SOURCES, EFFECTS
AND RISKSOF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
1988 Report to the General Assembly, with annexes

UNITED NATIONSNew York, 1988

NOTE
The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Forty-third Session, Supplement No. 45 (A/43/45).
The designations employed and the presentation of material in this publication d o
not imply the expression of any opinion whatsoever on the part of the Secretariat of theUnited Nations concerning the legal status of any country, territory, city or area. or of its
authorities, or concerning the delimitation of its frontiers o r boundaries.

UNITED NATIONS PUBLICATION
Sales No. E.88.IX.7
ISBN 92-1- 142143-8
09000PANNEX F
Radiation carcinogenesis in man

CONTENTS. ..... ....... ... ....

Paragraphs

14VTRODUCTIOh' . . .

I.

1-5

GENERAL CONSIDERATIONS . .. .

65%

.

6-29

A.

Terms. approaches and concepts . .
1. Terms and units of radiation
exposure ..................
2. Concepts of risk .. . . . .. . ...
(a) Dose-response pattern . .
(b) Risk measures and projection
3. Assignment of causation . . ...
4. The analytic approach to radiation carcinogenesis.. . . . . .

.

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

..

.

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

B. Sources of data.. ..
I.
2.
3.
4.
5.
6.
C.

Special exposed cohorts . . .. .
Patients treated with therapeutic radiation . .. ...... . .
Individuals receiving diagnostic
examinations ...............
Occupational groups . . . . . . . .
Populations receiving chronic
exposures ..................
Accident victims.. . . . .. . . . .

.

.

.

Types of studies . .. . . . . . . . . . . . .
1. Cohort studies . . . . . . . . . . .
(a) Ongoing investigations(b) Ascertainment of exposedand comparison individuals .................
(c) Suitability of comparisongroup ................
(d) Accurate determination of
expected risks.. ... . . . . .
(e) Meaning of relative risk
in a changing exposure
environment . . . . . . . . . . .
( f ) Identification of new exposed cohorts.. . . . . . . . .
2. Case-control studies. . .. . . ...

..

Paragraphs

11. ASSESSMENT O F DOSE-RESPONSE
AND RISK PROJECTION.. ..... . . .
A.

6-8
9-19
10-1 1
12-19
20-22

B.

23-29
30-37
31

C.

32
33
34

Problems associated with assessment
I . Form of the regression of
response on dose . .. .. . . . . . .
2. Contingency tables and proportional hazard models.. . . .
3. Mortality versus morbidity
data ......................

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

38-58
39-57
3944

59-66
59-62
63-64
65-66

Dose-response patterns . .. .. . . . . .
1. Assessment of the effects of low
dose ......................
2. Assessment of the effects ofhigh dose.. ....... .... .. . . .

67-76

Risk projection ... . . . . . . . . . . . . .
Latency time and the platcau
period ....................
Excess and baseline risk as afunction of time since exposure
Age and sex structure of the
population and baseline mortality rates . . ... . . . .. . . .. .
Age at exposure . . . . .. . . . . .
The dose-response function . .
Other exposure factors . . . . . .
Previous approximations oflifetime risk projection . . . . . .
Risk coefficients for high-LET
radiation . . . . . . . . . . . . . . . ..
Selection of preferred projection model.. . .. . . . . . . ... ...

77-1 19

.

.

35
36-37

59-1 19

.

68-72
73-76

.

.

35-47
48
49-50
5 1-5253-57
58111. BIOLOGICAL ISSUES IN THE
ASSESSMENT O F RADIATIONCARCINOGENESIS . . . . . . . . . . . .

..

A.

. 120-432

Biological models of radiation carcinogenesis .. . . ..... . . . .. . . . . . .
1. Multi-stage models and the roleof radiation in carcinogenesis

12 1- 15 1
12 1-1 35

Paragraphs

Paragraphs

2. Consideration of results ofoncogene studies in statisticalmodels . . . . . . . . . . . . . . . . . . . .
3. Does radiation induce uniquecancer characteristics at thecellular level? . . . . . . .. . . . . . .
4. Causal mechanisms: gene activation or inactivation?. . . . .

F.

Other diseases.. . . . . . . . . . . . . . . . .

.

THAT MODIFY RISK . . . . . . . .. . . .

Tissue susceptibility in children. . . .
1. Exposures in utero.. . . . .. . .
2. Exposures in childhood.. . . . .
la) Children exposed to radiation for treatment ofprimary cancers.. . . . ...
(b) Children exposed to radiation for treatment ofbenign conditions . . . .. .
(c) Children
exposedtoatomlc bombings and fallout...................
(d) Exposure of the female
breast in childhood and at
perimenarch~alages . . ..
3. Tissues apparently not susceptible to radiation-induced
carcinogenesis . . . . . . . . . . . . . .
4. Summary ofexposure effects inchildren . . . . . . . . . . . . . . ..

.

.

Hormonal effects . . . . . . . . . . . . .. .

V. E N V I R O N M E N T A L F A C T O R S

..

B.

E.

Smoking .

B.

Diet. .........................

C.

Interaction between therapeuticmodalities . . . . . . . . . . . . . . . .. . . . .

D. Statistical reflection of high population risks.. . . . . . . . . . . . . . . . . . .

..

E.

VI.

A.
B.

. .

Adultsexposed to radiation fortreatment of primary cancers(a) Treatment for Hodgkin's
disease. . . . . . . . . . .
(b) Treatment for cervicalcancer . . . . . . . . . . . . . .
( c ) Treatment for ovariancancer . . . . . . . . . . . . . . . .
( d ) Treatment for breast
cancer . . . . . . . . . . . . . . . .
2. Adultsexposed to radiation for
Immune suppression . . . . . . . .
3. Leukaemogenesis in cancer
radiotherapy generally. . . . . . .
4. Adults exposed to radiation fortreatment of benign conditions(a) Haematopoietic tissue. . .
(b) Son-dividing tissue.. . . .
(c) Dividing non-epithelial. . .. .
. .

.
. . . . ..
D. Uncertainties associated with risk
projections . . . .. . . . . . . . . . . . . .. .

C.

VII.

A.

B.

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

~ISSU~.

434-435. .
..

438-441C.

436-43944044 1442-450

351

General considerations.. .. . ..... .
1. Whole-body risk coefficients
2. Site-specific risk coefficients
Summary of risk projection methods
and risk estimates.. . . . . . . . . . ... .
The basic projection model
Analytical expression of themodel ....................
Calculation of the loss of life
expectancy ................
Demographic and backgroundepidemiological data required
The computational process~ e f e r e n c e ~ o ~ u l a t i.o.n. .. . .
Risk coefficients . . . . . . .. .
Indexes of harm . . . . .. . . .. .
Treatment of uncertainty . . .
Fractionated and low-doserate exposure . . . . . . . . . . . . .

..

433-457

B.

.

Uncertainties associated with risk
. ... . . . . . .. . .
estimates. . .

RISK PROJECTIONS.. . . . . . .. . . .

(d) Epithelial tissue .. . . . . . .
5. Occupationaily exposed adults
6. Exposurcs to elevated cosmic
and terrestrial radiation . .. .
7. Summary ofexposure effects inadults .....................

Sex ....... .... .. . .. ...........
Age of onset of tumour~i n exposed
adults: single and chronic exposures
1. Exposure to the atomic bombings in Japan. . . . .. . . . . . . . .
2. Exposures to nuclear tests andfallout . .. . . . . . . . . . . . . . ..
C. Genetic constitution.. . .. . . . . . .
D. Ethnic characteristics .. . . . . .. . . .

Studies providing summary risk
estimates . . .. . . . . . . . . . . . . . . . . . .
Projection of relatire risk in the
major studies . . . . . . . . . . . .. . . . . .
I . Results from exposure to treat
cervical cancer .. . . . . . .. .. . .
2. Results from exposure to treat
ankylosing spondylitis . . . . . .
3. Joint analysis of Japanese(T65D) and ankylosing spondylitis data . . . . . . . . . . . . . . . .
4. Recent results from studies of
the Japanese exposed to theatomic bombings . . . . . . . . . .

.

I.

4.

General considerations about interactions. . . . . . . . . . . . . .. . . . . . . .. .

SUMMARIES O F RlSK ESTlhfATES
IN iMAJOR COHORTS.. . . . . . . . . . . .

C. 'rissue susceptibility in adults . . . . .

1V. HOST F.ACTORS T H A T MODIFYRISK .............................

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

.4.

.. .
.

Results of projections.. . . . . . . .
I . The adult population.. . . . . .
(a) Excess lifetime mortality:
leukaemia .... . . . ... . .
(b) Excess lifetime mortality:
all cancers other than
leukaemia..........

.

...

Paragraphs

Loss of life expectancy:
leukaemia .............
(d) Loss of life expectancy: allcancers orher than leukaemia ..................
2. The population of children as apart of the population .......
3. Extrapolation to other populations. .....................
4. Comparisons with previous
studies ....................
D. Risks at low doses and low -dose rates

Poragraphs

I

Lifetime risk estimates for special
tissues ........................
I. Lung .....................
2. Bone.. ....................
3. Thyroid ...................
F. Risk assessment by cancer type. ...
C. Summary and conclusions ........
E.

(c)

571
572-574575-586587-590

59 1-599

600-607

Introduction
1. Carcinogenesis is the main late-stage somatic effectof ionizing radiation. The malignancies induced byirradiations are indistinguishable from those occurringfrom many other causes. Therefore, the observationsof these effects in man have been limited to study
populations who were more highly exposed in various
ways and for various reasons. These results form theprimary basis for assessments by UNSCEAR of therisks of ionizing radiation.

2. Previous UNSCEAR Reports on radiation carcinogenesis in man [U2, U3] have adopted a site-specificapproach, focusing on cancers of the breast. lung,thyroid and on leukaemia. This was inherent in thebasic descriptive epidemiological results available.
There has always been a desire to interpret resultsfrom the standpoint of an understanding of themechanisms of carcinogenesis. While there have beensome developments, particularly in the field of molecular biology. that are relevant and are reviewed here.
the updated and revised epidemiological results continue to serve as the primary basis for the risk
assessment. This Annex, however. attempts a more
analytical approach to risk evaluation. especially for
projection of risks beyond observational experience.
3. It is particularly propitious that risk assessments
be made now, in light of the revised dosimetricevaluations of the Japanese survivors of the atomic
bombings. the most important study population. This
re-evaluation, completed in 1986 and known as thedosimetry system 1986 (DS861, replaces the previous
estimates of 1965 (T65). Not all of the revisions could
be taken into account in analysing cancer incidence
frequencies, but the latest values are used in theCommittee's analytical evaluation of risk coefficientsfor mortality.
4.

Tables .................................

Of all of the factors that affect the carcinogenesis
process, age at exposure is particularly significant.
Susceptibility of tissues to radiation effects is related
to proliferative activity of cells, a n d periods of active
growth and development can be expected to beperiods of greater sensitivity. There are difficulties.
hon.ever. in accounting for age differences. Many
study populations involve individuals of particularpredispositions exposed under special circumstances.
Data from individuals who were youngest at the timeof the atomic bombings are incomplete, as they are
just now entering the important stage in their lateadult lives when cancer prevalence increases.
5. There are many reasons for uncertainties in therisk assessments. A main concern that cannot beadequately resolved is how to relare the results
obtained at high doses and dose rates to the low levelsof exposure that may be expected in environmental
and routine occupational settings. The difficulties anddevelopments in the field of radiation carcinogenesis
are discussed in this Annex. The risk evaluations
provided by the Committee reflect the current best
knowledge and approaches and are put forward toserve as background information for consideration ofinternational and national bodies of radiation protection.

I.
A.

GENERAL CONSIDERATIOSSTERMS, APPROACHES A N D CONCEPTS
1.

Terms and units of radiation exposure

6 . A variety of units are or have been used for thequantities needed in assessments of exposures toionizing radiation. However, it having been decided toadopt the modern metric system, the Systkme International (SI); throughout this Annex, SI units will be
used wherever practicable. A detailed account of thecorrespondence between the older units and the SI
units is found in [N3]. For the reader unfamiliar withthese units, it is sufficient to note that 1 rad, the oldunit for absorbed dose, equals 0.01 gray (Gy); 1 rem.
the old unit for dose equivalent. equals 0.01 sievert(Sv); and, finally, the curie (Ci). the old unit for
activity, equals 3.7 10'O becquerel (Bq).

