, 120 rad would
correspond to an induction rate of 5 (2-10) 10- 6 rad -i •255. In its 1972 report, the Committee recorded thefollow-up study by Albert et al. (I) of 2043 children
treated for tinea capitis by radiation epilation of thescalp and in whom the occurrence of malignancies wascompared with that in 1413 children who had had thesame infection untreated by radiation. These authors(139) now record the development of 6 intracranialtumours in 2215 irradiated children with none in 1395
controls. The crude incidence rate is quoted as 2.8 10-3 •The estimated brain dose varied from 70 to 175 rad witha mean of 140 rad. so that this rate per unit absorbed
dose corresponds to 20 (9-39) 10- 6 rad - t for a meanfollow-up of 20.5 years. A long latent period may
however elapse before diagnosis of radiation-induced
intracranial tumours and a mean value of about 27 years
was noted by Munk et al. (98). Indeed, Shore et al.
estimate from their data by actuarial methods that therisk of intracranial tumour development to 29 years
would be about 2.5 times that already observed in theirseries.
256. The sensitivity of the foetal brain may, however.
be high. since MacMahon (83) found tumours of thenervous system to constitute 24 per cent of ''all
malignancies·· apparently induced by intra-uterine
406

irradiation. If, as the Committee noted in its 1972
report, the total induction of malignancies in the foetus
corresponds to a rate of 200 10-6 rad- 1 , this would
suggest a high risk to the foetal brain. However, since
only 19 cases were observed as compared with 14.3
expected, the estimate, of 50 (neg.-145) 10-6 rad- 1 has
wide confidence limits and is not inconsistent with thatfor the brain during childhood. Moreover. it has been
noted that many pelvirnetries are carried out when the
foetus is in a breech presentation, when the absorbed
dose in the foetal brain is likely (106) to be considerably
higher than the mean foetal dose.

B. SALIVARY GLANDS
257. Modan et al. (92) record 4 malignant tumours ofsalivary (parotid) glands in their follow-up of
10 902 children irradiated for tinea capitis, with none ineither of the control series. The dose to the salivary
glands was not estimated. The mean thyroid dose of
6.5 rad. however. is similar to that of 6 rad estimated in
the New York study of tinea capitis irradiation inchildren, for whom a parotid dose of 39 rad has now
been estimated by Harley et al. (52). If this parotid doseis taken as applying also in Modan's series, the induction
rate for salivary cancers would be 9 (3-22) 10-6 rad -i .
258. Four salivary tumours were observed in the New
York series (139) of which one was malignant (138),
none being seen in the control series. The authors quotea crude rate of 1.8 10-3 for all such tumours. which
would imply risk rates for salivary cancers of
12 (I-35) 10-6 rad- 1 to 20 years.
259. Following neck irradiation in infancy or childhood. Saenger et al. (I 28) reported an excess of 2
salivary cancers in association with 11 thyroid cancers.
Hempelmann (58) reports 4 salivary tumours, all now
regarded as benign, in association with 24 thyroid
cancers. If the salivary glands were as frequently exposedas the thyroid in the radiation fields used for neckirradiations in childhood, these observations would
suggest an induction rate for salivary cancers of less than
one tenth that for the thyroid, or in the range(5-10) 10- 6 rad- 1 •260. Belsky (I 6) reports a significant excess of salivary
cancers in A-bomb survivors in Hiroshima and Nagasaki
exposed at over 300 rad kerma, with two cases observed
as compared with 0.12 expected. Since 1340 persons(16 172 person years) were exposed in this group, thisexcess rate is of 1.4 10- 3 : or, if the mean kerma in thegroup was between 400 and 500 rad, about 3 10- 6
rad- 1 over a period of 12 years (1957-1970). Thisestimate would have confidence limits (1-8) 10- 6 rad- 1 •No excess was observed (3 observed, 3.6 expected) in
those exposed at 1-299 rad, but absence of effect in thisgroup is not inconsistent with the significant excess inthe higher dose group. The rate in the latter would be
about the same if estimated as per rad weighted
absorbed dose ( with W = 7 at this dose level) .. orsomewhat higher (by about 40 per cent) per rad
unweighted absorbed dose.
261. T akeichi et al. (152a) now report a total of 17
cancers of salivary glands that have been diagnosed in
hospitals in Hiroshima during a 19-year period in
A-bomb survivors exposed within 5000 m of the groundzero. The number expected was I. 7, as judged by theestimated numbers of survivors and the rate ( 1.2 10:. 6
y- 1 ) in those who were over 5000 m distant. The excess
rate in those exposed at less than 1500 m was
21 (9-41) 10-6 y- 1 while for those exposed at between
1500 and 5000 m, it was 7 (4-14) 10- 6 y- 1 • Risk rates
cannot be derived, however. since mean doses are notknown for the total population of survivors. For
members of the Life Span Study, the total air dose at
1500 m in Hiroshima was about 32 rad (67), and themean dose over all shorter distances would be about
135 rad. If these dose levels apply also for all survivors,
it would suggest a low induction rate of a few cases per
million per rad in 19 years, but shielding factors become
important at short ranges and are not known forsurvivors as a whole.
262. All these estimates are thus somewhat lower thanthe values derived in paragraphs 257-259, perhaps
because the record is of cases following exposure at allages, and diagnosed only between 13 and 25 years fromexposure. All estimates have wide confidence limits,
however, and would be consistent with a risk rate in theregion 10 10- 6 rad -t to 20 years following exposure inchildhood. with perhaps twice this value after prolonged
follow-up. and with no evidence of any greater rate after
exposure in adult life.
263. No evidence is available as to the mortality fromany radiation-induced salivary tumours. The IS-year
survival of naturally occurring cancers of the salivary
glands is, however, high (70 per cent, see paragraph 18
and reference 23). The average risk rate per unit
absorbed dose for fatal salivary cancers may thus beabout 5 10-6 rad- 1 •fewer in numbers than are osteosarcomas in patients
following incorporation of 2 2 6 Ra with only about two
fifths the frequency of the sarcomas ( 127), so that thecontribution to fatal malignancies from this source
would. in the case of whole body radiation. be evensmaller than that from bone cancers, assuming equalmortality from each type of tumour. There is someindication that the number of these carcinomas is now
increasing more than is that of the sarcomas,
corresponding to a longer latency until these tumours
become detectable. The mucosa is closely applied tobone, so is likely to receive a dose at least equal to thatdelivered to endosteal cells, or larger if accumulatedradon makes any substantial contribution.
265. The relationship between incidence and meanbone dose from 2 2 6 Ra, quoted in paragraph 233. would
imply a risk rate of (2-5) 10-6 ra<f 1 if an RBE of 10 or
20 was taken for the alpha radiation from radium and if
no added dose was derived from radon retention. If
additional irradiation resulted from radon accumulation,
the risk rate would of course be lower. While it seems
likely. therefore, that these areas of mucosa may have arisk comparable with or lower than that from the wholeendosteum, no inference can be drawn as to the relative
sensitivity of two tissues per unit area or per unit massof cells.

D. DIGESTIVE ORGANS
266. The mortality statistics of the Life Span Study to1972 (97) showed a possibly significant excess ofcancers of digestive organs other than the stomach, but
did not indicate any high incidence for the stomach
itself. Thus by the end of 1972. 261 deaths had been
attributed to cancers of digestive organs other than thestomach, as compared with 232.8 expected on the basisof Japanese National Statistics. This excess of 28.2 has
90% confidence limits of 2.2 and 56.4.
267. Nakamura has now identified a significant increasein cancer of the stomach in irradiated populations in
Hiroshima (101). The Life Span Study data (14) for
both cities (for the 24 years to September 1974)
confirm an increased mortality from cancers of thedigestive organs, with significant increases for oesophagus as well as stomach in Hiroshima, possible
increases for large intestine, and an increase for thegroup of other digestive organs (see table 22).
268. Tumor Registry data for the period of 1959-1970
suggest a significantly (P..;; 0.02) increased incidence inHiroshima of cancers of the stomach. oesophagus. liverand large intestine, and perhaps in Nagasaki of cancers of
the pancreas (P = 0.06) and large intestine (P = 0.085):
Hiroshima

Nagasaki(Incidence rates per unit kerma, 10- 6 rad" 1)

C. MUCOSA OF CRANIAL SINUSES
264. As already stated, there is clear evidence of the
carcinogenic effect of radiation on the mucosa of the
mastoid and other air sinuses, but risk estimates cannot
be derived since no determinations have been made ofradon accumulation in these sinuses. It seems clear,
however, that the risk must be small. Such cancers are

StomachOesophagus
Liver
Large intestine
Pancreas18 (3-34)
6 (1-10)4 (2-7)6 (1-11)
0 (-4-5)

10 (-5-26)

4(-2-10)
3 (-1-6)
4 (0-8)It must be emphasized, however, that incidence rates, asbased on procedures of tumour registration, are liable tovarious possibilities of bias. These are not reflected in407

the confidence limits or probabilities of significancegiven here, which are determined only by the random
errors involved in estimating these rates (by contingency
table methods (66)).

showed an excess of deaths (occurring at more than 6
years after treatment) from cancer of several organs of
the digestive tract which were heavily irradiated,
although at unascertained dose. For the groups ofpatients completely followed up to 1 January 1960. orincompletely followed up to 1 January 1963. values
were as follows:

269. The studies of Court Brown and Doll (29) on
patients treated for ankylosing spondylitis by irradiation
Complete follow-up( 141 796 person years)

Cancers of:Pharynx
Oesophagus
StomachPancreas

Incomplete follow-up(165 631 person years)

Observed

Expeered

ExcessObserved

Expeered

Excess

4
3
28
9

0.70
2.25
16.0
3.8

3.3 (0.7-8.5)
0.75 (neg.-5.6)
12.0 (3.9-22.4)
5.2 (0.9-11.9)

5
3
38
12

1.05
3.37
23.6
5.7

3.95 (0.9-9.5)-0.6 (neg.-4.3)
14.4 (4.9-25.1)
6.3 ( 1.2-13. 7)

270. In a follow-up of the patients who had only one
course of radiotherapy for ankylosing spondylitis, Dolland Smith (36) observed numbers of deaths fromstomach, pancreas, large intestine and probably oesophagus, which were significantly increased as showneither in the total series (of 14 109 patients with meanfollow-up of 9.5 years) or in deaths at 6 or more years
after treatment (6838 patients with a further follow-up
to a mean time of 17 .3 years from exposure as follows:
Deaths after 6 years

All deaths

Cancers of:
StomachOesophagus
Pancreas
Large intestine

Observed

Expected

ExcessObserved

Expected

Excess

45
10
18
28

34.2
5.6
9.5
17.3

10.8 (0.4-24)
4.4 (-0.2-11)
8.5 (1.2-17)
10.7 (2.6-21)

36
9
12
18

24.6
4.3
7.5
13.1

11.4 (2.1-23)
4.7 (-0.4-11)
4.5 (-0.6-12)
4.9 (-1.5-13.6)