7. The subjective expressions "low", "intermediate","high" and "very o r ultra-high" as applied LO absorbed
doses of sparsely ionizing radiation are arbitrarily
defined here. following the convention established in
the UNSCEAR 1986 Report [UI], as 0-0.2. 0.2-2.0.
2.0-10.0, and above 10 Gy, respectively. For othertypes of radiation the corresponding dose equivalent
ranges are the same, but with units of sievert. This
correspondence does not necessarily reflect RBE, butrather assigned quality factor values. Following thesame convention, "low" dose rates for all radiations
are those below 0.05 mSv/min; "high" dose rates arethose above 0.05 Sv/min; and "intermediate" dose
rates fall between the two figures quoted.

8. Exposure of the lung to alpha particles fromradon daughter products is customarily expressed interms of working level (WL) or working level months(WLM). The WL is any combination of radon and its
daughter products in a litre of air that will result in
the emission of 1.3 loS ,MeV of potential alpha energy;
the WLM is the exposure resulting from the inhalationof air with a concentration of 1 WL of radon
daughters for 170 (working) hours.

2.

to high doses may be prevented from dividing by thesterilizing (or cell-killing or inactivation) effects ofirradiation. These matters have been thoroughly discussed in Annex B of the UNSCEAR 1986 Report.
11. The age, sex and other characteristics of the
exposed individual may o r may not be specified inassessing the dose-response pattern. Similarly, the age,
the time since exposure and the end-point used t oassess the response may vary from one application t oanother. In practice, all data from the time of
exposure to the time of analysis are often pooled, andthe cumulative excess risk in the exposed population,commonly expressed as excess deaths or incident
cases, is related to the dose received. However, inprinciple, there may be significant differences in thedose-response relationships between different groupsof people. e.g., between exposed children and adults.
These might be reflected as host-factor effects on the
shape of the dose-response function.

Concepts of risk

9. Conventionally, the risk associated with exposure
to radiation. either sparsely or densely ionizing, hasbeen expressed in absolute o r relative terms. Absoluterisk is usually taken t o mean the absolute increase in
the frequency of cancer, mutation. or the like. and theabsolute risk coefficient is the increase per unit
exposure per unit time of risk after adjustment for
confounding variables. Commonly, it is defined as theexcess deaths o r incident cases per gray (or rad) per
ten thousand (or million) person-years and is estimatedby regressing the difference between the observed
number of events and the expected number, based ona suitable comparison group o r population, as afunction of dose (see, e.g., [K7] or [W5]). Relative risk
is the ratio of the number of cases observed in an
exposed population to the number of cases expected ina non-exposed, but otherwise comparable. population.
(a) Dose-response parrern
10. One objective of risk assessment is to estimate
the relationship between the dose administered andthe response elicited, specific to exposed individuals ofdiffering ages, sex, or other biological characteristics.
This relationship is called the dose-response relationship, and is an expression of the formr = f(D)where r is a defined measure of response, e.g., a risk
quantity, usually an excess absolute o r excess relativerisk, and f(D) is a function of absorbed dose. The
function f(D) commonly takes one of the following
forms: (a) linear, i.e., a + b D ; (b) linear, non-threshold,better called proportional, i.e., bD; (c) quadratic, i.e.,a -+ b D + cD2; (d) pure quadratic, i.e., cD2; (e) properorder polynomials. In addition, any of these forms
may be modified by multiplying by a n exponential
term with the exponent containing negative terms in D
and D2. A quadratic term in the dose-response
function is usually included wh'en the effects at low
doses are less than would be predicted by a strictly
linear response to dose at intermediate doses. For
dose-response relationships going through a maximuma t intermediate doses, it is assumed that cells exposed(b) Risk measures and projecrion

12. A second objective of assessing risk is to follow
individuals after exposure has begun. or after it iscomplete, a n d to quantify the excess cancers during
the lifetime of groups of such individuals. Since theindividuals may vary in other respects than simply
their ages. different assessments may be made for eachsex, age at exposure, exposure to other risk factors
and s o on. It may also be important to be able t opredict future risk in exposed cohorts, even t o ages
beyond those for which current estimates exist.

13. In this Annex. the assessment of events after
exposure and beyond the period of observation will bereferred to as the projection of risk. When the risk inthe exposed individuals exceeds the spontaneous (nonexposed) risk level by the same amount at all ages, theeffect of exposure will be termed additive (often theterm absolute has been used in this context, since at
all ages the excess risk is constant). When the risk t o
the exposed is some constant fraction greater than the
spontaneous risk, this will be termed a multiplicative
effect (often the term relative has been used, in thesense that at all ages after exposure the relative risk,o r risk ratio, is constant). Actual effects map fit
neither of these simplified models, or they may fit
some combination of them.
14. When the risk experiences of several age (orother) strata are combined into a single summary
measure, one must be aware of the nature of the
exposure experiences over which the single value iscomputed. If no method is specified in the naming ofsuch a measure, then n o assumptions can be madeabout the way in which aggregate data were used t ocompute the expected risk. When the measures are
single values derived from the cumulative experienceof a n exposed cohort, this will be referred to as thetotal relative o r absolute risk.
15. The excess risk is usually computed from the risk
in a comparable group, either the population a t largeo r a control group. When using an unexposed control
group matched by age and sex, the number of cases inthat control group is considered to be the baseline
number. Often. however, the control group is theentire population of which the exposed are a part. The
risk schedule in that population. say r(s), is the annual
incidence (or mortality) per person at age .r per year;
this can also be made specific to sex and historicaltime period. In a cohort of exposed persons. over thecourse of the investigation, a certain number of
person-years of experience at age x will arise: this is thesum of all years spent by exposed cohort members at age
x. Let this number be c(x). Then the expected number ofcancers in the cohort, E, can be approximated by
E = ~c(x)r(.v)
and the excess number of cases is the observed
number, 0 , minus the expected number, 0 - E . The
number of person-year-grays (PYGy) of exposure towhich this excess applies is the sum over all exposed
individuals of the product of the dose to the i-th
individual, di, times the number of years that individual was followed in the study (up to the point of
manifesting the cancer of interest) yi. That is. summingover the n individuals in the cohort,

N = Ed,yi

years of observation or by pooling individuals withdifferent ages at exposure o r pooling both sexes. Suchmeasures are dependent on these pooling o r aggregating procedures and may not be comparable between
studies. Computation of an absolute risk in this way
does not imply that the projection effect (on postexposure age-specific risks) is additive, nor does
computing relative risk mean that the projection effectis itself multiplicative.
19. For these reasons, it is necessary to distinguishbetween the projection effect (additive or multiplicative) and the measure of risk based on observational
data (absolute risk. that is, excess deaths o r cases.
relative risk. attributable risk [see paragraph 221). Thisdistinction is not always clear in the literature. where
the same terms are often used in both circumstances.
T o make i t quite clear, when projection effects arereferred to in this Annex. the terms multiplicative o radditive will be used; when measures in data arereferred to, the terms absolute or relative risk will be
used.
3.

Assignment of causationI

The desired summary measure is then (0-E)/N excess
cases per 10' PYGy. Note that this measure aggregates
the experience of different ages and that i t is possible
to obtain the same value for N by including exposedcohorts of different age distributions, followed for
differing lengths of time, to a different distribution ofdoses. Life-table methods can make the computationof expected numbers of cases somewhat more precise
by accounting for the fraction of the exposed cohort
expected to die from causes of mortality other thanthe cancer of interest.
16. The relative risk is usually computed simply as
O/E, again aggregating the experience of individuals
at different doses and of different ages. When theirradiated population is actually a subset of thecomparison population under scrutiny. this ratio is
not strictly the relative risk of exposure compared to
non-exposure. and in this case 100 times (O/E),
should be referred to as the standardized mortality(or morbidity) ratio (SMR); however, because of its
nearly universal use in radiation epidemiology, theterm relative risk (RR) will be used, in general, for theratio of the observed to the comparison group.

17. In addition to depending o n the details of the age
pattern of cases since exposure. relative t o age at
exposure and dose, both of these measures also dependo n the background, or baseline, risk in the population[r(x)]. SO that it may be difficult to apply excess deaths(cases) o r relative risk estimates to populations epidemiologically different from the exposed population.
18. In the latest reports on the survivors of Hiroshima
and Nagasaki [P15, S48. S491, excess relative risk, at
1 Gy of exposure, has been computed. This is theexcess relative risk value (i.e.. RR-I) over all age, sex
a n d other strata in the data. This measure combines
aspects of the other measures, but is still a single,
cumulative measure of effect. Relative o r absoluterisks can always be calculated in this manner. For
example, they can be computed after any number of

20. An increasingly frequent question addressed toradiation biologists is whether a specific cancer could
have been radiation-induced. This question may arise
in litigation. in the adjudication of occupational
compensation o r in the legislative process o r it may
arise through simple curiosity. Rarely, if ever, is it
possible to state categorically that a specific cancer
was o r was not due to radiation exposure. At present.
there is typically no radiation-specific tumour pathobiology. a n d radiation-related tumours appear similar
to spontaneous tumours at the same site. Inasmuch a ssome tumours that are extremely rare in the general
population are much more common after radiation. it
may be that radiation alone is able to produce atumour. In general, however. radiation exposure
only increases the frequency of an already prevalent
tumour.
21. Despite these conceptual problems, it is possible
to consider causation in a probabilistic manner [B17].
Briefly, if an outcome. A, can occur only when one ofa series of exhaustive and mutually exclusive eventsoccurs, and if the a priori probabilities of these latter
events are known, then it is possible t o compute theconditional probability that A is due to a specific oneof the series of events. This latter, conditional probability is sometimes described as the a posteriori
probability of the event. In the present context, theprobability of causation, P, or. more formally (given
the occurrence of a cancer in an exposed individual),
the probability that it is due to radiation (one of aseries of presumably mutually exclusive causes ofcancer) is simply the ratio of the additional risk
imposed by the radiation dose D to the total risk; thelatter is, of course, the sum of the baseline risk a n d theradiation risk. It can be written as
P = [ D X R ] f l B + ( D X R)]
where R is the absolute annual site-specific risk pergray and B is the baseline cancer rate, specific for site.
age, sex and other pertinent concomitants.

22. A related, commonly employed epidemiologicalnotion is that of attributable risk. The latter is the
proportion of a health disorder that can be attributedt o a causal factor. Epidemiologists use a variety ofmathematical definitions of attributable risk. One isderived by subtracting the incidence of the disorderamong persons not exposed to the factor, e.g.,
ionizing radiation. from the incidence among persons
who were exposed. Thus, in the present context. it ismerelyAttributable risk =4.

observed - expected cases
person/years at risk

The analytic approach to radiation carcinogenesis

23. There are a number of factors that influence therisk of cancer in individuals exposed to radiation.
These include the nature of the individual receiving
the dose. often known as the host (genetic background. general health, specific health problems, sexetc.); the nature of the dose received (high or low,
acute o r chronic, radiation quality); other factors that
may interact with radiation o r affect the susceptibilityof the host (e.g., smoking, diet, weight. exposures tochemicals. other diseases and medical treatments); andthe nature of the carcinogenic process itself. Becauseof the existence of these factors, there is no single way
in which effects should be assessed. Actually, several
approaches have been taken.
24. The first is to examine the relationship between
biological n~odelsof carcinogenesis and the effect ofdifferent exposures or host conditions. There havebeen many different attempts to model radiation
carcinogenesis. Generally. the parameters of the process are estimated using epidemiological data on
exposed individuals to infer the action of radiationand to estimate the relative importance of different
components of the process. T h ~ s componentseusuallyinclude mutation, mutation-repair, growth stimulationand cell sterilization. Specifically, various multi-stage
processes have been applied to the age-onset distribution of cancers following irradiation in an attempt todetermine the consistency of such processes with theaction of ionizing radiation and to infer which part ofthe process is affected by exposure. These investigations d o not provide risk estimates for a given dose,
but they d o suggest aspects of risk, such as vulnerable
ages, and whether the effects of exposure can be
expected to be long lasting o r not.
25. Another approach is to analyse dose-response
and risk-projection relationships. much effort has
been devoted to assess the response of various tissues
to differing exposure levels o r durations, and numerous
studies have sought to estimate the cancer risk atvarious dose levels. Interest has been particularly greatin extrapolating risks from high-dose data to lout
doses and from high dose rates to low ones. It is
assumed that most controllable exposures, such as
occupational ones, will involve much lower doses (andgenerally lower dose rates) than those experienced by
the studied populations. One goal has been to provide
risk estimates so that individual exposures. such as
those experienced for medical o r occupational reasons,can be controlled in an informed way, Another goalhas been to use the limited epidemiological data toinfer the risks that attend other conditions of exposure.
26. A continuing objective has been to determine,for given exposures and tissue sites, ivhether there is alinear or non-linear (specifically. quadratic) doseresponse relationship at low doses. This issue has beenstudied, without resolution, in animals and in man,for decades. There is still no unambiguous answer, but
in many cases newer data have contributed to theability to infer the existence o r non-existence of risk
thresholds or the likely forms of the dose-response
relationships, a subject treated at length in Annex B of
the UNSCEAR 1986 Report [UI].