271. In the earlier report, a significantly increased
nuinber of deaths from cancers of the large intestine wasalso reported (25 observed and 14.8 expected) but theauthors hesitated to ascribe this excess to radiation inview of the known increase of cancer of the colon inulcerative colitis, and the association of ulcerative colitis
with ankylosing spondylitis. Similarly, it was thoughtthat the increased rate of stomach cancer might possibly
be attributable to drugs taken in the relief of pain inankylosing spondylitis.
272. Now, however. a series of patients with ankylosing
spondylitis, but not treated by radiotherapy, has beenfound to have no increased cancer incidence ascompared with a normal population {120). During amean observation period of 7 .9 years on 1021 patients.
the total number of deaths from malignant disease was18, compared with 19.1 expected. Of these, 3 were fromstomach cancer (2.6 expected) and none from cancer oflarge intestine (1.4 expected; one colon cancer occurred
during a further 3-year period which added 8 per cent to
the person years surveyed). It does appear likely
therefore that the increases in cancer rate for stomach
and large intestine. as well as for oesophagus andpancreas, may be attributable to radiation, and that risk
estimates may be obtainable from this source when theabsorbed doses to these organs from the courses oftreatment have been derived.
273. Brinkley and Haybittle (18) noted an increase of
fatal cancer of colon and rectum (7 observed, 1.5
expected) in 227 patients within an average period of 16
408

years after pelvic irradiation for benign disorders. Abouthalf of the large intestine is likely to have been in theirradiation field and to have received a mean dose in theorder of 800 R (54). Certainly 3, probably all 4, of thecancers of the large intestine arose from the area
included within the field. No cancers were observed ashaving occurred in the small intestine, of which about
half is likely to have been in the field. The observations
suggest a substantial induction rate in large intestine andrectum. perhaps of the order of 25 10-6 rad- 1 from half
the intestine, but these indications are necessarily very
approximate.
274. Smith and Doll {142) observed an increased
number of deaths from cancer of the intestine in 2067
patients followed for a mean period of 19 years after
treatment for metropathia haemorrhagica by pelvic
x irradiation. From cancer of the intestines, 24 deaths
occurred at 5 years or more after irradiation, with 13.86
expected; and for cancer of the rectum. 8, with 5.23
expected. It is of interest that of the intestinal cancers, 3were of small intestine (143). With 0.4 expected, 3 ormore would only occur by chance with P = 0.008. For
cancers of the large intestine and rectum. the excess of
29 - 18.69 = 10.31 (2.1-20.8) would only occur bychance with P = 0.028.
275. While these data indicate the likelihood of cancer
induction in both small and large intestine, no reliablerisk estimate can be derived because of the small
numbers of cases and the uncertainty as to the
proportion of small or large intestine lying within thepelvis and exposed in the primary beam. If it is assuJUed,however. that only about one third of each intestine(small or large), but all the rectum, was directly exposed
at a mean dose of 400 rad, approximate risk estimateswould be: small intestine 10 (2-25) 10-6 rad- 1 ; large
intestine 25 (2-60) 10-6 rad- 1 ; rectum 3 (0-10) 10-6
ra d

-1

.

276. In summary. therefore, it is clear that radiationinduces cancers of the gastro-intestinal tract anddigestive organs, although the total risk rate for all thesetissues is not high, the estimate for Hiroshima andNagasakimortality
1950-1974
being
about
25 (10-45) 10-6 rad- 1 kerma. Estimates for individual
sections of the gut are in the region of 5 10-6 rad- 1 foroesophagus, small intestine and perhaps rectum. The rate
for large intestine is similar on Japanese data, but issomewhat higher as inferred from pelvic irradiation(paras. 273-275). but these estimates depend uponassumptions as to the proportion of bowel present in the
primary beam. A value of (5-10) 10- 6 rad- 1 would
however be consistent with these data also. For thestomach a rate of(l0-20) 10-6 rad- 1 is suggested by thecurrent Japanese information, but a further estimate for
low-LET radiation will be available as soon as dosimetricestimates are obtained for the stomach irradiation during
the treatment of anlcylosing spondylitis. This applies also
to the pancreas. for which a significant excess of cancers
is detectable following this therapy. Estimates for theliver are discussed below (paras. 283-285).

E. PELVIC ORGANS
277. Palmer et al. (107) also noticed an excess of rectal
cancers following the irradiation of the pelvis by radiumor x rays or both in 651 patients with uterine fibroids
and 80 with other benign pelvic disorders. Seven rectal
cancers occurred within a mean follow-up period of 16.1
years as compared with 2.1 expected. No risk estimate
can be derived, both because of uncertainty as to dosage
and because ascertainment was by letters sent topreviously irradiated patients to which replies werereceived in rather less than 50 per cent of cases. Local
doses were quoted as of 2700 R, and 650-700 R. at 2
and 5 cm from the radium source in the cervix. and of"the equivalent of 1600 to 1800 mg.he" if x rays alone
were used. The cancers observed and expected were:

Fundus uteri
CervixOvary
RectumBladder
VaginaVulva

Observed

Expected

29
11
8
7

4.9
6.5
2.6
2.1
0.8
0.2
0.3

3
2

I

Mean late.'lcy(years)

9.7
8.5
10.1
10.7
14.0
12.7
14.5

278. The excess number for the rectum is thus about
equal to those for the cervix and ovary, although thedoses will not necessarily have been the same. This
excess is about one fifth of that for cancer of thefundus uteri, in which malignancies occurred in 4 percent of patients compared with 0.7 per cent expected,

after doses which presumably were about 700 rad. The
estimated excess incidence of all pelvic cancers was 6 per
cent, whereas that following irradiation for cervicalcancer in 471 patients, at dose levels higher by factors of
2 or 3, was only 0.35 per cent. The latter estimate isimprecise, as only 13 cancers were found as comparedwith 11.4 expected, but does suggest that the inductionof these tumours may be lower at high doses.
279. Palmer et al. (107) quote five surveys including a
total of 3968 patients in whom 27 uterine. I O cervicaland 8 ovarian cancers were observed following pelvic
irradiation, but they note that mean periods offollow-up were commonly less than 10 years and no data
are given of U1e local dosimetry or control series.
280. Following pelvic irradiation for metropathia
haemorrhagica, Smith and Doll (142) observed thefollowing numbers of deaths from pelvic malignancies,
occurring at 5 or more years after irradiation:
Site!CD Code

Observed

Expected

UterusOvary
Bladder
Other pelvic(171/174)
(175)
(181)
(176)

16
8
3
0

10.34
7.66
2.15
0.85

These data suggest (P = 0.08) an excess of fatal uterine
cancer, with an estimated risk-for death between 5 and19 years after 400 rad-of 6.8 (0-16.9) w- 6 rad- 1 if theincidence of uterine cancer is not increased in patientswith metropathia haemorrhagica. Data for other pelvic
organs indicate that risks higher than 8 10-6 rad- 1 forovary and 7 10-6 racf 1 for bladder are improbable(P<0.05).
281. Data for Hiroshima and Nagasaki (14) still show
no significant increase in mortality from cancer of cervix
and uterus, and appear to exclude a risk rate per unit
kerma higher than about 10 10- 6 rad- 1 -the estimatesfor excess mortality in both cities to 1974 being
3 (- 7-12) 10-6 rad -i. The mortality rate per unit
kerma for cancers of bladder and urinary tract is,however, just significantly in excess of expectation, witha value of 3 (0.5-6) 10- 6 rad- 1 • Turner Registry data for
1959-1970 confirm an increasing incidence withincreasing exposure for bladder (and urinary organs)cancers in both cities, and-for certain dose groups inHiroshima-suggest this also for the ovary (tube andligament) and for the cervix. No significant excess isobserved for cancers of the prostate or rectum.
Estimates rates during this 12-year period have been:
Hiroshima

Nagasaki(Incidence rate per unit kerma, lo·• rad-')Bladder
Ovary
Cervix4 (0-8)7 (2-12)13 (2-24)

4 (0-8)0 (-3-3)-3 (-17-11)

282. A suggestion of sensitivity of the bladder to cancer
induction by radiation at much higher doses is given bydata of McIntyre and Pointon, who observed 16
epithelial cancers of the bladder, with 9 expected, in
8950 patients treated for cancer of the cervix (89).
Ascertainment was likely to have been better than409

50 per cent, but was certainly not known to becomplete. The dose to the bladder, of 4000 rad or more.
is too high to allow any useful risk assessment of the
carcinogenic effects of moderate doses.

F. LIVER
283. Only a tentative risk assessment appears to bepossible for the liver. Cancer of the liver has repeatedly
been observed following Thorotrast administration but,
as stated earlier, much of the energy of the decay of thecontained thorium is expended in necrotic tissue and in
the Thorotrast deposits themselves. Estimates have
however been made (75) of the mean dose to liver froma given injection of Thorotrast, with corrections for
self-absorption depending upon the mass injected. In thelight of these dosimetric estimates. it appears from anumber of epidemiological surveys (see table 23) thatthe excess frequency of liver cancer is in the region of

5 per cent within 20 years of injections involving liverabsorbed doses of about 500 rad by this time. This
would imply a risk rate of I00 10- 6 rad -t of alpharadiation if the carcinogenic effect of Thorotrast wasdue essentially to its radiation. rather than to its
chemical, effect. It _is suggested that this is so in the lightof observations on animals injected with a "thorotrast"
in which the 232 Th content is enriched with 230 Th.
These surveys would suggest that the lifetime carcinogenic risk of liver irradiation of low LET would be in theregion of {10-20) 10- 6 rad- 1 if an RBE of 10 or 20
were applicable to alpha radiation from 2 3 2 Th at thesedose levels. It remains uncertain however, how much of
the estimated dose is "wasted" radiation, either becauseof irradiation of already necrotic cells, or because thetumours have already been induced while exposure iscontinuing. It also remains uncertain whether any of thecancers observed are chemically or mechanically inducedby the thorium oxide preparation (see also Annex I,
paragraph 253).

TABLE 23. OCCURRENCE OF LIVER CANCERS FOLLOWING THOROTRAST INJECTION
Mean doseofThorotrast(ml)

Mean volumeofThorotrast
injected(ml)

Accumulated
dose in
20 years
(rad)

30
28
10

26
23
24

6.4
3.6

530

30
33

30
16

7.0
4.5

570
370

Approximate
mean
follow-up
Reference

141
42
69
72
96

Country(years)Portugal
Denmark
United States
Germany,
Fed. Rep. ofJapan

284. The induced tumours are mainly cholangiocarcinomas and haemangioendotheliomas, with smaller
numbers of hepatomas arising from liver cells themselves. This distribution may of course reflect therelative sensitivity of epithelial and parenchymal tissues
to cell killing by radiation rather than to tumour
induction alone.

470

standardize for population distribution and for theskewed distribution of age in the population at the timeof the bomb owing to the paucity of civilian males of
military age. For multiple myeloma, 6 cases wereobserved with 2.6 expected on this basis, an excess of
3.4 (0.0-9.2). The numbers in the two cities were:
Malignant lymphoma

285. The incidence of liver cancer in Hiroshima andNagasaki, as observed in Tumor Registry data for
1959-1970, increases with increasing estimated kerma,
the excess incidence during this period being
4 (2-7) 1Cf 6 rad- 1 in Hiroshima and 4 (neg.-10) 10· 6 ·rad-, in Nagasaki.

G. MALIGNANT LYMPHOMA AND
MULTIPLE MYELOMA
286. An apparent increase in both these types oftumour was noted in the Committee's last report. withthe reservation that more data were needed to conclude
that A-bomb sun•ivors were at increased risk ofdeveloping these forms of malignancy.
287. Data published by Nishiyama et al. {104) showthat 23 cases of malignant lymphoma were recorded in
1945-1965 among 44 509 survivors in the extended Life
Span Study sample at Hiroshima and Nagasaki. This
number can be compared with 18.0 expected on thebasis of findings in 34 675 survivors exposed at less than
1 rad in both cities, adjustments . being made to410

Multiple myeloma

Obsen•ed

Expected

Observed

Expected

Hiroshima
1-99 rad;.,.100

7
8

11.0
1.3

3

I

1.6
0.2

Nagasaki1-99 rad;.,.100

6
2

4.7
1.0

2
0

0.7
0.15

Total

23

-18.0

-

6

-2.6

288. The total excess of cases of malignant lymphoma
is thus only 5.0 (0-14.6). It is suggestive, however, thatthe greatest excess occurred in the highest exposuregroup at Hiroshima. In this group of 3138 survivors
there were 4 cases of lymphosarcorna (0.4 expected on abasis of those exposed at less than 1 rad at Hiroshima), 1
case of reticulum cell sarcoma (0.5 expected) and threecases of Hodgkin's disease {0.2 expected). Since thisgroup corresponds to about 0.76 106 man rad, theexcess per unit kerma for all malignant lymphomaswould, durinj the period of observation, represent about9(4-I8)1d- rad- 1 , or 12(5-23)10"" 6 rad- 1 absorbed
dose, assuming absorbed-dose/kerma ratios as for th~stomach (53). If the high-LET component were
weighted by about 10 (para. 55), the rate would be
10 (4-20) 10- 6 rad- 1 .
289. Court Brown and Doll (29) found an excess of
4.7 (1-11) deaths from cancers of lymphatic andhaematopoietic tissues to be associated with 30 (21-41)
deaths from leukaemia at periods of 6 years or more
after treatments for ankylosing spondylitis. This ratio ofrates appears to be broadly consistent with estimates for
lymphoma noted in paragraph 288 and for leukaemia in
chapter II of this annex, assuming that the relevant
lymphatic and marrow tissues received about equal dosesin these treatments.
290. Malignant neoplasms of lymphatic and haematopoietic tissues (apart from leukaemia) have now been
identified as contributing a small increasing mortality inthe Life Span Study cohort from 1950-1974, the excess
rates per unit kerrna over this period being: (10- 6
rad- 1 ):Hiroshima
5 (1-8)
Nagasaki
4 (0-9)Both cities
4 (1-7)291. In the study of Doll and Smith on patients treatedwith a single course of radiotherapy for ankylosing
spondylitis (36), no dose estimates· are yet available for
lymphatic tissues (excluding those from Hodgkin's
Disease which were not increased), but the excess deaths
from malignant tumours of these tissues can becompared with those from leukaemia in the same series
suggesting that lymphatic malignancies are less frequentand develop later than leukaemia:
Excess deaths
Numberofpatients

Mean period
during which
deaths occu"ed(years)

14109
6 838

0-9.2
6-17.3Fromleukaemia

24.5 (16-35)
10.4 (5-18)

Frommalignandes
of lymphatic

tissues
8.2 (0.3-16)
7 .6 (2.5-15)

292. Matanoski et al. (89a) have recorded an increase instandardized mortality ratio (SMR) for certain tumours
arising from lymphoid tissues in members of theRadiological Societies of North America, as comparedwith those found during the same periods in members of
pathologists· and oto-rhino-laryngologists' societies. The
increases were observed for lymphosarcoma andreticulum cell carcoma (ICD 200) for 1920-1929 and
1930-1939, although not for 1940-1949; and for
Hodgkin's Disease (ICD 201) for the last of these periods
only. For other neoplasms of lymphatic and haematopoietic tissues (ICD 202), increases occurred during thelast two of these periods, and particularly during
1940-1949 when the SMR was 5.7 for radiologists ascompared with 1.0 for pathologists and 2.2 foroto-rhino-laryngologists. Risk estimates cannot bederived from these data, however, in the absence ofadequate estimates of the doses received at work.
H. SKIN
293. Malignant tumours of skin were the first cancers
reported to have been induced by radiation ( 46), but noestimate yet appears to be available of the frequency

with which they are induced. The absence of reports ofskin tumours occurring either in the populations
exposed at Hiroshima and Nagasaki, or in the closely
studied populations on Rongelap Island or following
neck radiation in infancy, strongly suggest that suchtumours must be infrequent at moderate dosage. In
these populations, the low mortality from skin tumours
would presumably not prevent their occurrence being
detected on examination, even if they had been excisedor cured by radiation therapy. It can be argued that
infrequent reporting of skin tumours following radiation
therapy in adults does not constitute evidence against
the sensitivity of the skin as a whole for moderate doses.
in view of the small fields, high levels of skin irradiationand often of the short survival of patients after
treatment. These observations, however, do not apply topopulations exposed to moderate whole-body radiation.
294. Some indications that the skin has low sensitivity
to carcinogenesis by radiation is suggested by thefindings of Modan et al. (92) of only one skin cancer (onthe scalp) in the 10 902 children given scalp irradiation(with 5 fields at 350 R per field). No skin tumours wereseen in the control series. It is likely, in view of the
known variation of head circumference and the bodysurface area with age, that about 4 per cent of the totalskin area may have been irradiated, so that a low ratewould apply even for whole skin irradiation. Modan etal. emphasize, however, that skin tumours, being
associated with a low mortality, may have been missed ifthey occurred during the early years after irradiation
before the National Tumour Registry was established.
295. Albert and Omran (1) record the occurrence of
two basal cell carcinomas of the scalp within 12 years ofirradiation of 2043 children of average age 7.5 years,
with none in their control group of 1413 children. Since
the scalp dose was of 500-800 rad, this implies a low risk
level of 1 or 2 skin cancers per million per rad forirradiation of this area. Further follow-up to a meantime of 20.5 years ( 139) now shows 10 skin tumours tohave occurred within the unshielded areas (in contrast to
only one in the control group), the majority being basal
cell carcinomas. The total incidence of epithelial cancers
corresponds to an induction rate per unit absorbed doseof about 5 (2-10) 10" 6 rad- 1 by 20 years for this area
exposed in childhood, although with no excess mortality
from this cause.
296. Rowell ( 126) notes the occurrence of 5 skincancers (one squamous and four basal cell) in 100
patients treated for benign dermatoses during 1930-1964
and examined in 1964. Patients were selected for
examination if the treatment doses had exceeded
1500 R to hands or 1600 R to face, nails or feet. Skincancers occurred in 1 of 59 patients whose hands weretreated, and in 4 of 25 patients who had treatment to
the feet. The mean doses are not stated, but the tumours
developed after exposures of 2000-3200 R. The fields, if
used for treatment of dermatoses, may have involved thewhole of hands or face but would still represent only asmall percentage of body area, and a 5-per-cent tumour
incidence following, say, 2500 R to a few per cent of theskin surface would suggest a substantial sensitivity of theskin to carcinogenesis at these dose levels. It is clear,
however, that more and larger series require to bestudied.
411

297. Delarue et al. (31) record the occurrence of only
one skin cancer in the area likely to have been exposed
during multiple fluoroscopies done in management ofpneumothorax treatment of 308 patients. Since anaverage of 142 examinations were made. at a mean skindose of 6-12 rad for each,· this corresponds to an
incidence rate of about 4 (0.2-18) 10-6 rad- 1 following
exposure presumably of about 3-5 per cent of the totalskin area.
298. In patients who received a single course ofradiotherapy for ankylosing spondylitis, Doll and Smith(36) have recorded no deaths from skin cancer, with 1.6
expected, in the 6838 patients followed from 6 years
after the course for a further mean period of 11.3 years.
A typical treatment is likely to have involved a total skindose in the region of 1000-1500 rad to 3-5 per cent of
the total skin area. Since the upper limit of the 90%
confidence zone (with O observed and 1.6 expected)
would correspond to a possibility of 1.4 cases, themaximum estimated annual rate for whole-skin exposure
at these dose levels would be about 0.5 10-6 y- 1 rad- 1 ,implying a relatively low mortality even if the rate
operated over several decades.
299. Sevcova et al. (137) observed the incidence during
a 5-year period of skin cancer in uranium miners at a
rate of 18. 7 (8.0-38.0) 10-4 (95% confidence limits), as
compared with an expected rate of 4.1 10-4 for Czech
males of the same age distribution. The rates in otheruranium workers (not miners) were 4.8 (0.6-17.0) 10-4
observed and 7.2 10-4 expected. The tumours in theminers were predominantly basal cell cancers of thecheek and forehead. The estimated absorbed dose tobasal cell layers of the epidermis from the alpharadiation from radon daughters was estimated as 6 rad
per year, as derived from epidermal thickness data ofWhitton (161) and from measured average skincontaminations of 6 pCi cm- 2 under current exposure
conditions. Having regard to average lengths of mining
experience prior to skin cancer diagnosis (14.2 years)
and the probable occurrence of higher contaminationlevels previously, the accumulated dose to basal cells wasestimated as 100 rad or more. On this basis, theinduction rate for facial skin can be estimated as 3 10- 6
rad- 1 y- 1 or less. Alternatively, since an estimated dose
rate of 6-10 rad -i y- 1 was leading to an incidence of
290 10-6 y- 1 , the total induction rate could be
regarded as at least 30-50 10- 6 rad- 1 of alpha radiation,and this estimate should be increased owing to therelatively short mean times of exposure and survey andthe known long latency for many skin cancers.
300. It may be questioned however whether theascertainment of skin cancer in the mining populations,surveyed for the development of this condition, might
have differed in efficiency from that for the general
population as derived from nationwide oncologicalnotifications, but the rates recorded for the non-mining
uranium workers. from registrations at the same healthinstitute, were in fact somewhat lower than those
expected on the nationwide basis. All tumours were
removed surgically and no signs of recurrence had been
observed at the time of reporting. It may be noted that412

no excess incidence of laryngeal cancer was observed inCzechoslovak uranium miners by Plarek and Sevc in1975 (113).
301. Any estimates of this type, however, arenecessarily approximate and should be treated withconsiderable reserve in view of the long latencies thathave been reported for radiation-induced tumours of theskin. Pegum (110) has noted a mean latency of 31 years
after treatment of tinea capitis; Andrews ( 4), a meanvalue of 27 years in patients following radiotherapy; andPetersen (111), one of 27.5 years in 21 patients; while
Spittle (para. 12, table 1) observed the very long meanlatency of 41.5 years for basal cell cancer in a group ofpatients after treatment of tinea capitis by radiotherapy ..
302. It is important, however, to note the low mortality
associated with skin cancer. Andrews (4), for example,
has observed a mortality of only 6 per cent during
10 years after diagnosis. It is likely, therefore, that thecontribution of the skin to a fatal radiation-induced
cancer rate must be low.