27. A different approach to the dose-response relationship has also been taken [F6]. Species-specific parameters for a theoretical model of cancer have been
fitted to experimental data and used to estimate loudose response rates. While the theory seems to workfor cellular effects in vitro. it is not obvious that it
applies in vivo, where species-, individual- and tissuespecificities, as well as differences in the nature of
the radiation action, are not controllable and often
cannot be measured accurately. Ho~vever,a theoretical
approach is necessary when actual observational datad o not exist.
28. Finally, ?.here have been direct regression
approaches to risk assessments. Recently, multiple
regression theory has been extended to the evaluationof risk factors in a complex disease (exposure)phenomenon. This has been very useful in chronic
disease epidemiology and, given the nature of thedata, seems appropriate to assessing the risk ofradiation carcinogenesis. Several applications of thesemethods, generally those called proportional hazards
models (see, e.g., [K12]), have been made in thiscontext and will be reviewed.
29. Since the carcinogenic effects of very low doses
cannot be shown directly with existing data (see, forexamplc, [U5]) nor reliably extrapolated from highdose data (for a discussion of some of the problems
associated with extrapolation, see [D25]), the shape of
dose-response relationships at low doses of ionizing
radiation remains conjectural. An understanding ofthese relationships will involve a kno~vledgeof carcinogenesis as a biological process and the relation ofradiation to this process (e.g., [FS. F6]).

B.

SOURCES O F DATA

30. Data on radiation carcinogenesis in man can bederived from a limited number of sources. The maintypes of human exposures that have occurred and thestudy populations available are listed in Table 1.
These include the survivors of the atomic bombings ofHiroshima and Nagasaki; nbsenrers of nuclear tests
and those exposed to fallout: patients irradiatedtherapeutically to treat cancers or other disease
conditions: workers in nuclear installations, miners
and radiologists: individuals exposed at home toelevated levels of background radiation; and indivi-duals involved in nuclear accidents. The exposure
conditions have included single, multiple and chronic
irradiation from external and internal sources. The
main categories of exposure are reviewed below.
1. Special exposed cohorts

3 1. Xl~ichof the knowledge about radiation carcinogenesis still comes from the study of the Japanese
populations exposed during the atomic bombings at
Hiroshima and Fjagasaki and from data on MarshallIslanders exposed to substantial doses of fallout
during the testing of nuclear weapons. The accident at
the Chernobyl nuclear reactor in the USSR has also
exposed a sizeable number of people to non-trivial
doses, and their experience may become a valuable
source of information. These exposures have contributed importantly. and will undoubtedly continue tod o so, t o the limited data on the lifetime risks, withregard to all cancer sites and all ages and doses,
associated with acute radiation, t o an ostensibly
healthy and unselected population.

2.

Patients treated -ith therapeutic radiation

32. Numerous cohorts of individuals have been
identified to whom substantial doses of radiation wereadministered for various therapeutic purposes. The
doses were typically given over a short period of timea n d usually administered locally. Individuals in thesegroups were exposed, for example. to radiotherapy forcancer o r for ankylosing spondylitis or to radiation to
the thymus and thyroid for various reasons. t o thehead for tinea capitis or various parts of the body forhaemangiomas, to treat Hodgkin's disease or tosuppress the immune system to prevent the rejectionof tissue transplants. Although many of these exposures
no longer occur, other forms of radiation therapy
continue to increase. The Patterns of Care Study
sponsored by the American College of Radiology has
shown that in the United States over the 10 years fromthe first of its surveys, in 1973. to the fifth. in 1982,
the number of new radiation therapy patients per
thousand population per year has grown over 1795,
from 1.46 to 1.71. or from 304,020 to 401,263
individuals [KIO]. The improved survival of many
cancer patients means that there will be an increasing
amount of data on the risk of second cancers among
these people, especially those treated in childhood.
Such risks will have an impact on the management of
selected diseases and thereby o n the structure andprocess of clinical care and outcome [D6. H3, H4.
K9]. It is worth noting that the beams in the newer
radiological techniques are more sharply edged thanin the older techniques. and exposures can be more
readily restricted to the tumour itself.
3.

Individuals receiving diagnostic examinations

33. Millions of individuals have been exposed to low
doses of radiation for the diagnosis of a great varietyof conditions or for the monitoring of treatment. With
the continued improvement of roentgenographic andother diagnostic techniques and equipment. the doses
per examination are being reduced and the exposures
becoming more focused. The availability of ultrasound and magnetic resonance imaging techniques isalso diminishing the frequency with which ionizing
radiation is used. However, the development ofcomputerized tomographic methods. including positronemission tomography. and the various uses of radioisotopes for diagnostic purposes may have increased
the doses received and frequency of irradiations.
While the individuals exposed to moderate doses may
be few, diagnostic radiation, in general. is likely tocontinue t o be an important source of exposure. Since
these exposures usually occur where serious disease ispresent. risk-benefit analysis will be particularly valuable in justifying and optimizing them (see Annex C.
"Exposures from medical uses of radiation").

4.

Occupational groups

34. Several earlier groups of people have been
exposed to substantial doses of ionizing radiation overlong periods of time, commonly because the dangers
of such exposure were unrecognized. These groups
include radium dial painters, radiologists, radiology
technicians and industrial radiographers, all of whomwere exposed earlier in this century, and miners who
worked for many years in environments with highlevels of radon. The exposures have generally been in
the intermediate-to-high (0.2-10 G y ) dose range.

5.

Populations receiving chronic exposures

35. Many individuals are chronically exposed to low
doses (below 0.2 G y ) of radiation, but few have beenstudied as well-defined cohorts. Commonly they havebeen exposed because of the place in which they live.
or because of their occupations, o r because of various
medical o r other exposures (e.g.. those that involve
radioisotopes with long half-lives), or because of radioactive fallout. In man): countries, radon in homes may
be the largest single source of chronic exposure t o low
doses of ionizing radiation that the average person
confronts [C13]. Populations in all countries are
exposed, but the distributions of individual exposures
are largely unknown. Instances have been recorded of
persons residing in houses where the exposure toradon amounted to as much a s 30 WLM, that is,almost eight times the limit set for uranium miners.
These persons are usually unaware of the risk they
face, for their homes are not necessarily built o n o r in
the vicinity of mine tailings, but rather o n rockcontaining high levels of natural radioactive substances. Water sources ma): also contain radon that isreleased to air in the houses. While inhaled radon is
not chemically bound in body tissues nor is its
solubility in tissues high, the simultaneously inhaledradon daughter products are deposited in the respiratory tract. and these, notably the shorter-lived ones.
decay. exposing the bronchial epithelium. This isdiscussed in Annex A, "Exposures from natural
sources of radiation". As yet, there have been few
epidemiological studies of populations exposed intheir homes to radon and its daughter products thatenable reliable quantification of the risk of cancer ofthe bronchial tree.
6.

and matched normal individuals are ascertained andtheir prior exposure histories compared. These typesof investigations on available population groups are
outlined in Table 2.

Accident victims
1. Cohort studies

36. There will continue to be isolated cases of highexposures due to accidents of various sorts. Heretofore, these cases have provided little insight into thelong-term consequences of exposure to ionizing radiation, but with the establishment of a world-wide
Registry of Radiation Accidents at Oak Ridge in the
United States, they may become more informative[D7. F4]. At present the Registry lists more than
230 accidents; by far the largest number were the resultof either a mishandling of industrial, sealed radioisotope sources or an inadvertent exposure to x rays
used for quality control [S25]. Often the accidents
involved unsuspecting individuals, not a few of themchildren, who picked up a metal object and carried it
home, where they and other household members
became exposed, unknowingly, to the radiation emitted
by what was a metal-encapsulated source. No fewer
than 1,100 individuals are enumerated. 38 of whom
died, presumably as a direct consequence of their
exposure; about half of those who died received
significant exposures of 0.25 Sv or more to the wholebody or of 6 Sv locally to the skin, or of 0.75 Sv or
more to a critical organ. The accident at Ciudad
Juarez in Mexico is typical of the accidents thatinvolved general populations. There, a cobalt-60
source. improperly disposed of, resulted in the exposureof 300-500 individuals, some of whom received dosesof 0.5-1.0 Gy. A similar but more recent accident at
Goiania, Brazil, involved some 244 individuals. 54 ofwhom were subsequently hospitalized and 4 of whom
have died; exposure in that instance was to "'Cs.
Accidents have also occurred when fuel rods werebeing inserted or removed from reactors [see. e.g.,
W7, R78,W9]. In ihese latter instances. the subsequent
health experience of the exposed individuals is generally
being carefully scrutinized by the employing laboratories or utility companies.
37. In the review of radiation carcinogenesis that
follows, data from all these sources will be considered.
Of necessity, this review will overlap in some particulars with material contained in other UNSCEAR
documents. specifically in Annexes A and B of the
UNSCEAR 1986 Report [UI]. The reader should
consult these for further details and for aspects ofradiobiology that do not apply directly to humanradiation carcinogenesis. Thus, for example. no effort
will be made here to review the data on radiationinduced cancers in experimental animals.
C. TYPES OF STUDIES
38. Of the ways in which radiation carcinogenesis
may be studied,.two have predominated: (a) cohort
studies, in which individuals exposed in some special
way and individuals not exposed are compared. The
follow-up can be retrospective or prospective, or both;and (b) case-control studies, in which cancer cases(a) Ongoing invesrigarions
39. Most of the investigations in progress in 1977.
when UNSCEAR last reported on human radiation
carcinogenesis, have continued, and additional results
have since been reported. Moreover. the investigations
concluded prior to the last Report have received fresh
scrutiny and much of the older data has been
subjected to further analysis and interpretation. In
several instances. the early findings have been improved
and joint estimates of dose-response patterns mademore precise by combining data from several investigations (see, e.g., [Dl I] or [T16]). In other instances.
previous results have been called into question because.
for example, doubts had been cast upon the dose
estimates or ascertainment biases or because better,
later studies had yielded conflicting observations.
40. There are further data on women who received
chest fluoroscopy (to monitor pneumothorax), irradiation for mastitis. or other exposures to the breast inconnection with breast cancer [H6].These results
show (a) a higher susceptibility of the young; (b) dose
fractionation does not reduce the risk of breast cancer
in all studies; and (c) there is uncertainty as to thelevel of risk a[ low dose rates. Similarly, much has
been added to the literature on the effects of exposing
the thyroid to various kinds of irradiation in childhood [RI. S131. Quantitative estimates of dose-effects
have been improved; however, the pattern of radiationinduced thyroid cancer has been extensively reviewed,
leading to the suggestion that, while radiation does
have an effect at moderate doses, the clinical significance of this in terms of active thyroid cancer, rather
than subclinical thyroid changes, is not patent [C6,P4].
41. Studies of cancer following pelvic irradiation for
malignancies of the cervix have not discovered theexcess of leukaemia that had been expected [BIZ, B13.
W6], although cancers have appeared at other exposedsites and more information should arise as follow-up
cont'inues. New studies of cancer resulting from theuse of injected radioisotopes, including radium andThorotrast, have been reported, and substantial reanalysis of the older data has occurred. The doseresponse patterns of bone and liver cancer in relation
to sources of alpha-particle radiation have been
improved, but some concern has been voiced about
the meaning of estimates of effective dose to susceptible
cells, in the presence of local cell necrosis. Related
issues have been advanced in regard to lung, thyroid
and cenlical cancers. There are additional data on
leukaemia subsequent to diagnostic radiation. showing
very low frequencies of occurrence. and there isfurther information on individuals exposed to localized
high doses of therapeutic radiation for the treatmentof childhood cancers. Data on radium dial paintershave been re-analysed [RIO], and there are moreestimates of exposure risks in underground miners[M19. M42. R5, R7, S20, S51].
42. Several studies, interpretations, and reinterpretations have appeared since 1977, particularly in connection with occupational exposures (Hanford [e.g., GI?,
K201; Portsmouth Naval Shipyard workers [N6, R17,
R21, S331; and plutonium handlers [C21, V2, V3.
W 181). The earlier results have often been shown, on
closer examination, to have been spurious, and theeffects of different ascertainment or reporting biases
have been revealed.
43. The Life Span Study in Hiroshima and Nagasaki,
continues and three further reports on mortality data.
as well as additional incidence data have become
available. The consequences have been to improve
estimates of dose effects for some tumours, to include
others in the list of radiation-induced sites (e.g.. colon.
ovary and, possibly, multiple myeloma), to confirm
the absence of excess cases at some sites (e.g..
pancreas, uterus and chronic lymphocytic leukaemia)
and to confirm the existence of only marginal risk forsome sites (urinary tract and oesophagus) [K7, P15, S48,
S491. The Hanford study, the study in the MarshallIslands and studies in British patients irradiated forankylosing spondylitis, pneumothorax, mastitis or
thymus-related conditions continue. While details of
the dose-response curve at low exposure levels remain
unclear, much has been added to the high-level data
and to the nature of the relative risks. In some series,
the time distribution of leukaemia seen in Japan andelsewhere has been further corroborated. Absoluteand relative risks continue to increase in Japan formany sites. and further follow-up could reveal elevatedrisk at other sites, clarify some relationships and add
new ones.
44. The large series of 14.000 British ankylosing
spondylitis patients has continued to accumulate
person-years of observation, and some of the patients
have been followed for more than 30 years [D21. S3 I].
The doses received by the patients have been reevaluated, although not on an individual basis, andseveral new patterns have been observed. Most notably,
unlike the findings in Japan and elsewhere, adult solid
tumour risk appears to diminish more than 30 years
after exposure.
(b) Ascerrainment of exposed and comparison
individuals
45. A few new problems have been identified in theascertainment of cases and matched controls, orcomparison individuals since the UNSCEAR 1977
Report. Mostly, however, there has been continued
concern over the nature and level of exposure toindividuals. For example, as a result of variation in
the calibration of equipment and therapeutic technique, it is uncertain how much radiation was actually
delivered to the thyroid in children irradiated for tinea
capitis or to different tissues in spondylitic patients.
There is also the problem of resolving whether, insome instances, the cases were similar to the general
population in regard to other cancer risk factors. In