VIII. MALIGNANCIES IN
PRE-NATALLY EXPOSED CHILDREN
303. In its 1972 report, the Committee described indetail the results of studies of Stewart and Kneale (149,150) and of MacMahon and Hutchinson (84), showing
an increased risk in the · development of malignancies
during the first I O years of life of children who had been
irradiated in utero during pelvimetric or other x-ray
examinations involving the pelvis of the mother. It wasstated that, although children born from mothers
x-rayed while pregnant seem to have an increased risk ofcancer after birth, a possibility still remained that theassociation, or at least part of it, was caused by factors
other than radiation, and that further studies wereneeded to clarify this point.
304. This uncertainty was partly because of adiscrepancy in the frequency of such .malignancies
following irradiation in utero in the studies referred toand in those of Jablon and Kato (65) of children whose
mothers were pregnant at the time of the A·bomb
explosions in Hiroshima and Nagasaki. A second possible
criticism of the evidence, however, was that a subgroupof mothers might have been more frequently x-rayedthan others because of hereditarily determined abnormalities (for example. of the pelvis) and that thissubgroup might have a preponderance of children who
developed malignant disease as a result of someassociated and transmitted congenital abnormalities.
305. Mole (93) has now pointed out, by a further
analysis of the data of Stewart (151, 152), that pelvic
x rays are much more frequently carried out (in 55 percent of cases) on mothers with twin pregnancies, than onmothers with other, or "singleton", pregnancies (ofwhom only 10 per cent are x-rayed during the
pregnancy). Despite this, the excess frequency ofmalignancies in twins who were irradiated in utero is nohigher than that in singletons so irradiated. The factors
which called for a greater frequency of pre-natal x rays,

at least in this type of pregnancy, do not therefore
appear to be associated with an increase in childhood
malignancies. Thus, in singletons, leukaemia developedin 3.4 I 0-4 of all live-born children who had been
x-rayed i11 utero, but in only 2.3 10-4 of those not
x-rayed. In twins, leukaemia developed in 2.6 10-4 ofthose x-rayed and in 1.2 10-4 of those not x-rayed. The
difference in rate apparently attributable to radiation isthus about equal in singletons and twins, beinf( 1.18 ± 0.15) 10-4 in the former and ( 1.43 ± 0.46) 10in the latter.
306. For other malignancies a similar result wasobserved. In x-rayed singletons the rate was 3.9 10-4,
and 2. 7 I 0-4 in those not x-rayed. In x-rayed twins therate was 3.1 10-4 , and 2.0 10-4 in those not x-rayed.
The difference in rate attributable to radiation is(1.24 ± 0.17) 10-4 in singletons. and (1.14 ± 0.53) 10-4
in twins. Provided the higher still-birth rate in twins(5.7 per cent) than in singletons (2.1 per cent) did not
introduce bias by including an excess of still-born twins
who would have developed leukaemia or solid cancers,
the evidence clearly supports a likelihood that theincrease in malignancies was attributable to radiation
rather than to selective factors.
307. Newcombe and McGregor (102) and Holford (59)have discussed the apparently linear relationshipobserved by Stewart and Kneale (150) between excess
cancer risk and number of films per examination andregard the data as showing a close correlation to a simple
linear relationship with dose, down to doses in the rangeof 0.2-0.25 rad.
308. Mole (93) discusses the apparent discrepancy
between the excess of childhood cancers following
diagnostic x rays in utero, and the apparently Jack ofany such significant excess in Japanese A-bomb survivors
who had been irradiated in utero (65, 73). He suggeststhat the higher foetal doses received in Hiroshima andNagasaki may have been associated with cell-killing
effects which may have reduced the subsequent
incidence of cancers that would otherwise have been
expected. He points out also that, with only 1 childhood
malignancy observed after irradiation in utero in thesecities, as compared with 0.4 expected on the basis ofJapanese National Statistics, the confidence limits of theresulting risk estimate would in any case have been wideand might be consistent with the Committee's estimate,in its 1972 report, of the risk of malignancies following
foetal irradiation. With 34 900 man rad to mothers andwith absorbed doses to the foetus as given by Auxier etal. (9), the foetal risk per unit kerma would be
43 (neg.-316) 10-6 rad- 1 ,or25 (neg.-186) 10-6 rad- 1 if
the high-LET component of absorbed dose were
weighted as in paragraph 55. Such estimates are notnecessarily inconsistent therefore with the Committee'srisk rate per unit absorbed dose for foetal irradiation, as
given in its 1972 report, of230 10-6 rad- 1 (for doses in
the range of 0.2-20 rad). In summary therefore, the risk
per unit absorbed dose of fatal induced malignancies by
foetal irradiation may be in · the region of
200-250 10-6 rad- 1 , half of these malignancies being
attributed to leukaemia and one quarter to tumours of
the nervous system (see also Annex I, paragraph 303).

IX. CONCLUSIONS
A. CARCINOGENESIS IN DIFFERENT ORGANS
309. The evidence on radiation carcinogenesis in man
that has been reviewed in this Annex indicates a
progressive increase in information as to the tissues andorgans in which malignancies may be induced atabsorbed doses in the region of a few hundred rads orless. It also allows approximate estimates to be made of
the risk of inducing a malignancy at these dose levels for
an increasing number of such organs if selectively
irradiated, or for the whole body if more uniformly
exposed.
310. The risk of the development of a malignancy
following irradiation of individual tissues at dose levelsof the order of 100 rad may vary with the LET of theradiation, sometimes with the age and sex of the subject
exposed (see Annex I, paragraph 289), and probably alsowith the dose rate or "fractionation'' with which thedose is delivered (see Annex I, paragraph 179).
311. The risk estimates obtainable for individual organs
or tissues cannot be determined with great accuracy, but
for several tissues, such as those of the bone marrow andthe thyroid gland, approximate estimates are obtainablefrom several different sources and are mutuallyconsistent within the accuracy of their determination. It
is thus becoming possible to classify different bodyfosues into groups with different degrees of sensitivity
to induction of malignancies by radiation. It must be. emphasized, however, that such classifications, and thevalues for the induction rates themselves. are derived
from the results of exposure at high dose levels,
ordinarily in excess of 100 rad (of low-LET radiation).
As stated above for leukaemia (paragraph 96) the
corresponding rates per unit absorbed dose at doses of a
few rad, while unlikely to be higher, may besubstantially lower.
312. The thyroid and the female breast appear to havehigh rates of cancer induction by radiation at levels
usually in excess of 100 rad, at least for certain ages at
exposure. Average risk rates for all ages appear to be in
the region of 100 10-6 induced cancers per rad absorbed
dose of low-LET radiation. The low mortality rate forradiation-induced thyroid cancers and the moderately
low rate for breast cancers probably bring thecorresponding average risk rates for fatal cancer
induction for these two issues to about 10 10-6 and50 10-6 rad- 1 respectively.
313. The induction rate for lung cancer also is high formales of over 35, insofar as a value can be derived fromexperience of uranium mining and probably also forfemales at these ages. Rates at other ages are difficult toestablish but seem clearly to be lower, and a mean rate
for all ages in the region of (25-50) 10-6 rad- 1 of
low-LET radiation seems probable.
314. The induction of leukaemia, of the acute andchronic granulocytic forms, occurs with a risk whichappears to fall, probably from about 50 10-6 rad- 1 atmoderately high doses. to" the region of 20 10-6 rad- 1
413

as the dose level is · reduced. For radiation-induced
leukaemia, the mean interval between exposure anddeath is in the region of 10 years, and is much shorter
than the mean interval for other malignancies, which
typically appears to be 25 years or more; The total
induced mortality from leukaemia can thus be estimatedwith greater confidence in most present surveys thanthat from other malignancies.
315. The risk rates for stomach, liver and large intestine
are less reliably determined, but appear to be
substantially lower, and are probably in the region of(10-15) 10- 6 rad- 1 for fatal cancers. For the brain,
quantitative information is scanty, but the rate for all
tumours, which may prove fatal in this situation, may besimilar. The salivary glands appear to have an induction
rate in about this range also, but the risk rate for fatal
cancers is likely to be lower.
316. For bone. oesophagus, small intestine, urinary
bladder, pancreas, rectum and the lymphatic tissues,
risks of cancer induction are identifiable but appear to
be lower again, with values probably in the region of(2-5) 10- 6 rad- 1 • The risk for the mucosa of cranialsinuses appears to be similar. No good estimate isavailable for skin cancer induction. but the induction of
fatal cancers of skin appears also to be low. All estimates
quoted in these paragraphs (312 to 316) are "rounded"values which are broadly consistent with figuresobtainable from different sources, but reference should
be made to the paragraphs of the annex which deal withthe various tissues for reviews of the different bases forrisk estimation and the reservations or limitations which
apply to each.
317. Evidence is given in paragraph 24 7 which suggeststhat the total of all fatal malignancies which may
ultimately result from a given uniform whole-body
exposure, may be in the region of 4-6 times that forleukaemia alone. The average. rates quoted in paragraphs 312-317 are necessarily tentative, but do notappear inconsistent with this possibility. Thus, the total
rate of all fatal solid cancers for the various tissues ororgans for which some estimate has been made, amounts
to about 200 10-6 rad- 1 for moderately high doses (e.g.
of a hundred to a few hundred rads of low-LET
radiation). If these tissues have been identified because
they are the main contributors to the carcinogenic
effects of radiation, and if leukaemia is induced with arate of 50 10-6 rad- 1 at these dose levels, the final ratioof all total malignancies to leukaemias could thus be in
the region of 6.
318. It is to be expected that low-LET radiation is
likely to be less carcinogenic per unit absorbed dose atdoses of a few rads than at levels of one or a few
hundred rads. For dose levels at which a leukaemia
induction rate of (15-25) 10-6 rad- 1 may apply (seeparagraph 96), a ratio of 4-6 between the frequency ofother induced fatal malignancies and that for leukaemia
would imply a total for all fatal induced malignancies,
including leukaemia, of (5-7) times (15-25) 10- 6 rad- 1 •suggesting a value of about 100 10-6 rad- 1 at such doselevels. It must be emphasized again, however, that such avalue is derived essentially from mortalities induced atdoses in excess of WO rad. The value appropriate to the414much lower dose levels involved in occupational
exposure, and even more so in environmental exposuresto radiation, may well be substantially less: and thisreservation applies also to values quoted for individualorgans or tissues. Moreover, these values, although often
consistent with several different sources of evidence. are
only very approximately determined. and indicate theneed for further investigation of many points. They do,
however, form some basis for assessing the possible
significance of occupational exposure and for planningof protection measures.
319. It is likely that malignancies may be induced in the
foetus by exposure in utero at average absorbed doses in
the range of 0.2-20 rad from diagnostic x rays
(para. 308). The induction rate of fatal malignancies perunit absorbed dose is difficult to determine with any
confidence, but is estimated as being in the region of{200-250) 10-6 rad- 1 •B. INDICATIONS FOR FUTURE WORK
320. Quite clearly, however, much further informationis needed before the carcinogenic risks of radiation canbe estimated with accuracy and confidence, particularly
at low doses. The Committee wishes to emphasize theimportance of further investigations, particularly in fourareas:(a) The continuation of surveys of cancer
induction following radiation exposure, for long periodsof time-ideally throughout the lifetimes of thoseinitially exposed;{b) Further study of the basis for assessing risk
from low-LET radiation at various dose levels, from that
resulting from high-LET radiation:(c)Continued examinations of the effects upon
the risk of malignancy. of the uniformity of radiation
exposure, both within a tissue of which the cells all havea similar sensitivity to tumour induction. and withinorgans in which the malignancy may result only from
irradiation of certain types of cell;{d) Further investigation of the proper basis for
inferring risk rates at low doses from those observed
following high doses, and in assessing the influence ofdose rate.

These fields of investigation are discussed in thefollowing paragraphs.
321. The need for prolonged continuation of epidemiological studies is obvious. since it cannot otherwise be
known what types or frequencies of cancer may occur atseveral decades after exposure. or what cancers may
develop when those who were exposed in childhood
reach an age at which hormonal or other influences
facilitate the expression of cancers induced many years
previously (see Annex I, paragraph 68). These considerations apply very strongly to the extremely important
observations in Hiroshima and Nagasaki. of which theprolonged continuation is regarded by the Committee as
being of the greatest value. The same applies also to thestudies of uranium miners and to those exposed inchildhood or in adult life to local radiotherapy forbenign conditions. Further possible studies of irradiatedpatients are. discuss:d in ~nnex F with review of thedosimetric information available (para. 138) or needed(para. 11 O) in evaluating the carcinogenic effects ofradiation on other organs.
322. There is an urgent need for establishing a reliablebasis for inferring the risk from a given absorbed dose of
tow-LET radiation from that resulting from high-LET
radiation. Most occupational and environmental
exposure is to radiation of low LET. However, four very
important sources of human epidemiological evidence
yield risk estimates only for. or largely in terms of,high-LET radiation, namely, following the irradiation ofbone cells with 224 Ra and 2 2 6 Ra, of lung tissues ofuranium miners with radon daughters, of liver cells withthorium, and particularly of the whole body in the
populations of Hiroshima who were exposed to absorbed
doses from neutrons of up to a hundred or more rads.
Investigations in animals have compared the frequencies
with which mutations. chromosomal aberrations andcell-killing effects are induced by high- and low-LET
radiations at various dose levels. It appears mostimportant that similar comparisons should be madebetween the carcinogenic effects of such radiations at
different dose levels. and should extend over various
animal species (see Annex I, paragraphs 13 and 339) andtypes of tumour, so that the RBE for carcinogenesis, andany variations of it with dose, should be explored on as
wide a basis as is practicable.
323. It would be valuable also if available human data
could be examined for any evidence as to the RBE for
any forms of human carcinogenesis, for example, by theuse of epidemiological surveys yielding better values forsarcoma induction in bone following external radiotherapy, or by a more sophisticated intercomparison of
the leukaemia induction rates in Hiroshima and Nagasaki
than has been possible in the present report.
324. The identification of the cell types at risk withinvarious organs and of the relative importance of
homogeneous or non-homogeneous irradiation of a given
tissue are essential to an understanding of the process
and of the frequency of tumour induction and to theestimation of the relevant dose for risk evaluation (seeAnnex I, paragraph 301). The approximate consistencyof leukaemia risk estimates derived from irradiation of
the whole marrow or of only a fraction of the marrow,suggests that a given integral dose of moderate size may
be about equally effective whether distributed uniformly
or not. When smaller fractions of a tissue are exposed tomuch higher local doses, the effects are likely to dependon the form of the dose-effect relationship at high doses
and the way in which the yield of tumours falls whenlocal doses are very high. The problem has been closely
examined on a theoretical basis (86) but further
experimental examinations are needed.
325. The direct determination of the risk to man fromexposure of the whole body or of particular body tissues
to low doses presents considerable difficulties. but theCommittee wishes to emphasize the importance of any
practicable studies that would be likely to yieldstatistically reliable information on this question. Large
irradiated populations need to be studied. however, if asmall increase in a common form of cancer is to be
distinguished from the natural incidence of the cancer inthe control population. The raised incidence of thyroid
cancer following an estimated dose of 6.5 rad to thegland (para. 122) resulted from a study of the records ofabout 11 OOO irradiated children and about 16 OOO controls. The increase in childhood cancers after irradiationin utero at a probable mean dose of only a few rads
entailed identification of whether x-ray examinations
had occurred in utero on 7500 children who died ofmalignancies, in Stewart's survey (para. 303).
326. Extended studies of malignancies in occupationally exposed workers would be informative andvaluable, if exposures to both external and internalradiation were adequately known. if an appropriate
control population was studied, and if the numbers
observed-and the time of observation-were sufficient.
It can be estimated that the number of deaths from··spontaneous" cancer occurring, for example, in
30 years in a male population of 100 OOO of age 18-65(distributed by age as in the general population) would
be 11 200 (as based on mortality rates in the United
Kingdom of Great Britain and Northern Ireland). In agroup of this size, therefore, and with a sufficient
control group, cancer induction by radiation would only
be detectable (at the 2-SD levels) if it caused 212
additional deaths within this period, corresponding to an
induction rate of over 70 10- 6 y- 1 from the doses
received by this population. To evaluate the excess ratewith any accuracy would require 1.5-2 times this rate,unless unusual forms of cancer were detected. Unless thepresent estimates of total cancer induction are
substantially in error, therefore, it would require studies
covering some millions of person-years of workers
exposed at annual average whole-body doses of over
1 rad, to evaluate directly the risk of such doses. Equal
or smaller surveys might, of course, still be valuable in
excluding higher risks than have been estimated, or
unexpected forms of malignancy due to undetected local
tissue irradiation.
327. In surveys of patients who have had diagnostic
examinations with radionuclide5 involving moderate or
low tissue-absorbed doses, the interpretation of epidemiological surveys for the induction of malignancies
may involve two problems in particular. In the firstplace, it will be difficult to know-without suitable
control series-whether the patients· diseases may not be
associated naturally with an excess incidence of certain
types of malignancy. Secondly, it may be difficult to be
sure that the radionuclide test itself was not occasionallydone to investigate a condition which was in fact due toa developing malignancy. For thyroid scans, forexample, this may be particularly difficult, since thyroid
cancers may cause modularity or enlargement of thegland which. in the absence of operati·on, may only
become diagnosable as malignant many years later. Any
survey of the sequels of diagnostic radionuclide tests
should only be undertaken if it is clear that suchdifficulties will not necessarily make the results uselesswhen they have finally been obtained.
328. The potential importance of examining malignancy rates in populations living in areas of high natural
background radiation has frequently been emphasized,
415

,.
..

provided that adequate medical records were obtainable,
and that parallel studies could be made in a comparison
area differing only in being exposed to lower
background radiation. However, when the raised
background radiation is due to increased externalradiation, populations hitherto identified have been ofsuch a size, in relation to the elevation of backgroundradiation, as to require a very prolonged observation
with efficient ascertainment of causes of death to detect
or evaluate an increase in total cancer mortality abovethat to be expected from natural causes in a comparison
population.
329. It has been estimated (117) that an increased
cancer mortality is likely to be detectable in aconsiderably shorter time if studied on the basis ofdeaths of those aged less than a certain optimum age,which is likely to vary with the population studied, thanif based on deaths at all ages, when the rising natural
cancer mortality at higher ages is likely to make theradiation-induced mortality harder to detect. (A similarargument may apply to surveys of occupationally
irradiated groups.) Problems of ascertainment, however,continue to be the major difficulty in existinghigh-background areas with adequate populations, and it
may be that studies on larger populations exposed toonly moderate elevations of background radiation might
be more informative if good records of death rates frommalignant diseases were already available and had
previously been maintained in these areas. (For given
rates of natural cancer incidence and of cancer induction
per unit dose, the duration of survey required to detect aradiation-induced increase in rate should vary inverselywith the size of exposed population and also inverselywith the square of the elevation of background radiation
rate as compared with that of the control population.)
330. Populations are also exposed to raised radiationlevels in certain areas in which various dietary
constituents are unusually radioactive or when living ataltitudes at which increased cosmic radiation causes
elevation of the external radiation background. It seems

416

unlikely that either situation gives opportunities for
useful epidemiological studies. With increased internalradiation from dietary radioactivity, the known
populations are small and dosimetric evaluations might
be difficult to make on a reliable basis, even for theorgans that might be selectively irradiated. For
populations living at high altitudes, it would probably be
difficult to identify control populations with the same
cultural, medical and dietary practices.
331. Some guidance as to the relative risk of high andlow exposures may also be obtainable from any
practicable analyses of the form of the dose-effectrelationship for cancer induction. Particular importanceattaches, therefore, to any studies of human carcino·
genesis in which that is possible, since it will pe seen thatin much of the work reviewed in this Annex, the risks
determined at lower doses are evaluated too imprecisely
for the likely values at very low dose to be estimatedwith confidence.
332. It remains of considerable importance, therefore,that the likely form of the dose-effect relationships for anumber of different types of radiation carcinogenesis
should be closely studied in experimental animals, andpreferably in a range of. species (see Annex I,
paragraphs 13 and 339). so that any quantitative
generalization that might apply to different species
might be recognized (as appears to hold very
approximately for the induction of chromosomal
aberrations (20)). In particular, if the form of suchdose-effect relationships could be reliably shown todepend mainly on terms in dose and (dose) 2 , withmodification at high doses from cell killing (as discussed
in paragraph 35), and if the coefficient of the linear andquadratic terms were determined for a number ofdifferent types of tumour in different species, someindication might be obtained of the amount by which
the risk per unit absorbed dose at moderately high doses
is likely to exceed that at very low doses for
carcinogenesis in general.

!

--·

REFERENCES

J.

Albert, R. E. and A. R. Omran. Follow-up studyof patients treated by X-ray epilation for Tinea
Capitis. Arch. Environm. Health 17: 899-918(1968).

13.