one study of radiation effects in childhood leukaemogenesis, it has been suggested that children exposed inutero during diagnostic radiation examinations may
already have been at risk of leukaemia. because no
similar risks had been observed in Japan [K6].
Exposed individuals at the Portsmouth Naval Shipyard
seem more likely to have been discovered if they later
developed cancer, and a potential ascertainment bias
exists in situations where extraordinary efforts weremade to detect cancer in individuals or their exposure
to irradiation [B6]. This bias may well exist in studiesof military servicemen exposed to the testing of
nuclear weapons [C16. C17, KZI] or of children
exposed in Utah to fallout. A "healthy worker" effect.
in which employees in a given industry are healthierthan the general population, may have led to spurious
interpretations in many epidemiological studies andmust be accounted for wherever possible. In several
studies, the unexposed group disclosed excess cancers
at sites that had been associated with elevated risk
from radiation exposure; clearly the status of suchindividuals in regard to other risk factors must be
evaluated. Such an evaluation can be especiallydifficult if the later effects are small (as in low excess
risks of late-onset tumours), if the dose estimates are
uncertain or if the investigators are so thorough as toperhaps over-define cancer, as may have occurred inregard to thyroid tumours.
46. In population studies such as those in Japan and
the Marshall Islands, the exposed individuals are
known and the task is to continue reporting the results
as the diseases appear. I t is clear that even 40 years ofsurveillance is not sufficient to exhaust all of theeffects, so these large studies must be continued
throughout the lifetimes of the exposed. Similarly, insmaller special-cohort studies, such as those of uranium
mine workers and therapeutically exposed patients,
the long-term effects must be continually monitored as
the cohorts diminish through attrition.
47. The more challenging ascertainment problems
are to determine the actual exposure levels of theindividuals and the correct expected cancer risks forthem. The exposure levels are reasonably well known
in some of the cohorts, but not well known in others.
Even when exposure is well known, the amount ofradiation delivered to specific tissues or cell types may
not be. This has become an important considerationin regard to liver. bone. and lymphatic cancers inpatients exposed to internal radium sources andThorotrast, for example. Furthermore, it is vital todetermine the comparability of exposures to othercarcinogens to which the individuals in these cohorts
may have been subject.
(c)

Sui~abili~yof comparison group

48. For a number of potentially relevant studies,
there is a continuing debate and re-analysis of data to
determine whether the control individuals have been
appropriate. For example, it is not obvious whether
individuals suffering from disorders such as thymus
enlargement or tinea capitis, many of whom were
economically underprivileged, were normal in all theother health respects that might relate to cancer.

Similarly. second tumours may arise because of othereffects of the treatment for cancer. independently ofirradiation: the treatment may debilitate o r it mayalter hormonal or other physiological states. It isdifficult to know the extent to which this may occur,
since in the absence of therapy most cancer is fatal,
a n d not much data exist on the subject. If an
inappropriate comparison is made, the relative risk
applies only to that comparison, not to a more general
population. It is essential that the control data, o r the
population-based expected risks used, d o not confound different exposures with other risk factors.
(d) Accurate dererminorion of especred risks

49. One of the most serious problems that has arisen
in connection with estimating risks in exposed cohorts
is the problem of defining the appropriate expectations for the cohort. The first question is whether the
exposed are comparable to the contemporary population from which the expected rates are derived.
Specifically, it is critical to determine whether they are
similar to the general population in regard to thecancer-related aspects of general health, to socioeconomic status as it bears on exposure t o otheragents, and to other factors that may have affectedascertainment or that may be affected by the subject's
awareness of his continued surveillance. In the Life
Span Study in Japan this matter of comparability isless likely to be a problem, although it could beserious in the smaller studies in which specific cancers(such as thyroid cancer, following childhood exposure,or leukaemia, following fallout exposure) may havebeen screened much more carefully, or defined moreloosely, than in the general population. In Japan,
internal controls have often been applied, whereby
those exposed to high doses are compared t o thosereceiving essentially no exposure.
50. In a large series of cervical cancer patients. thereis evidence that other risk factors, presumably involving
environmental exposures, make the results less representative for more general populations. In a similarway, the results of the ankylosing spondylitis series
indicate various causes of death at different rates fromthe general British population.
(e)itleaning of relative risk in a changing
esposure environmenr

51, Many significant changes in esposure to nonradiation risks are taking place in regard to diet. theuse of tobacco, exogenous hormones and other drugs,
toxic agents in the work-place, pollutants, and thelike. When these interact non-additively with radiation, they may materially alter the lifetime radiogenic
risk of cancer. Such changing regimes of esposure toother risk factors may seriously affect the meaning ofrelative risk and the dose-response patterns for radiation exposure unless these other factors are taken into
account. This is clearly important in risk assessment.
because for many organ sites the relative risk for agiven radiation dose is a function of the general risk
for the tumour.
52. The dependence of the cancer risk due toradiation o n the general level of risk for that cancer

may not be a serious problem at high doses if thoseeffects appear as very unusual tumours, or as tumours
in locally irradiated tissues. However, this dependence
is more likely to be important in regard to low-dose
effects or to late-onset, long-latency tumours that
occur naturally with substantial frequency.
Idenrificarion of new e.rposed cohorrs

53. Since the UNSCEAR 1977 Report [LT2]. several
additional groups of exposed individuals have comeunder scrutiny, and others are potentially available.
The groups being studied include nuclear workers[B22, C21, D24, RZI] and military senpicemen fromGreat Britain [D26] and the United States [C16, C17,
R16] exposed to fallout from nuclear weapons testing.
The results are equivocal and may remain s o even if
the cohorts continue to be followed. T o date. most
claims have been for leukaemias. and the occurrenceof new radiogenic cases, if any, should have ceased.
based on what is known about radiogenic leukaemias
in other exposed cohorts. Another group is composedof children exposed in southern Utah to fallout from
nuclear weapons testing [L4]; this study is controversial. and its estimates of risk are not accepted bymost critical investigators (see. e.g.. [L5]).
54. A more consequential group of individuals now
being studied is one that comprises children exposedto therapeutic radiation for childhood cancers. The
continuing investigation of these individuals suggeststhat second primary turnours occur more frequently
than in non-irradiated children. Many of these areleukaemias or sarcomas in the irradiated areas, but
carcinomas also occur, including those of the thyroid.
These subjects may afford risk estimates for second
turnours, especially for sarcomas for which little data
exist (excepr for bone): the doses in these cases werelarge, and they are reasonably accurately known.
55. Another important new group is a series of over
180,000 women, in a number of countries, who havebeen followed after treatment for cervical cancer.
These women received high pelvic doses and moderate
to low doses to more distant organs. Since the
UNSCEAR 1977 Report was issued, many reports
have appeared on this set of patients. The number of
person-years of observation has become substantialand excess cancers are appearing [B 12, B73, D9].
56. Many disparate groups of individuals have incommon the fact that in the course of their lifetimes
they have been or will be exposed to atypical amountsof external, low-LET radiation. .4mong these groups
are radiologists and radiographers, nuclear shipyard
and atomic energy workers, as well as segments ofthe general population exposed to high-LET radon
daughter products in their homes or to higher-thanusual backgrounds as a result of where their homes
are sited. Most receive small to modest amounts ofradiation above the average, but some (early radiologists, for example) may have accumulated lifetime
exposures of 2-20 Gy. More and more data arebecoming available on the cancer risks in these groups[see, e.g., M 18, M301. Data are also accumulating on
nuclear laboratory employees who have been exposed

in the course of their occupational lifetimes (e.g., [W7,W8. U'9. W201). For example, causes of death havebeen examined for employees of the Chalk River
Nuclear Laboratories in Canada who received lifetime
occupational doses of 0.2 Sv or more. Through 1982,
413 long-term, traceable employees had accumulated
exposures of this magnitude (their average lifetime
occupational dose was 0.42 Sv). There have been no
excess cancer deaths among the 64 members of thiscohort who succumbed; indeed, only 12 cancer deaths
were obsened where 17.6 had been expected [W9].
57. Information should be available shortly from thestudy of employees of the United States Atomic
Energy Commission (and its administrative successors) who have received occupational esposures of
0.05 Sv or more.

2.

Case-control studies

11. ASSESSMENT OF DOSE-RESPONSE A N D
RISK PROJECTION

1.