Beebe, G. W., H. Kato and C. E. Land. Mortality
experience of A-bomb survivors 1950-1974. 24th
Annual Scientific Meeting of Radiation ResearchSociety, San Francisco, June 1976.

2.

Alderson, M. R. and S. M. Jackson. Long-term
follow-up of patients with menorrhagia treated byirradiation. Br. J. Radio!. 44: 295-298 (1971).

14.

3.

Anderson, R. E. and K. Ishida. Malignant lymphoma in survivors of the atomic bomb in
Hiroshima. Ann. lnt. Med. 61: 853-862 (1964).

Beebe, G. W., H. Kato and C. E. Land. Studies ofthe mortality of A-bomb survivors. 8. Mortality
experience of A-bomb survivors, 1950-74. Radiation Effects Research Foundation, RERF Technical Report 1-77 (1977).

15.

Belsky, J. L., K. Tachikawa, R. W: Cihak et al.
Salivary gland tumours in atomic bomb survivors,
Hiroshima-Nagasaki 1957-1970. J. Am. Med.
Assoc. 219: 864-868 (1972).

16.

Belsky, J. L., N. Takeichi, T. Yamamoto et al.
Salivary gland neoplasms following atomic radiation. Additional cases and reanalysis of combined
data in fixed· population. Cancer 35: 555.559(1975).

17.

Boice, J. D. Jr., and R. R. Monson. Breast cancer
following repeated fluoroscopic examinations of
the chest. J. Natl. Cancer Inst. (In course of
publication).

4.

Andrews, P. Rodent ulcers induced by X-rays andradium. Thesis for M.D., University of London,
March 1957.

5.

Archer, V.E. and J.K. Wagoner. Lung cancer
among uranium miners in the United States.
Health Phys. 25: 351-371 (1973).

6.

Archer, V. E., J. D. Gilliam and J. K. Wagoner.
Respiratory disease mortality among uranium
miners. Ann. N. Y. Acad. Sci. 271: 280-293(1976).

7.

8.

Armenian, H.K. and A. M. Lilienfeld. The distribution of incubation periods of neoplastic
diseases. Arn. J. Epidemiol. 99: 91-100 (1974).
Arnold, J., S. Pinsky, U. Y. Ryo et al. 99 mTcpertechnetate thyroid scintigraphy in patients predisposed to thyroid neoplasms by prior radiotherapy to the head and neck. Radiology 115:653-657 (1975).

8a. Atkinson, H. R. Bone marrow distribution as afactor in estimating radiation to bloodforming
organs. J. Coll. Radio!. Austr. 6: 149-154 (1962).
9.

Auxier, J. A., F. F. Haywood, T. D. Jones et al.
Dosimetry for human exposures. p. 79-82 in Oak
Ridge National Laboratory report ORNL-5056(1975).

10.

Baker, H. W. Anaplastic thyroid cancer 12 years
after radioiodine therapy. Cancer 23: 885-890(1969).

11.

Baral, E., L.-E. Larsson and .B. Mattsson. Occurrence of breast carinoma in women treated with
X-rays for benign diseases of the breast (in press).

12.

Becker, F. 0., S. G. Economou, H. W. Southwick
et al. Adult thyroid cancer after head and neckirradiation in infancy and childhood. Ann. Intern.
Med. 83: 347-351 (1975).

17a. Boice, J. D. Personal communication.
18.

Brinkley, D. and J. L. Haybittle. The late effects
of artificial menopause by X-radiation. Br. J.
Radiol. 42: 519-521 (1969).

19.

Brown, J.M. Personal communication (1976).

20.

Brown, J. M. Linearity vs non-linearity of dose
response for radiation carcinogenesis. Health Phys.
31: 231-245 (1976).

21.

Campbell, A., E.W. Emery, J. N. Godlee et al.
Diagnosis and treatment of primary polycythaemia. Lancet 1: 1074-1077 (1970).

22.

Casarett. G. W. Radionuclide Carcinogenesis. U.S.
Atomic Energy Commission Symposium SeriesNo. 29, Washington. 1973.

23.

Chong, G. C., 0. H. Beahrs, M. L. C. Chen et al.
Management of parotid gland tumours in infants
and children. Mayo Clin. Proc. 50: 279-283(1975).

24.

Cihak, R. W., T. Ishimaru, A. Steer et al. Autopsy
findings and relation to radiation. Cancer 33:
1580-1588 (1974).
417

25.·

Conard, R. A., B. M. Dobyns and W.W. Sutow.
Thyroid neoplasia as l;i.te effect of exposure toradioactive iodine in fallout. J. Arn. Med. Assoc.
214: 316-324 (1970).

26.

Conard, R. A. Acute myelogenous leukaemia following fallout radiation exposure. J. Arn. Med.
Assoc. 232: 1356-1357 (1975).

27.

Conard, R. A. Personal communication (1976).

28.

Cook, D. C., 0. Dent and D. Hewitt. Breast cancer
following multiple chest fluoroscopy: the Ontario
experience. Can. Med. Assoc. J. 111: 406-409 and412 (1974).

29.

Court Brown, W. M. and R. Doll. Mortality fromcancer and other causes after radiotherapy forankylosing spondylitis. Br. Med. J. ii: 1327-1332(1965).

30.

De Groot, L. J. and E. Paloyan. Thyroid Carcinoma and Radiation. A Chicago Epidemic. J. Am.
Med. Assoc. 225: 487-491 {1973).

31.

Delarue, N. C., G. Gale and A. Ronald. Multiple
fluoroscopy of the chest: carcinogenicity for thefemale breast and implications for breast screening
programs. Can. Med. Assoc. J. 112: 1405-1413{1975).

32.

Dickson, R. J. The late results of radium treatment
for benign uterine haemorrhage. Br. J. Radio!. 42:
582-594 (1969).

33.

Dobyns. B. M., G. W. Sheline, J. B. Workman et al.
Malignant and benign neoplasms of the thyroid inpatients treated for hyperthyroidism: a report of
the Cooperative Thyrotoxicosis Therapy Followup Study. J. Clin. Endocrinol. 38: 976-998{1974).

34.

Doll, R. and P. G. Smith. The long-term effects of
x-irradiation in patients treated for metropathia
haemorrhagica. Br. J. Radiol. 41: 362-368 (1968).

35.

Doll, R., C. Muir and J. Waterhouse (eds.). Cancer
incidence in 5 continents Vol. II. International
Union Against Cancer, Springer-Verlag Berlin,
1970.

36.

Doll, R. and P. G. Smith. Mortality from cancer
and other causes after radiotherapy for ankylosing
spondylitis: further observations. (To be published).

37.

Doll, R. Cancer following therapeutic external
irradiation. Paper presented to the l 0th International Cancer Congress in Houston (1970).

38.

Dolphin, G. W. The risk of thyroid cancers
following irradiation. Health Phys. 15: 219-228{1968).

39.

Dolphin, G. W. and W. G. Marley. Risk evaluation
to the protection of the public in the event of418

accidents at nuclear installations. United Kingdom
Atomic Energy Authority report AHSB (RP)R95,
Harwell, 1969.
40.

Duncan, W. and G. R. Kerr. The curability ofbreast cancer. Br. Med. J. 2: 781-783 (1976).

41.

Evans. R. D. The effect of skeletally depositedalpha-emitters. Br. J. Radio!. 39: 881-895 (1966).

41a. Evans, R. D., A. T. Keane, R. J. Kolenkow et al.
Radiogenic tumours in the radium and mesothorium cases studied at M.I.T., p. 157-194 in
Delayed effects of bone-seeking radionuclides(C. W. Mays, W. S.S. Jee, R. D. Lloyd et al, eds.).
University of Utah Press, 1969.
42.

Faber, M. Follow-up of Danish thorotrast cases.
p. 137-150 in Proceedings of the Third International Meeting on the Toxicity of Thorotrast.
Danish Atomic Energy Commission report Ri5<6
294 (1973).

43.

Faber, M. The effect of thorotrast enriched with
230
Th. p. 294-302 in Proceedings of the Third
International Meeting on the Toxicity of Thorotrast, Danish Atomic Energy Commission report
Ris1' 294 ( 1973).

44.

Faber, M. Dose effect rel~tions in hepatic carcinogenesis. p. 308-315 in Proceedings of the Third
International Meeting on the Toxicity of Thorotrast, Danish Atomic Energy Commission report
Ris(i! 294 (1973).

45.

Favus, M. J ., A. B. Schneider, M. E. Stachura et al.
Thyroid cancer occurring as a late consequence ofhead-and-neck irradiation. New Engl. J. Med. 294:
1019-1025 (1976).

45a. Finkel, A. J ., C. E. Miller and R. J. Hasterlik.
Radium-induced malignant tumors in children andadults. p. 195-225 in Delayed effects of boneseeking radionuclides (C. W. Mays, W. S.S. Jee,R. D. Lloyd et al., eds.). University of Utah Press,
1969.
46.

Frieben, A. Demonstration eines Cancroids desrechten Handriickens, das sich nach langdauernder
Einwirkung von Rontgenstrahlen entwickelt hat.
Fortschr. Roentgenstr. 6: 106-11 I {1902).

47.

Goolden, A. W. G. Radiation cancer. A review
with special reference to radiation. tumours in thepharynx, larynx and thyroid. Br. J. Radiol. 30:
626-640 (1957).

48.

Greene, M. The treatment of thyrotoxicosis withiodine-131 and partial thyroidectomy. M.D.
Thesis, University of Sheffield. 1964.

49.

Gouskova, A. K., V. A. Soldatova. E. A. Denisova
er al. Late effects of occupational irradiation.
Gov.Report 34-40 VII, 1975.

50.

51.

52.

53.

Ham, J.M., F. R. Hume. C. C. Gray et al. Reportof the Royal Commission on the Health andsafety of Workers in Mines. Government of
Ontario, Canada, 1976.

63.

Ishimaru, T., T. Hoshina, M. Ichimaru et al.
Leukaemia in atomic bomb survivors, Hiroshima
and Nagasaki, 1 October 1950-30 September
1966. Radiat. Res 45: 216-233 (1971).

Hamrick, P. E. and P. J. Walsh. Environmental
Radiation and the Lung. Environ. Health Perspect.
9: 33-52 ( 1974).

64.

Ishirnaru, T., R. W. Cihak, C. E. Land et al. Lungcancer at autopsy in A-bomb survivors andcontrols, Hiroshima and Nagasaki, 1961-1970. II:
Smoking, occupation and A-bomb exposure.
Cancer 36: 1723-1728 (1975).

65.

Jablon, S. and H. Kato. Childhood cancer in
relation to prenatal exposure to Atomic bombradiation. Lancet 2: 1000 (1970).

66.

Land, C. E. Personal communication.

67.

Jablon, S. and H. Kato. Mortality among atomic
bomb survivors, 1950-1970. Atomic Bomb Casualty Commission report ABCC-TR 10-71 (1971).
'
Janower, M. L. and 0. S. Miettinen. Neoplasms
after childhood irradiation of the thymus gland.
J. Am. Med. Assoc. 215: 753-756 (1971).