60. The attractiveness of this model resides in its
simultaneous provision for the estimation of linear
and quadratic effects ascribable to radiation and thosecompeting effects of radiation, such as cell sterilization or killing, that could obscure the carcinogenic
effect itself. Commonly, when the absorbed doses are
not large, the exponential term is ignored. A still
simpler, frequently used model is of the form:
R = (a bDh) exp (-fD - gD2)+

58. Case-control studies have been. for several reasons.
less valuable than cohort investigations in the present
context. The shortcomings of case-control studies areseveral. First. in most situations the frequency of priorradiation exposure among cancer cases will be low.
requiring very large case numbers in order to estimate
relative risks accurately. Second, the absolute doseresponse relationship cannot be estimated statisticallyfrom retrospective designs alone, since the affected
and non-affected fractions are specified through thesampling strategy rather than being the observed
outcome proportions among exposed and unexposed
individuals [B19]. Third, it is often difficult, retrosprcti\,ely, to select a truly comparable control groupwhose risk-factor characteristics closely match thoseof the cases; this is not a problem in some prospective
designs. Finally. there are several sources of potential
bias in terms of case ascertainment tvhen exposure
history must be ascertained long after the fact (such asa more intensive search for a history of exposure
among the exposed group than among the ostensibly
non-exposed group).

A.

where R is the response. or increased risk of cancer(such as absolute o r excess relative risk), D is theabsorbed dose, and a, b, c. f. and g are coefficients tobe estimated from the epidemiological data. These
coefficients are usually determined by either the
method of least squares or the method of maximum
likelihood. In many circumstances it is more accurate
to express the value of R as a function of variables in
addition to dose; for example, age, sex and history of
exposure t o other carcinogens.

PROBLEMS ASSOCIATED
WITH ASSESSMEST

Form of the regression of response on dose

One of the central problems in risk es~imation
continues to be the shape of the dose-response
relations hi^. an issue treated exhaustivelv in ~ n n e xBof Ihe U'SCEAR 19*'['11'
number ofmodels have been used or advocated; these include a
linear model, a linear-quadratic model. and a quadraticmodel, t o each of which a separate term (or terms)
may o r may not be added for neutron exposures andfor cell sterilization ( a decline in response at very highdoses). Many of these alternatives are special cases ofthe more general form:
R = (a + bD + cD') exp (-fD-gD2)
59.

*

Its merit rests largely in its incorporation of either a purelinear effect (when h = I ) o r a quadratic effect (whenh = 2). with o r without competing effects (f and g) andin the fact that it approximates a linearquadratic
form when h has a value between 1 and 2. Thus, it canreflect a convexity in the dose-response curve. However. h can also be less than l, which poses problems,for then the slope becomes infinite at zero dose.
61. Each of these approximations t o the true, biological dose-response relationship has its limitations
or potential pitfalls. Common to all the approximations is that inferences based on the shape of the doseresponse curve are .more susceptible t o error thaninferences based on the overall slope. In addition.
there are errors that stem from (a) an inappropriate
choice of the reference value; (b) systematic o r random
mismeasurement of exposure; and (c) inadequate
allowance for latency or too short a period of follow-up.
Errors in the measurement of exposure are particularly
troublesome, for even the inevitable random mismeasurements can introduce a spurious curvilinearity
and cause the slope to be underestimated [G13, ~ l i ]and the intercept to be overestimated. unless the latteris constrained to its true value, which is, however,rarely, if ever. known.
62. Much of the data that have helped to identify
radiogenic tumours have limited applicability to theanalysis of the dose-response relationship, for thedoses are either too pooriy known or too invariant topermit discrimination among different models. The
data on the atomic bomb survivors constitute one ofthe very few bodies of2.

Contingency tables and proportional hazard models

63. Past analyses of the Hiroshima and Nagasaki
data have leaned heavily o n contingency table methods(a full explication of these can be found in Appendix 3of [B16]). Essentially, the subject population is divided
into several categories (by age, sex, exposure level a n d
so on)... and the relative risks uithin eiven exDosure
categories are determined among individuals similar inuother characteristics. This identifies category-specificpatterns in which risk is elevated and estimates theexcess in each such category. More recent analyses
have employed proportional hazard models.
64. Proportional hazard models combine features of
traditional multivariate analysis and life-table analysis.
The latter method allows one to calculate survival
rates and cumulative survival rates making use of allof the data, even if the periods of observation of thesubjects differ; the former method allows one toestimate, when several factors are associated with adisease, the extent of the association for a specificfactor when all of the other factors are considered. All
methods entail assumptions about the presence orabsence of interaction and about the nature of therelationship of the causal variables to the occurrenceof cancer, which assumptions may not obtain.
3.

Mortality versus morbidity data

65. Dose-response relationships at Hiroshima andNagasaki had at one time been based almost exclusively
on the results of the continuing mortality surveillance.
However, in 1958 tumour registries were established inthese two cities under the auspices of the respective
City Medical Associations and with the technicalsupport of the Atomic Bomb Casualty Commission(ABCC). predecessor to the present Radiation Effects
Research Foundation (RERF). The specific purpose
was to develop and maintain a source of information
on tumours diagnosed in the two cities. Like mostsuch regislries in Japan and elsewhere. they incorporate
various kinds of information (clinical, pathological,
radiological, etc.); however. because they employ field
investigators who visit all large hospitals periodicallyto collect data. their ascertainment of the occurrenceof a tumour and its confirmation is more complete
than that of most other registries. which depend upon
voluntary reports from participating hospitals. Thus,
for example, in the Nagasaki registry, 72% of thetumour cases are confirmed (that is, there is, inaddition to the clinical report, autopsy, surgicalpathological or surgical operational data on theturnour) and only 7%' of cases are ascertained solely
through death certificates. This contrasts markedly
with the figures obtained from other registries inJapan, where, on average. only 50% of the cases are
confirmed and 37% are ascertained through deathcertificates alone. These superior methods of ascertainment notwithstanding, the utility of the registry data
hinges ultimately on the absence of bias. No exposure
status bias in data collection has been revealed in thedata of either city [W5].Method of diagnosis of thetumour, reporting hospital and frequency of doubtful
cases do not differ as a function of dose.
66. For fatal cancers, the relative risks based on
excess incidence cases, rather than excess deaths, andon T65 doses are generally either the same as orslightly higher than the relative risks based on
mortality for the same years (1959-1978); however, theabsolute risk estimates (excess incidence cases per
IOJ PYGy) are higher. The mortality data suggest an
overall average excess risk of death from a solid

malignant tumour of about 2 per lo4 PYGy; registrydata from Nagasaki, on the other hand. limited
though they are, suggest a morbidity risk six to seventimes higher. Thus, for all cancers except leukaemia.
the number of excess incidence cases per loJ PYGy is
9.6 whereas the number of excess deaths is 1.4. In
Hiroshima, similar data suggest a twofold greater
absolute risk; the values are 13.6 excess incidence
cases and 6.2 excess deaths per lo4 PYGy. In bothcities, a substantial proportion of this difference is ofcourse accounted for by tumours of the breast,
prostate and thyroid. which are seldom identified
immediately as the causes of death. However. an
important contribution is also made by cancers of thedigestive organs, notably the stomach.
B.

DOSE-RESPONSE PATTERNS

67. The accurate estimation of dose-response patterns
for each tumour site and the evaluation of low-dose
effects are impeded by several facts: (a) the long
average latent period (the continuing increase inabsolute risks of cancer among the atomic bomb
survivors in Japan suggest this period exceeds 40
years): (b) the relatively small expected additional risk,even at intermediate or high doses: and (c) changes in
exposures to other carcinogens. which could interact
with radiation exposure and make it difficult tointerpret dose-response patterns in terms of the futurerisks of current exposure levels. It is certain also thatthe increased accuracy of dose measurements and theincreasingly sharp focus of the beams used in therapeutic radiation will cause dose-response estimates tochange.
1.

Assessment of the effects of low dose

68. As was stated and thoroughly discussed in
Annex B of the UNSCEAR 1986 Report [UJ], an
assessment of the effects of low dose is clouded by theneed for large samples, the difficulty of accurately
estimating exposure and the growing importance of
extraneous sources of variation, including diagnostic
and therapeutic exposures that are less compromisingwhen the doses are large. Two of these difficulties
warrant special consideration. Precise direct estimation requires impracticably large samples. Estimates of
low-dose risks based largely on high-dose data must
depend heavily on the assumptions about the shape ofthe dose-response curve and are, of necessity, no
better than the model is applicable. Current datasuggest that resolution of these difficulties will not beeasy, and it seems likely that there will be many sitespecific differences.
69. Many individuals who entered Hiroshima or
Nagasaki soon after the bombs (to carry out relief orother activities) are included in the "not-in-city"group of the Life Span Study cohort in these twocities, a group which has not been used in recent
analyses of the Life Span Study data. Early entrants,
defined as individuals who entered Hiroshima or
Nagasaki within one month of the bombs, arerepresented by 4,5 12 individuals in the cohort sample

[K13]. Most presumably, they received some exposure
to residual radiation from fallout and neutron activation in soil (if they were in the vicinity of the
hypocentre). It is difficult to estimate precisely thedose received by these individuals, for it attenuates
rapidly with distance from the hypocentre, and theexposure depends upon their proximity to the hypocentre and time spent in a particular location. However. since it is improbable that individual exposures
could have been large. as they were for directly(promptly) exposed persons, a remarkable increase inradiation-induced cancers is highly unlikely.
70. hlortality among early entrants has been followed,
a n d some site-specific incidence studies have sought todetermine whether they are at increased risk of thespecific malignancy. Kato and his colleagues [K13]found n o increased incidence of leukaemia and othercancers among the early entrants. However. Rotblat[R8] has described an increased incidence of leukaemia
among these subjects, based on a report of Hirose[H9], and maintains that this is an example of a lowdose effect. The latter report is flawed in many ways.
First, there is a problem in the estimation of thedenominator (the base population) used t o calculate
the leukaemia incidence. In the studies of Hirose andRotblat [H9, R8] the number of early entrants residingin Hiroshima and Nagasaki is estimated o n the basisof data from two or three cross-sectional surveys
conducted from 1950 to 1974 and not on the basis ofdata from a cohort. Second, migration is not taken
into consideration. Estimation of the base population
is a particularly serious problem since the authors did
not employ a compelling method to examine the doseresponse through grading early entrants by time andplace of entry. Third, although the leukaemia cases
among the early entrants have a distribution by typesimilar to that seen among atomic bomb survivors, thepeak annual incidence does not occur in the early
1950s. as it does among atomic bomb survivors, but inthe early 1960s. when leukaemias among the survivors
themselves were few in number. Ohkita has called
attention to still other difficulties [04].
71. More recently, as part of a general study of theincidence of thyroid cancer among atomic bomb
survivors, Ishimaru and his colleagues looked for, but
did not find, excess risk of malignancy among early
entrants in Hiroshima and Nagasaki. Indeed, only one
case of thyroid cancer was observed in Hiroshima(and none in Nagasaki) among those early entrants
who were close to the hypocentre within two days ofthe bombing. Patently, the number of cases are too
few to evaluate the effect of exposure to residual
radiation rigorously, but no difference in incidence
was seen among early entrants, late entrants andsurvivors who had received a dose of less than 0.01 Gy
in either Hiroshima or Nagasaki.
72. The discussion here focuses o n specific studies,
namely, those that involve high dose rates (albeit
low doses), from which most of our knowledge isderived. However, to the extent possible. it will also
consider low-dose, low-dose-rate exposures such as
those received occupationally or those received byindividuals who live in houses with high radon levels.

Limited though the data may be, they are summarized
on a site-specific basis to illustrate differences and toindicate approximately values of relative risks.
2.

Assessment of the effects of high dose

73. The mortality experiences of the survivors ofHiroshima and Nagasaki have been, and will undoubtedly continue to be, the most relevant single
source of information on the frequency of occurrenceof radiation-related cancers. These experiences have
not only identified those malignancies that increase infrequency following exposure but also provided insights
into the probable dose-response relationships thatobtain. These differ by site in biologically consequential
ulays .
74. Estimates of tissue-absorbed dose for Hiroshima
and Nagasaki were published in 1978 [K14] (see also
for the foetus [H7]). though they had already beenused in the UNSCEAR 1977 Report; these estimates
will be discussed later in connection with the reassessment of the individual exposures of the sunrivors of
the atomic bombings. Revised estimates for the
Marshall Islanders will soon be available.
75. Re-evaluation of the exposures of the survivors of
the atomic bombings of Hiroshima and Nagasaki has
disclosed that their estimated neutron doses were substantially lower than had previously been thought [R9,R201. The findings, particularly those for Hiroshima,
are therefore much less informative about the effects
of neutrons than heretofore presumed. Differences,albeit not statistically significant ones, exist between
the cities, and there remains a need to find alternative
explanations for these. I t will also be necessary t o reexamine carefully the even more limited epidemiological data on the relative biological effectiveness(RBE) of neutrons, if this source of radiation is tofigure appropriately in the estimation of risk.
76. Risk assessment from results of the cervicalcancer series are complicated by the very different
doses delivered to the various organs. In particular,
pelvic organs were exposed to doses high enough t omake cell sterilization probably quite important (i.e..
risk is less than would be expected under linear doseresponse assumptions), while other tissues were so
little exposed that accurate dose-response information
cannot be obtained. Under such circumstances, it isdifficult to use the results of this series to determine
whole-body risk estimates.

C . RISK PROJECTION
77. From the public health and regulatory points ofview, it is important to know as accurately as possible
the impact which a given radiation exposure would
have o n a population. so that criteria for controllingsuch exposures, or for anticipating the results ofaccidents, can be developed. An important aspect ofsuch knowledge is the need to estimate the lifetime
cancer experience of an exposed cohort of individuals.
Lifetime data are rare, even for single-site risks, a n dcomplete lifetime multi-site data are not yet available
from the major cohorts that have been under surveillance for the past three o r four decades. As aconsequence, i t is still necessary to project lifetime
risks from data based on only portions of the lives of
exposed individuals. Such risk projections depend
heavily on: (a) the actual risks observed in theavailable cohorts and (b) the model used t o extend therisk beyond the currently available data. Thus, incomparing the results to be discussed below ofdifferent projections made at different times, one must
recognize not only the changes in the observational
data as a result of further follow-up o r estimateddoses. but also in the projection model that was used.
It must also be borne in mind that the projections areinvariably least certain for those individuals exposed
early in life.
78. Risk projection. generally o r site-specifically,requires knowledge of ar least the following: (a) the
latency time (that is, the time from exposure to thefirst expression of excess risk) and the plateau period(that is, the time from the first expression of excess
risk until the excess risk disappears); (b) the relationship between excess risk and baseline risk, as afunction of time since exposure; (c) the age distributionof the exposed population and the baseline pattern ofage-specific mortality rates from all causes and fromthe cancers under consideration; (d) the effect of age
at exposure: (e) the effect of sex: (f) a dose-response
function; and (g) the effect of environmental exposures.
Other factors may also need t o be considered, such as
the different effects of low- and high-LET exposures,and of low and high dose rates.
Knowledge of these factors can only be derived
from the experience of a small number of cohorts (thesurvivors of Hiroshima and Nagasaki, the ankylosing
spondylitis patients, and the large international seriesof cervical cancer patients). The details of thesestudies and their site-specific risk coefficients will bepresented later in this Annex. Most of the otherstudies serve primarily t o confirm these three studies.
(These comments pertain mainly to low-LET, highdose rate exposure.) There are a s yet no definitive
studies from which to estimate lifetime effects of
exposure to high-LET radiation (e.g.. occupational
exposure in mines, radon in homes) o r very low-dose
a n d low-dose-rate exposures of either high- o r lou1LET radiation.
79.

80. There have been several recent attempts toproject the long-term post-radiation effects of wholepopulation exposure, Notable are ( a ) the BEIR 1980
Report [CJ]; (b) a study by the United States Nuclear
Regulatory Commission regarding risks in a population from exposures due to a nuclear accident [GI I];
and (c) an attempt by the National Institutes of
Health of the United States to estimate the probability
that a specific cancer was radiation induced at times
subsequent to exposure [U4]. These studies have had
specific objectives, and all have been applied to the
population of the United States.
81. The purpose of the BEIR computations was toestimate as accurately as possible the lifetime risk in a

population of the United States exposed to a givendose of radiation according to two different projection
models [C4]. The purpose of the report of the Nuclear
Regulatory Commission was to provide estimates ofthe lifetime additional risk from a whole-population
exposure, such as in a reactor accident, based o n arange of assumptions that were consistent with theavailable radiation data. The purpose of the National
Institutes of Health study was to assess the probabilityof causation of a given cancer by radiation exposure
as a function of time since exposure: the computations
could be useful for assigning compensation to persons
in whom radiogenic cancer may have occurred.
82. This section will review the factors that must be
known in order to make risk projections. I t will also
summarize the main studies that have attempted suchprojections. and will outline the basic concepts ernployed by the subsequent review of the literature. The
same concepts will be used in chapter VII of thisAnnex, where new lifetime risk projections will bemade. Most of the parameters for the risk projections
have been estimated from the Japanese data [K7, W5]
and the ankylosing spondylitis data [S28. S311. Bothsets of data have undergone major risk estimate
revision [e.g., D21, P15. S48, S49] and dose estimate
revision [L16. N9. R201. While these revisions d o notalter the number of excess cases from these exposures,
they d o change the level of risk per unit dose. While
the following discussion on risk projections is notbased on the most recent dose-estimate data. themethods themselves are appropriate. Chapter VII
provides risk projections based on the most recent
data.
1.

Latency time and the plateau period

83. Epidemiological data cannot distinguish between
the first occurrence of a radiogenic tumour and its
clinical appearance, so that in this Annex the time
until the tumour is clinically detectable is referred t oas the "latency time" for a cancer. As will be shown
belou, different human cancers have clear and characteristic latency times following radiation exposure~91.
84. For adult exposures, leukaemias and bone cancers
have a minimum latency time of 2-5 years, whereas
solid tumours have a minimum latency time of
approximately 10 years [UI]. For solid tumours,
excess tumours commonly occur a[ ages comparable
to those at which spontaneous tumours of the samesite occur. The evidence is not clear or consistent as towhether other risk factors, such as smoking in the caseof lung cancer, interact with exposure to hasten theonset of radiogenic tumours.
85. The pattern following childhood exposure issomewhat variable. Tunlours that typically arise inchildhood, such as osteosarcomas. occur in the exposed
at ages similar to those at which they occur naturally.
Bone cancers and leukaemias have a 2-5 year latency.
For carcinomas of typically adult onset, the latency
time is 10 years or more. and current evidence
suggests that they also arise at their normal ages. late
in adult life.

86. The appearance of radiogenic leukaemias andbone cancer commonly follows approximately a lognormal distribution [C4]; as earlier noted. the excess
risk appears after about 2 years and reaches a peak by
10 years. Data on other tumours are less clear, and it
is usual to assume that after the latency time fullexcess risk is, approximately, attained [C4]. One
report [U4] has fitted a cubic function in order toproduce a smooth transition from zero risk tomaximum risk over the period from 5 to 10 years after
exposure.
87. The plateau periods, or periods of expression ofexcess risk. observed for specific tumours are generally
consistent over a variety of studies, although there are
exceptions. For leukaemias and bone cancers. excess
risk typically declines with time. but still exceeds thatin the controls as much as 40 years later in the caseof the atomic bomb survivors and the ankylosing
spondylitics. though it has ended after 25-30 years inother studies.

88. The plateau period for adult carcinomas amongindividuals exposed as adults appears to be openended; that is. in almost every instance, once risk has
become elevated it remains elevated for the rest of thelife of the exposed individual. Most major exposedcohorts are still under investigation. and this finding
could change: in one major study, that of theankylosing spondylitics [DZI], the excess risk of adultcarcinomas seems to disappear 25 years after exposure.
Since this finding tvith respect to the spondylitics has
not generally been seen with respect to adult atomic
bomb survivors or the subjects of other studies, it may
be unique to that study. However. i t should be notedthat in Hiroshima and Nagasaki among the two
youngest cohorts, i.e.. 0-9 and 10-19 years of age at
the time of the bombing (ATB), the risk has been
declining significantly in the 0-9 year group, also in
the 10-19 age group. but not significantly so.
2.

Escess and baseline risks as a function of timesince exposure

89. As was stated in paragraph 13. there are twobasic models for the pattern of expression of risk after
exposure (once the latency time has passed). These areoften known as projection models. The first is theconstant additive projection model. according towhich there is a constant number of excess cancers inany given year per unit number of persons exposed
per unit dose. That is, the number of excess cancers isfixed. regardless of the baseline risks:
where A is the absolute excess risk for all t > latency
time. The value A is usually estimated in one of two
related ways. In the first, the total number of cancers
expected in the cohort had they not been exposed (i.e.,the baseline risk) is computed. and subtracted fromthe number obsenred in the cohort. and divided by the
total number of person-year-Gy (PYGy) of observation. In the second, a regression model may be fitted
to the time of onset of every cancer: such models
express the excess risk and the baseline risk as afunction of age. sex, time since exposure and perhaps
other risk factors. If the additive projection model iscorrect, then at any post-latency time the difference
between observed and expected cancers, divided by
the total PYGy observed, will be constant. Sometimes
a variable excess risk model is used, in which the valueof A is estimated from the data by regression
methods, specific to sex. age at exposure. time since
exposure, and/or other variables.
90. The second basic projection model is knon-n a s
the multiplicative projection model. According to it.
the ratio of incidence or mortality rate in the exposedto that in the unexposed is constant once the latency
time has elapsed. That is,where R R is constant for all t > latency time. The
value R R has been estimated in two ways. First. thenumber of observed cancers at some time t after thelatency time is divided by the number of expectedcases. Sometimes, the excess relative risk per G y iscomputed. If the multiplicative projection model is
descriptively correct, there should be an approximately
constant relative risk at any post-latency time in an
exposed cohort. In some instances, a variable rnultiplicative risk model is used. in which the value of RR
is estimated from the data by regression methods.
specific to sex. age at exposure. time since exposure
and/or other variables.
3.

Age and sex structure of the population andbaseline mortality rates
9 1. T o predict future cancers in an exposed cohort. it
is important to know the age (and sex) distribution of
the cohort. This is so because with either themultiplicative o r the additive risk models, sincebaseline cancer risks change with age and sex. thenumber of cancers expected depends on how many
person-years of experience at different age (and sex)
categories occur in the data. In an exposed populationof mixed ages the number of expected cases per
exposed person of age t is E(t) and a fraction f(t) of
the exposed cohort is in that age category, the total
number of expected cancers will be

A similar weighted expectation can be computed foreach sex. The observed number of cancers can then becompared to this aggregate expectation.

92. The number of expected cancers depends o n thenumber of person-years at risk experienced at eachage (after the latency period) and the baseline risk.
The number of person-years to be lived between ages y
and y + n, per person now in age group x to x + n, is astandard life-table function which depends solely on
the baseline age-specific mortality rates, m(t). for ages
x < t < x n. The number of person-years declines
each year as mortality occurs (i.e., as survivorship
declines). The cause-specific mortality rate for a
specified tumour site is a component of the m(t)schedule, and the expected deaths at any given age can+be computed approximately by multiplying the causespecific rate by the number of person-years. Thisapproach is followed in risk computations for thisAnnex i n chapter VII, and is essentially the method
used by the BEIR 111, the National Institutes of
Health, and the United States Nuclear Regulatory
Commission computations referred to earlier [C4,G11. U4].
93. On the assumption that current mortality rates
do not change, life-tables may be constructed for an
actual or hypothetical exposed cohort to compute theperson-years and expected cancers. The excess cancers
are determined by multiplying the person-years by aseries of coefficients appropriate to a given projection
model. For example, with the additive projection
model. the number of excess cancers per person-year
is the coefficient. With the multiplicative projection
model, the baseline rate [m(t, cause)] is multiplied by
the relative risk coefficient. RR. This is multiplied by
the person-years to determine the number of cancers
in the exposed group. Excess cancers are this number
minus the number expected in the population in theabsence of exposure. Given the assumption of unchanging risk coefficients and baseline mortality rates,
it is possible to compute the additional risk to any
exposed group of persons in the population for which
the baseline risks are applicable.
4.

Age at exposure

94. The age at exposure can affect the coefficients ofsubsequent absolute or relative risk (i.e.. the values ofA or RR can be specific to age at exposure). Few
statistically sound generalizations can be made about
this, except (as will be shown later) that for sometumours, notably those of the female breast, exposurein childhood can lead to much greater risks, andexposure after age 50 to lesser risks, than exposure atintermediate ages. Childhood exposures leading tochildhood cancers are generally treated separately;other than for leukaemia and bone cancer. there isrelatively little data on the details of the projection
effects for such exposures because the Japanese
exposed to the atomic bombs in childhood (the main
source of data) are still too young for the late-age
effects to have been expressed.