Harley, N. H., R. E. Albert, R. E. Shore et al.
Follow-up study of patients treated by X-ray
epilation for tinea capitis. Estimation of the doseto the thyroid and pituitary glands and otherstructures of the head and neck. Phys. Med. Biol.
21: 631-642 (1976).
Hashizume, T. and T. Maruyama. Physical dose
estimates for A-bomb survivors-Studies at Chiba,
Japan. J. Radiat. Res., Vol. 16, Supplement 12:
12-23 (1975).

53a. Hashizume. T., T. Maruyama, K. Nishizawa et al.
Mean bone marrow dose of atomic bomb survivors
in Hiroshima and Nagasaki. J. Radiat. Res. 18:
67-83 (1977).
54.

Haybittle, J. L. Personal communication.

55.

Hazen, R. W., J. W. Pifer, E.T. Toyooka et al.
Neoplasms following irradiation of the head.
Cancer Res. 26: 305-311 (1966).

56.

Hempelmann, L. H., J. W. Pifer, G. J. Burke et al.
Neoplasms in persons treated with X-rays ininfancy for thymic enlargement. A Report of theThird Follow-up Survey. J. Natl. Cancer Inst. 38:
317-336 (1967).

57.

Hempelmann, L. H. Risk of thyroid neoplasms
after irradiation in childhood. Science 160:
159-163 (1968).

58.

Hempelmann, L. H., W. J. Hall, M. Phillips et al.
Neoplasms in persons treated with X-rays ininfancy: fourth survey in 20 years. J. Natl. Cancer
Inst. 55: 519-530 (1975).

59.

Holford, R. M. The relation between juvenile
cancer and obstetric radiography. Health Phys. 28:
153-156 (1975).

60.

61.

62.

Hutchison, G. B. Leukaemia in patients withcancer of the cervix uteri treated with radiation. A
report covering the first five years of aninternational study. J. Natl. Cancer Inst. 40:
951-982 (1968).
lchimaru, M., T. Ishimaru, J. L. Belsky et al.
Incidence of leukaemia in A-bomb survivors bydose, years · after exposure, age and type ofleukaemia 1950-71, Hiroshima and Nagasaki.
RERF Technical Report 10-76.
International Commission on Radiological Protection. Report of the Task Group on Reference
Man: ICRP Publication 23, Pergamon Press,
Oxford, 1975.

68.

69.

Janower, M. L. Follow-up of Thorotrast patientsfrom Boston, Massachusetts and Ann Arbor,
Michigan, USA, p. 126-136 in Proceedings of theThird International Meeting on the Toxicity ofThorotrast. Danish Atomic Energy Commission
report Ris~ No. 294 (1973).

70.

Jone, T. D. A CHORD Simulation for insult
assessment to the red bone marrow. Oak Ridge
National Laboratory report ORNL-5191 (1976).

71.

Jones, T. D .. , J. A. Auxier, J. S. Che.lea et al. In
vivo dose estimates for A-bomb survivors shieldedby typical Japanese houses. Health Phys. 28:
267-381 (1975).

72.

Kaick, G. van and K. E. Scheer. Actual status of
the German Thorotrast study, p. 157-162 inProceedings of the Third International Meeting on
the Toxicity of Thorotrast. Danish Atomic Energy
Commission report Ris0 No. 294 (1973).

73.

Kato, H. Mortality in children exposed to the
A-bomb while in utero. Am. J. Epiderniol. 93:
435ff(l971).

74.

Kato, H. Personal communication on work inby
M. Tokunaga,
M. Asano,
preparation
S. Tokuoka et al., Malignant breast tumours andtheir relation to radiation. Hiroshima andNagasaki, 1950-74.

75.

Kaul, A. Mean organ dose rates in man following
intravascular injection of thorotrast, p. 40-51 inProceedings of the Third International Meeting on
the Toxicity of Thorotrast. Danish Atomic Energy
Commission report Risit> No. 294 (1973).

76.

Kellerer. A. M. and H. H. Rossi. RBE and theprimary mechanism of radiation action. Radiat.
Res. 47: 15-34 (1971).
419

77.

Kikuchi, A., C. Watanabe, M. Abe et al. Head andneck cancer following therapeutic irradiation and abrief review on those in Japan. Nippon Acta
Radiologica 34: 491-501 (1974).

89a. Matanoski, G. N ., R. Seltser; P. E. Sartwell et al.
The current mortality rates of radiologists andother physician specialists: specific causes ofdeath. Am. J. Epidemiol. 101: 199-210 (1975).

78.

K.itabatake, T., S. Kurokawa, M. Yamasaki et al. A
prospective survey on the incidence of chest
malignancies after repeated fluoroscopy during
artificial pneumothorax therapy for pulmonary
tuberculosis. Nippon Acta Radiologica 35:
895-899 (1975).

90. Medical Journal of Australia 1: 1171 (1973).
lodine-131 and carcinogenesis (editorial).

79.

80.

81.

82.

Kolibe, D., R. Masse, P. Fritsch et al. Greffe chezla souris athymique de tissu pulmonaire de rat
contamine par l'oxyde de plutonium. p. 95-107 in
Biological and Environmental Effects of LowLevel Radiations, Vol. 2. IAEA publication STI/
PUB/409. Vienna, 1976.
Lindsay, S. and I. L. Chaikoff. The effects ofirradiation of the thyroid gland with particularreference to the induction of thyroid neoplasms: areview. Cancer Res. 24: 1099-1107 (1964).
Lundin, F. E., J. K. Wagoner and V. E. Archer.
Radon daughter exposure and respiratory cancer,
quantitative and temporal aspects. U.S. Department of Health, Education and Welfare, National
Institute for Occupational Safety. and National
Institute of Environmental Health Sciences joint
monograph 1 (1971).
Mackenzie, I. Breast cancer following multiple
tluoroscopies. Brit. J. Cancer 19: 1-8 ( 1965).

83.

MacMahon, B. Prenatal X-ray exposure and childhood cancer. J. Natl. Cancer Inst. 28: 1173-1191(1962).

84.

MacMahon, B. and A. B. Hutchison. Prenatal X-ray
and childhood cancer: a review. Acta Unio. Int.
Contra Cancrum 20: 1172-1174 (1964).

85.

MacMahon. B., T. M. Lin, C.R. Lowe et al. Lactation and cancer of the breast. A summary of aninternational study. Bulletin of the World HealthOrganization 42: 185-194 (1970).

86.

Mayneord, W. V. and R.H. Clarke. Carcinogenesis
and radiation risk: a bio-mathematical reconnaissance. Br. J. Radio!., Suppl. No. 12, 1975.

87.

McDougall, I. R., J. S. Kennedy and J. A. Thompson.
Thyroid carcinoma following iodine-131 therapy.
Report of a case and review ·of the literature.
J. Clin. Endocrinol. 33: 287-292 (1971).

88.

89.

420

McGregor, D. H., C. E. Land, K. Choi et al. Breast
cancer incidence among A-bomb survivors,
Hiroshima and Nagasaki, 1950-69. Atomic Bomb
Casualty Commission, Technical Report 32-71.
McIntyre, D. and R. C. S. Pointon. Vesical neoplasms occurring after radiation treatment for
carcinoma of the uterine cervix. J. Royal Collegeof Surgeons, Edinburgh 16: 141-146 (1971).

91. Mettler, F. A., L. H. Hempelmann, A. M. Dutton
et al. Breast neoplasms in women treated with
x-rays for acute postpartum mastitis, a pilot study.
J. Natl. Cancer Inst. 43: 803-811 (1969).
92. Modan, B.. D. Baidatz, H. Mart et al. Radiationinduced head and neck tumours. Lancet 1:
277-279 {1974).
93. Mole, R.H. Antenatal irradiation and childhood
cancer: causation or coincidence? Br. J. Cancer
30: 199-208 (1974).
94. Mole, R.H. Ionizing radiation as a carcinogen:practical questions and academic pursuits.
Br. J. Radio!. 48: 157-169 (1975).
95. Mole, R.H. Personal communication.
96. Mori, T., Y. Nozue, T. Miyazi et al. Thorotrast
injury in Japan. p. 175-192 in Proceedings of theThird International Meeting on the Toxicity ofThorotrast. Danish Atomic Energy Commission
report Ri59 No. 294 (1973).
97. Moriyama, I. M. and H. Kato. Mortality experienceof A-bomb survivors 1970-1972. 1950-1972;
JNIH-ABCC Life Span Study Report 7, Technical
Report 15-73.
98. Munk. J ., E. Peyser and J. Grusskiewicz. Radiationinduced intracranial meningiomas. Clin. Radio!.
20: 90-94 (1969).
99. Myrden, J. A. and J.E. Hiltz. Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis.
Can. Med. Assoc. J. 100: 1032-1034 (1969).
10. Myrden. J. A. and J. J. Quinlan. Breast carcinoma
following multiple tluoroscopies with pneumothorax treatment of pulmonary tuberculosis.
Annals of Royal College of Physicians andSurgeons of Canada 7: 45 (1974).
101. Nakamura. K. Personal communication.
102. Newcombe, H. B. and J. F. McGregor. Childhood
cancer following obstetric radiography. Lancet 2:1151-1152 (1971).
103. Newill, V. A. Distribution of cancer mortality
among ethnic sub-groups of the white populationof New York City, 1953-1958. J. Natl. Cancer
Inst. 26: 405-417 (1961).
104. Nishiyama, H., R. E. Anderson, T. Ishimaru et al.
The incidence of malignant lymphoma andmultiple myeloma in Hiroshima and Nagasaki
A-bomb survivors 1945-1965. Cancer 32:
1301-1309 (1973).

120. Smith, P. C., R. Doll and E. P. Radford. Cancer
mortality among patients with ankylosing spondylitis not given x-ray therapy (in press).

105. Nitze. H. R. Radiogene Tumoren in H.N.O. Bereich. Archiv fiir Klinische und Experimentelle
Ohren-. Nasen- und Kehlkopfheilkunde 199:
634-638 (1971).