5. The dose-response function
95. The dose-response function is discussed fully in
the UNSCEAR 1986 Report [U I]. For projecting risk.
the dose received by each exposed individual must be
taken into account. Where a linear dose-response
pattern is assumed. the dose is used directly. Where amore complex pattern is assumed. the dose is translated into some selected function of dose via theequation relating risk to dose for that pattern. The
risk is then linear relative to this function of dose. The
equations used in human studies have essentially all
been variants of those described in paragraphs 59 and60.
96. Usually, in projection, a model of excess deaths(cases) or relative risk per unit dose is determined. If a

non-linear dose-response is desired, the number ofexcess deaths (cases) or the relative risk per unit doseis multiplied by the appropriate function of the dose(e.g.. a + bD + cD2).
6.

Other exposure factors

97. Where adequate information is available, theprojection of risk may take into account such factors
as exposure to smoking or other environmental
hazards. other radiation exposures. or the different
biological effectiveness of high-LET radiation. As
long as one can supply an appropriate dose-response
function, a projection model, and an estimate ofadditive or multiplicative projection coefficients, thesame principles should apply.
7.

Previous approximations of lifetime risk projection

98. I t is useful to summarize thc most important
recent attempts to estimate lifetime risks, or related
measures, from population exposures. As was noted
earlier. while these studies attempted to synthesize risk
coefficients from the world literature, they relied mostheavily on the Japanese and ankylosing spondylitis
data; however, the latter studies have since been
updated, in terms of both new dose estimates andlonger follow-up times, so the specific risk estimates
they once provided must now be reconsidered.
99. The BEIR 1980 Reporr [C4]. The BEIR Committee
attempted to synthesize the data on radiogenic cancer
risk as of approximately 1979. It used a life-tableprojection approach, employing the 1969-1971 lifetables from the United States. and baseline cancer
mortality rates for five-year age groups. A table wasdevised to convert mortality data to incidence data.
based on cancer survival rates, so that estimates could
be made for both the commonly fatal and the rarely
fatal radiogenic cancers. This is given here as Table 3.
A table of risk coefficients, excess cancer incidence per
10' PYGy was derived, and estimates of the lifetime
risks associated with single exposures and continuous
exposures were computed, based on linear and linearquadratic dose-response functions, for both risk projection models. Estimates were made separately forleukaemia and bone cancer and for all other cancers
combined. Representative summary tables from the
BEIR 111 Report are repeated here as Tables 4 , 5. 6
and 7 for comparison with the projections presented
in chapter VII.
100. The Unired Stares Nuclear Regularory Cornrni3sion study. As part of a study sponsored by the UnitedStates Nuclear Regulatory Commission, Gilbert [Gl I]
developed estimates of lifetime risks that would
pertain to the population of the United States were it
exposed to a nuclear accident. These estimates are for
low-LET. single-exposures and are specific to the
population of the United States (e.g.. baseline cancer
rates from the United States were used).
101, Gilbert used (a) the age and sex distribution in
the United States: (b) the age, sex, and cause-specificmortality rates in the United States; (c) a model of thedose-response pattern, latency period, and projection
effects: and (d) estimates from past studies of theabsolute or relative risk per unit exposure. largely
from the BEIR 1980 Report updated by subsequent
papers from Japan and the spondylitics. She provided
methods for computing the total number of years oflife expected to be lost as a result of the esposure
incident. The input characteristics used in her study
are given in Table 8, which is an adaptation ofmaterial from the Nuclear Regulatory Commission
study.
102. Gilbert's projection of lifetime effects is basedo n a linear-quadratic dose-response model, with nonlinear effects at intermediate dose rates (C0.05 Gy/day)of low-LET radiation, as might obtain in a nuclear
power plant accident. Upper and lower bounds andcentral estimates for the effects of exposure werecomputed. These d o not have statistical meaning as.
for example, mean and confidence limits do; in fact.
there is currently no way to provide probability
statements on the likelihood that the true effects willtake any particular value. Gilbert merely provided
what appeared to be reasonable limits for the plausible
range of effects.
103. Gilbert used a linear-quadratic dose-response
equation to account for the incomplete human data
for low-LET radiation [C4], consonant with animal
experimental data [N I]. The extent of effect-reduction
at low doses a n d low dose rates is not yet known, but
the National Council on Radiation Protection andMeasurements of the United States (NCRP) has
suggested that the correction coefficient is in the range
2- 10 [N I]. which is the range used by Gilbert [G 111.
104. For comparison with chapter VII, a summary
table of Gilbert's results (Table 9), provides herbounds. for various sites. for years of life lost as well
as excess cases. Gilbert provided both relative andabsolute projection computations. Her absolute risk
coefficients were based on empirical data and her
relative risk coefficients were those multiplying factorsthat would produce the same number of excess casesa s actually observed.
105. Probability of causation: the radioepidemiologicaItables of rhe National Insritures of Heairh [U4]. For
some purposes. it is of interest to estimate whatfraction of cancers occurring in a given exposed
population at a specific time post-exposure may havebeen caused by the exposure. Even if a specific cancer
cannot be said to be radiogenic, it can be estimated bywhat fraction the baseline risk is elevated. In generalepidemiology this would be termed the attributablerisk, but in radiation epidemiology i t is often referred
to as the probability of causation (PC). The probabilityof causation of a specified cancer by radiation was
defined earlier as the excess cases due to radiation
divided by the total cases (see paragraph 21).
106. The study of the National Institutes of Healthused essentially the same data as Gilbert, withmodifications to various components but a comparable

life-table approach. The study computed a value. R.
defined from PC a s follows:
PC = [Prob(cancer w exp.) - Prob(cancer w/o exp.)]/Prob(cancer w exp.) = R/( 1 + R)
where R is the excess relative risk. defined as theincrease due to dose D as a proportion of theprobability of cancer in the absence of the exposure.
These probabilities are specific to a given dose, sex,
and age at and since exposure.
107. The National Institutes of Health report defined
R in terms of its components as follows:
R=FXTXKXW
where F is a function of dose. T gives the dependenceof R on time since exposure, K is the dependence of R
on age at exposure and W is the effect of an additive
interaction between radiation and other (known) risk
factors. The study described each of these parameters
for each tumour site.
108. Qualitatively, the results of this study can besummarized as follows. For leukaemias a n d bone
cancers. the probability of causation rises rapidly withtime after the minimum latency time, reaches a peak(whose height depends on dose and which is maintainedfor 10-20 years) and then falls to zero at the end of therisk period. For other cancers, the probability of
causation is roughly constant at all ages after theminimum latency time has passed, but is a function ofage at exposure. I t is typically highest for young ages
at exposure, declines t o a minimum (which varies bysite) for ages 40-50 a t exposure and then may riseslightly o r stay roughly constant.

8.

Risk coefficients for high-LET radiation

109. Much of the collective dose from high-LET
radiation received by human beings comes fromexposure to inhaled radon daughters. thorium decay
producls and the like. The radiation dose in these
instances is mainly from alpha emissions. In addition,
the exposure is chronic over many years. as, forexample, in the cases of underground miners in hardrock or miners of radioactive ore, and of the many
individuals who live where the bedrock o r soil
provides a source for radon gas entry into homes.
110. Because the doses received under these circumstances are chronic in nature, the models discussed
above are not really applicable (they project the risk
subsequent to single or short-term exposures.) In
chronic exposures, the cancer effects are the results ofa dose that continues to build over many years. The
most widespread risk is cancer of the lung due t o theinhalation of radon daughters.
111. Thomas and McNeill [ T I ] , TI61 estimatedexcess deaths and relative risk of lung cancer fromavailable data on exposures of underground miners toradon and daughters. Their results, which are given in
Table 10, are discussed further in chapters 111 and VII.

112. The risk estimates varied considerably from one
study to another in the survey by Thomas andMcNeill. This variation may be due to several factors,
including the effects of smoking. differing dose rates(i.e., ambient concentrations of radionuclides in the
air of the mines), inaccuracies in dose estimation, o rother confounding factors. Some of these factors are
discussed below. No simple, single risk pattern emerges;
there is about a fourfold difference in estimatedlifetime risks, per WLM. depending on which exposedcohort is used as the basis for the estimate.
113. The risk coefficients derived from these highLET exposure data have not been used to project
lifetime risks in exposed cohorts. A method for suchcomputations will be suggested later in this Annex.

9.

Selection of preferred projection model

114. The BEIR 1980 Report [C4] predicted lifetime
risks under a variety of assumptions by projecting
risks estimated from observed data into the future. but
unobserved. lifetimes of e x ~ o s e d individuals. The
number of excess cases estimated using an additivemodel of risk per lo4 PYGy was about a factor ofthree less than the number of excess cases estimatedusing a multiplicative model. Although they had
employed somewhat different assumptions a n d updated data, Gilbert's results were essentially the same
[GI I].
115. When the additive and multiplicative projection
models provide differing results, it is obviously important for practical applications to determine uphich. if
either. model is to be preferred. In examining this problem and its consequences for risk projection, Muirheada n d Darby [M36. M37] developed a generalized
statistical model for risk projection and tested its fit.
a s well as the fits of' the additive and multiplicative
projection models, which are special cases of thegeneralized model, to the available data. The authors
expressed risk in the exposed, R(d). in relation t o theage-specific risk, R(O), in the unexposed. as a functionof dose. d. The); used the general function
R(d) = { [ ~ ( o ) ]+; [I + a d exp (L/l,x,)];- 1) I/:
where the .u values in the exponential term arecovariates and the /Ivalues are their regression
coefficients. taking into account age at exposure. timesince exposure and sex, and 1 implies summation overall such covariates. The parameter ;-can be thought ofa s indicating the model type: if ;,= 1, the additive
projection model results; if ;*= 0. the multiplicativemodel results; other values of ;. express intermediatetypes of model.
116. Muirhead and Darby tested this approach withmortality data on all cancers except leukaemia in
Hiroshima up to 1978 between the 0-0.09 Gy andabove I Gy dose groups. Table I I shows the results ofsome of their fitting efforts, and Table 12 theimplications of the different models for lifetime risk
projection. While this work was not based on the mostrecent dose estimates, the qualitative nature of theirfindings seems unlikely to be changed appreciably
with new doses.
117. In the absence of covariaies, the best-fitting
value of the parameter lies between 0 and 1, but the fitof this model to the data is not good. Adding age at
exposure improves the fit. which is even further
improved by adding time since exposure. Thosemodels which d o fit well are shown in Table I I. Whatis clear is that none of the simplest models fits [hedata best. and a variety of models can generate astatistically comparable fit. Yet, as shown in Table 12,( a ) these models lead to very differen1 lifetime risk
projections: ( b ) the multiplicative and additive projection models d o not necessarily provide upper and lotver
limits to the risks among this family of models; a n d(c) the number of years of life lost. which Gilbert's
projections had shown to be relatively similar undermultiplicative and additive models (cornpared to theexcess number of deaths). are quite variable among
the possible models. The latter difference is probably
due to Gilbert's using a constant risk coefficient for allages at exposure.
118. This work shows the importance of knowing
the nature of the effects of radiation after exposure,on the projection of lifetime risks, and that it isdifficult with present data to determine a clearly bestfitting model. Different data sets would be fitted bestby somewhat differing models. Only if the total
lifetime effect of radiation is known can a choice of a
projection model be made confidently. If. as has
recently been found in the spondylitis data. excess riskof solid tumours, in fact, diminishes or disappears
after 30 years, then the hulk o r tunlour expression
may have been seen in some of the current cohorts,
and projection efforts c o ~ ~ lbed made with relati\*cly
less uncertainty. However, the Japancsc data d o not
yet show such a decrease, except at the youngest ages
at time of exposure.
119. The major importance of the work by Muirhead
and Darby is to suggest that current data cannot yet
provide a model by which to project lifetime risk
accurately, or even confidently to bracket the range of
likely risks. Indeed, even if (with currently available
cohoris of data) one projection model fits the data
best, this must be taken to be a numerical rather thanbiological fact; not enough is known about radiation
carcinogenesis to construct a single biologically correct
projection model. if indeed one exists.