121. Raven, R. W. and V. B. Levison. Radiation cancerof the pharynx. Lancet 2: 683-684 (1954).

106. Osborn, S. B. Radiation doses in radiographic
pelvimetry. Br. J. Radiol. 24: 174 (1951).
107. Palmer, J.P. and D. W. Spratt. Pelvic carcinoma
following irradiation for benign gynaecologicaldiseases. Am. J. Obstet. Gynaecol. 72: 497-505(1956).
108. Paloyan, E., A. M. Lawrence, M. H. Brooks and
J. R. Picleman. Total thyroidectomy and parathyroid autotransplantation for radiation associated thyroid cancer. Surgery 80: 70-76 (1976).
109. Parker, L. N. J. L. Belsky, T. Yamamoto et al.
Thyroid carcinoma diagnosed between 13 and26 years after exposure to atomic radiation. A
study of the ABCC-JNIH Adult Health Study
Population Hiroshima and Nagasaki 1958-71.
Technical Report 5-73.
110. Pegum, J. S. Radiation induced skin cancer. Br. J.
Radiol. 45: 613-614 (1972).
111. Petersen, 0. Radiation cancer. Report of 21 cases.
Acta Radiol. 42: 221-236 (1954).
112. Pifer,J.W., E.T.Toyooka, R.W.Murray et al.
Neoplasms in children treated with X-rays forthymic enlargement. I. Neoplasms and mortality.
J. Natl. Cancer Inst. 31: 1357-1377 (1963).
ll3. Plarek, V. and J. Sevc. K otazce rizika rakoviny
hrtanu u horniku uranovych dolu. Prac. Lek. 27:
113-115 (1975).
114. Pochin, E. E. Untoward effects of radioiodine
treatment of hyperthyroidism. Minerva Nucleare
8: 106-110(1964).
115. Pochin, E. E. Prospects from the treatment of
thyroid carcinoma with radioiodine. Clin. Radiol.
18: 113-125 (1967).
116. Pochin, E. E. Frequency of induction of malignancies in man by ionizing radiation, p. 341-355 in
Handbuch der medizinischen Radiologie. Springer
Verlag, Berlin, 1972.
117. Pochin, E. E. Problems involved in detecting
increased malignancy. rates in areas of high naturalradiation background. Health Phys. 31 : 148-151(1976).

122. Raventos, A. and T. Winship. The latent interval
for thyroid cancer following irradiation. Radiology
83: 501-508 (1964).
123. Refetoff, S., J. Harrison, B. T. Karanfilski et al.
Continuing occurrence of thyroid carcinoma after
irradiation to the neck in infancy and childhood.
New Engl. J. Med. 292: 171-175 (1975).
124. Registrar-General's Statistical Review, England andWales, for 1968-70. Supplement on Cancer. Her
Majesty's Stationery Office, London, 1975.
125. Rossi, H. H. and A. M. Kellerer. Radiation carcinogenesis at low doses. Science 175: 200-202 (1972).
126. Rowell, N. R. Microanatomy and thickness of theskin. Br. J. Radiol. 45: 610 (1972).
127. Rowland, R. E., P. M. Failla, A. T. Keane et al.
Some dose-response relationships for tumour
incidence in radium patients, p. 1-17 in Radiological Physics Division, Center for HumanRadiobiology
AnnualReport,July 1969June 1970. U.S. Atomic Energy Commission
report ANL-7760 (Pt. 2).
128. Saenger, E. L., F. N. Silverman, T. D. Sterling etal. Neoplasia following therapeutic irradiation for
benign conditions in childhood. Radiology 74:
889-904 (1960).

0. P. Schumacher, A. Rodriguez.
129. Safa, A. M.,
Antunez. Long-term follow-up results in children
and adolescents treate~ with radioactive iodine(iodine-131) for hyperthyroidism. New Engl. J.
Med. 292: 167-171 (1975).
130. Sampson, R. J ., C. R. Key, C. R. Buncher et al.
Prevalence of thyroid carcinoma at autopsy,
Hiroshima 1957-1968, Nagasaki 1951-1967.
Atomic Bomb Casualty Commission report
ABCC-TR 25-58 (1968).
131. Schulz, R. J. and R. E. Albert. III. Dose to organsof the head from the x-ray treatment of tinea
capitis. Arch. Environ. Health 17: 935-950 (1968).
132. Segi, M., M. Kurihara and T. Matsuyama. Cancer
mortality for selected sites in 24 countries
1964-1965, No. 5, Sendai, Japan, Dept. of Public
Health, Tohoku Univ. School ofMed., 1969.
133. Seideman, H. Cancer death rate by site and sex for
religious and socio-economic groups in New York
City. Environ. Res. 3: 234-250 (1970).

118. Pochin, E. E. Personal communication.
119. Pointon, R. C. S. Personal communication.

134. Seltser, R. and P. E. Sartwell. The influence ofoccupational exposure to radiation on the421mortality of American radiologists and othermedical specialists. Am. J. Epidemiol. 81: 2-22
(1965).
135. Sevc, J. and V. Placek. Radiation induced lungcancer; relation between lung cancer and long term
exposure to radon daughters. Proceedings of Sixth
Conference on Radiation Hygiene, CSSR, 1973.
136. Sevc, J., E. Kunz and V. Plarek. Lung cancer inuranium miners and long-term exposure to radon
daughter products. Health Phys. 30: 433-437(1976).
137. Sevcova, M.. J. Sevc and J. Thomas. Alpha irradiation of the skin and the possibility of late effects(in press).
138. Shore, R. E. Personal communication {1976).
138a. Shore, R., L. Hempelmann, E. Kowaluk et al.
Breast neoplasms in women treated with x-rays for
acute postpartum mastitis. J. Natl. Cancer Inst (inpress).
139. Shore, R. E., R. E. Albert and B. S. Pasternack.
Follow-up study of patients treated by X-ray
epilation for tinea capitis. Arch. Environ. Health
31: 21-28 {1976).
140. Silink, K., J. Soumar and J. Nemec. Occurrence
and pathogenesis of childhood thyroid cancer.
Neoplasma 20: 465-469 ( 1973).
141. Silva Horta, J. da. Tumours developed in people
injected with thorium dioxide (Thorotrast) (Portuguese experience). p. 233-258 in Proceedings of
the Third International Meeting on the Toxicity ofThorotrast. Danish Atomic Energy Commission
report Ris0 No. 294 {1973).
142. Smith. P. G. and R. Doll. Late effects ofX-irradiation in patients treated for metropathia haemorrhagica. Br. J. Radio!. 49: 224-232 {1976).
143. Smith, P. G. Personal communication.
144. Snihs, J. 0. The approach to radon problems in
non-uranium mines in Sweden, p. 900·91 l in
Proceedings of Third International Congress of the
IRPA. U.S. Atomic Energy Commission report
CONF-730907 (1973).
145. Spiess, H. and C. W. Mays. Bone cancers induced
by 224-Ra (ThX) in children and adults. HealthPhys. 19: 713-729 {1970).
146. Spiess, H. and C. W. Mays. Protraction effect onbone sarcoma induction of 224-Ra in children andadults, p. 437-450 in Radionuclide Carcinogenesis.
U.S. Atomic Energy Agency Symposium SeriesNo. 29, Washington, 1973.
147. Spittle, Margaret F.
{1976).
422

Personal

communication

148. Stewart, A. M. Measuring latent periods of juven·ile cancer. Proc. R. Soc. Med. 62: 684 (1969).
149. Stewart, A. M. and G. W. Kneale. Letter to theeditor. Lancet ii: 1190 {1970).
150. Stewart, A. M. and G. W. K.neale. Radiation dose
effects in relation to obstetric X-rays andchildhood cancers. Lancet ii: 1185-1188 {1970).
151. Stewart. A. M. Cancer as the cause of abortion andstillbirths; the effects of these early deaths on therecognition of radiogenetic leukaemias. Br. J.
Cancer 23: 465 {1973).
152. Stewart, A. M. Factors controlling the recognitionof leukaemia and childhood cancer in Health
Physics and Healing Arts. 7th Media TopicalSymposium of the Health Physics Society. U.S.
Department of Health. Education and Welfare.
1973.
152a. Takeichi, N., F. Hirone and H. Yamamoto.
Salivary gland tumours in atomic bomb survivors,
Hiroshima, Japan. I. Epidemiological observations.
Cancer 38: 2462-2468 (1976).
153. Toyooka, E.T .. J. W. Pifer, S. L. Crump et al.
Neoplasms in children treated with X-rays forthymic enlargement. II. Tumour incidence as afunction of radiation factors. J. Natl. Cancer Inst.
31: 1357-1377 (1963).
154. United Nations. General Assembly. Report of theUnited Nations Scientific Committee on the
Effects of Atomic Radiation, 1964. Official
Records of the General Assembly, Nineteenth
Session, Supplement No. 14 (A/5814).
155. United Nations. A report of the United Nations
Scientific Committee on the Effects of Atomic
Radiation to the General Assembly, with annexes.
Vol. II: Effects (United Nations publication, sales
No. E.72.IX.18), New York, 1972.
157. Vanderlaan,M., F.J.Bums and R.E.Albert. A
model describing the effects of dose and dose rateon tumour induction by radiation in rat skin,p. 253-263 in Biological and Environmental
Effects of Low-Level Radiation. Vol. 1. IAEA
publication STI/PUB./409, Vienna. 1976.
158. Wanebo, C. K., K. G. Johnson. K. Sato et al.
Breast cancer after exposure to the atomic
bombing of Hiroshima and Nagasaki. New Engl. J.
Med. 279: 667-671 {1968).
159. Werner, A., B. Modan and D. Davidoff. Doses tobrain, skull and thyroid following x-ray therapy
for tinea capitis. Phys. Med. Biol. 13: 247·258{1968).
160. Werner. A., B. Modan and E. Ron. Thyroid dosimetry re-evaluation after treatment for scalp tinea.
Communication given at 14th International
Conference on Medical Physics, July 1976,
Ottawa.

166. Yamamoto, T. and T. Wakabayashi. Bone tumours
among atomic bomb survivors of Hiroshima andNagasaki. Acta Pathol. Jpn. 19: 201-212 (1969).

J61. Whitton , J. R. New values for epidermal thickness
and their importance. Health Phys. 24: 1-8 (1973).
162. Wilson, S. M., C. Platz and G. M. Block. Thyroid
carcinoma after irradiation. Arch. Surg. 100:
330-337 (1970).

167. Yoshizawa, Y. and T. Takeuchi. Search for thelowest irradiation dose from literatures onradiation induced cancer in pharynx and larynx.
Nippon Acta Radiologica34: 903-909 (1974).

163. Wood , J. W.. H. Tanagaki, S. Nerrishi et al. Thyroid carcinoma in atomic bomb survivors,
Hiroshima and Nagasaki. Am. J. Epidemiol. 89:
4-14 (1969).

168. Yoshizawa, Y. and T. Kusarna. Search for thelowest irradiation dose from literatures onradiation induced breast cancer. Nippon Acta
Radiologica 35: 1125-1130(1975).

164. Woolner, L.B. et al. Occult papillary carcinoma of
the thyroid; a study of 140 cases observed in a 30
year period. J. Clin. Endocrinol. 20: 89-105(1960).

169. Yoshizawa, Y., T. Kusama and K. Morimoto.
Search for the lowest irradiation dose fromliteratures on radiation induced bone tumours.
Nippon Acta Radiologica 37 (4) (1977) .

165. Yamamoto, T. and T. Wakabayashi. Bone tumours
among atomic bomb survivors, 1950-1965 ,Hiroshima and Nagasaki. Atomic Bomb Casualty.Commission report ABCC-TR 26-28 ( 1968).

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