111. BIOLOGICAL ISSUESIN THE ASSESSMENT
OF RADIATION CARCINOGENESIS
120. The data available for the assessment of radiation carcinogcnesis in man come from several sources,
the most important of which have already been cited.
A number of different approaches have been used toevaluate the patterns of cancer that occur in irradiatedindividuals. While some studies have combined several
approaches, and the approaches are not incongruent.
most have employed only one, o r a few.

A.

BIOLOGICAL MODELS O F RADIATIONCARCINOGENESIS

1.

\lulti-stage models and the role of radiationin carcinogenesis

171. At the cellularlevel,cancer isa clonal. moleculargenetic disease. One way to understand the response of
a n individual to radiation is to model the process ofcarcinogenesis itself in terms of the events thought tooccur at the cellular level during the transformation ofcells from normal to malignant. Generally, suchmodels consider cancer to be a multi-stage process; itis presumed that for a cell to be affected. a series of k
events must occur in its lineage: the time. or age, to atuniour is a functiuri of the rate at which these eventstake place. The k events must occur in a single celllineage, the last event rendering some single cell
cancerous a n d causing it to become the progenitor of
the entire subsequent tumour and its metastases. Thishas been established biologically for such a wide
variety of tumours that i t can be accepted as a fact.

122. Numerous multi-stage models have been proposed (see [WI] for a review). One of the motivating
factors behind the development of these models has
been the obser~.ationthat many tumours in man andanimals exhibit a linear increase in the logarithm of
the incidence (or hazard) function. h(t). plottedagainst the logarithm of age. t; that is,where A is a constant of proportionality. usually afunction of the transformation rates of the k events.
among other things. Empirically. the slope of such aplot on a log-log scale is 4-6 for a wide array ofhuman [Cl] and animal [PI] cancers. It should be
noted that many non-mutational chronic diseases
show similar patterns.
123. Many other variations of multi-stage models
have been proposed. but there are probletns associatedwith any purely formal approach to radiation-induced
carcinogenesis. Stochastic models of carcinogenesis
model the process at the cellular level, yet data on
human radiation carcinogenesis used to test thosemodels come from observations on populations ofindividuals. It may be unrealistic to infer from suchdata much about the nature of the process itself or of
the role of radiation. Additional errors may arise fromthe heterogeneity of the exposed population, which is
not considered by statistical models.
124. Based on the way the multi-stage statisticalmodels were developed. some investigators have interpreted the slope of a log-log plot of cancer incidence
data (4-6) as directly reflecting the number of stages
involved. For a variety of reasons. it is unlikely that
this interpretation, based on population data used toinfer cellular processes, is useful for this purpose[W3]. However, it is possible, without specifying thenature or even the number of stages, to express theeffect of exposures of varying intensi~yto carcinogenic
agents that affect only one of the required stages. Thishas been done by Whittemore [Ur2], by Day [D2] andby Day and Brown [Dl]; Whittemore derived a tableof the expected effects on both the absolute andrelative risks of constant exposures, single exposuresand short-term exposures [WZ]. If the first of thenecessary transforming events is affected by the
exposure. the number of individuals already partiallytransformed should increase, and even after the
specific exposure terminates, they will remain at excess
risk, having to await only a smaller number of eventsin subsequent years. If the last stage is affected. thenthose cells that have already experienced some events
will be quickly transformed. but once the exposure
ceases there will be no further excess risk in the
exposed cohort relative to the unexposed cohort. If anintermediate event is affected by the exposure, thefraction of the cohort in a more highly prepared state(and. hence, the rate of occurrence of disease) should
increase, as with an early stage event. However, aftersome time has passed, the remainder of the cohort will
also gradually accumulate these stages. and the excess
risk in the exposed cohort will diminish.
125. These predictions have been applied to ageonset data in exposed cohorts of individuals to infer
what event may be affected by radiation in thegeneration of cancer in various organs; the results are
sunimarized in Table 13. The bases for these inferences
are the relationship between age at exposure. therelative risk, and time since exposure. A major point isthat if a late stage is affected, then individuals who
have already experienced all prior stages will quickly
manifest a cancer; because a higher fraction of older
individuals are presumably in such a condition, late
age of exposure should, according to this model,
manifest more. and quicker, excess cancers than inyounger individuals. On the other hand, if an early
event is affected by radiation, there will be a long time
until those affected will manifest their excess tumours.
Further. the effect of radiation would be less at laterages. since more of the older population would
already have experienced these early stage events. The
logic of the interpretation is given in [C?2]. andseveral applications can be found in [W2].
126. As Table 13 shows. these ideas may have merit.
but they have not yet led t o easily understoodconclusions. In leukaemia and other tumours, there
are no simple o r clear patterns of relationship of latent
period with age at exposure. or latency itself. Therefore, epideniiological evidence alone cannot be used tomake reliable inferences about the nature of the
carcinogenic process either in terms of the number ofstages invol\ied. or which of those stages is affected byradiation.
127. T o account for smaller numbers of events. o r
for the differential growth of tumours relative tonormal tissue. several models have been proposed[WI]. One is a three-stage model that includes dosedependen1 cell killing (or sterilizing) effects. originallyproposed by Neyman and Scott [N2]. It is consistent
with data on radiogenic osteosarcomas in dogs andhumans caused by 226Ra (half-life: 1,600 years) in
showing that a response is proportional to the squareof the dose at low doses: that incidence is notdependent on time and dose at high doses; and thatradiogenic tumours may appear at a much later time

after exposure than simply the tumour growth period[M3, W 1, W4]. The first two events are assumed to beaffected by the radiation directly, perhaps as mutations with effect proportional to dose, while the third
is a bone growth phenomenon related to bone
remodelling and the eventual stimulus for transformed
cells to grow.
128. This result is somewhat different from the result
observed in individuals, both children and adults, who
had been given lZJRa,which has a shorter half-life anda very different skeletal dosimetry. In those individuals.
excess cancers occur a few years after exposure but nolonger occur about 25 years after exposure. The
Marshall-Groer model calls for a cell-division effect,
which should lead to different results in children,
whose bones are more actively growing, and adults;
however. this has not been observed [M22].
129. In an attempt to generalize the carcinogenic
process, taking into account the promoter and mutational effects, and still generating age-incidence curves
which are proportional to the 4 6 t h power of age,
Moolgavkar and his colleagues [M 1, M2] have developed a two-stage model, with differential growth ofnormal or partially transformed cells (or both). This is
an improved version of earlier work of Armitage andDoll [A2]. The Moolgavkar paradigm makes predictions similar to those of modified Armitage-Dollmodels [Al, W2] in regard to the effects of age at
exposure and the incidence pattern as a function oftime since exposure. I t has been fitted to data on
breast cancer [M5]. where hormonal (and possibly
dietary) effects are influential, and to data on smoking
and lung cancer. The results are consistent withradiation being a mutagen for both of the mutational
stages required in the model. if the known facts ofbreast tissue growth are taken into account. First,
nulliparous women have fewer cells susceptible totransformation which will later undergo extensive
mitosis [BI]. Second, the risk of post-pubertal radiation carcinogenesis decreases with increasing age at
exposure, again agreeing with the circum-pubertal
tissue growth. Finally. pre-pubertal irradiation shouldhave less of an effect. since few breast cells are
dividing at that time. Until recently, no pre-pubertal
effect had been seen in atomic bomb survivors [TI];
however, this no longer is the case [T6, T7]. From themost recent data, i t now appears that in fact the risk
may be highest in ages under 10 years and greaterthan in ages 10-19 years. The longer the interval
between irradiation and menopause, the longer will be
the period during which partially transformed cells
can proliferate and hence be vulnerable to a final
transforming event: this age effect has been observed[B21.
130. A number of experimental observations support
a model based primarily on the biological nature oftumour formation rather than on formal concepts.
Within the framework of this model, two biologicallydifferent stages of carcinogenesis are singled out:
initiation and promotion. To develop a specific modelof radiation carcinogenesis based on a two-stage
theory i t is necessary to discover the mechanisms
underlying these processes (for a comprehensive review
see [F9, FIO, P13, P141).

131. The chain of events culminating in a clinicall?
manifest tumour starts with the initiation process in anormal target cell. I t is clear that in at least sometumours the event causing initiation is a mutation in
the DNA. This can be a point mutation or achromosomal rearrangement; many examples of bothare known. Filyushkin and Petoyan [F9], Petoyan andFilyushkin [P13], and Sandberg IS421 have suggesteda hypothesis relating carcinogenesis to symmetricalchronloson~etranslocations (reciprocal translocations
without loss of chromoson~e material). Initiation
seems to occur frequently [G16. G171, but most
initiated cells never result in a lumour. Several
mechanisms ensure that most potentially carcinogenic
cells do not cause a cancer.
132. One of the principal mechanisms preventing thedevelopment of a tumour, even though mutation has
occurred, is the repair of the damaged DNA within a
few hours or days of initiation. The time. between amutation and the next mitosis is critical for the final
result: stimulation of proliferation after exposure
results in a higher number of transformed cells [B39.
K24]. This may be due to the diminished time
available for repair before fixation of the lesion duringmitosis [B34. M331. Proliferation seems also to be
essential with regard to the persistence of the potentiallycarcinogenic character of the initiated cell. Studies ofthree different cell lines in vitro revealed that between
four and six mitoses must occur after irradiation tolead to a fixed transformation; the first mitosis has totake place within the first 24 hours [B33, K25. L141. If
it does not, the potentially carcinogenic character ofthe initiated cell is lost.
133. In radiation-induced mouse myeloid leukaemiasa partial deletion of the long arm of chromosome 2 isnecessary but not sufficient for the disease [H29,
H301. The cells with the deletion proliferate without
manifesting malignant phenotypes in the mouse unlessa second transforming step occurs [H30]. This stage
may be explained as the loss of a suppressor gene orby a second somatic mutation at the gene located on
the intact homologous chromosome, as occurs in
retinoblastoma and other human cancers.
134. Another important. though seemingly trivial,
fact should not be overlooked. An initiated cell may
be the cause of a tumour only if the radiation-induced
lesions are compatible with cell survival. In the highdose range, there will be competition between celltransformation and cell death.
135. A fixed transformation still does not mean thata tumour will inevitably develop. The affected cells
can apparently remain quiescent for a long rime,
during which they may be recognized and eliminated,
perhaps by the immune system. This process surely
takes place, even though i t is poorly understood. If allof the mechanisms mentioned above fail, there is still
the need for the transformed quiescent cells to start
dividing. This activity is thought to be induced by apromoter. Hormones are of particular interest in thisconnection, as has been shown by different expenmental approaches [N7. S43, Y5, Y6]. Generally,
substances that stimulate cell proliferation enhancecarcinogenic processes [S43]. It is not clear to what
extent radiation can act as a promoter [ F l , UJ].
Finally, the developing tumour must be vascularized
when it has reached about 0.2 millimetres in diameter,in order to maintain an oxygen supply to the cells.
Only after all of these processes have taken place andadditional growth has occurred will a tumour be
clinically manifest [S44].
2.

Consideration of results of oncogene studies
in statistical models

136. Recently, a rather elaborate picture of thenature of some of the genetic events involved in
carcinogenesis has emerged. A limited series of genes,
commonly called oncogenes, has been implicated in
the transformation of cells to the n e o ~ l a s t i cstate.
Some of these oncogenes seem to be incorporated into
the cellular genome by viruses that transfect cells. but
the genes themselves, or structurally very similar ones,
are known to exist in nornlal cells. It has been shownin some cases that simple mutations in members ofthese gene families have transforming activity. Mutation in an oncogene can lead to a modified structurein the coded protein. or. by changing the mechanismsthat regulate the coding and expression of such genes,
i t may cause the ectopic production of a normal geneproduct. o r its production in improper amounts. The
biochemical activity of several of these agents has
been characterized; they appear to affect a variety ofpathways in the control of cell division a n d proliferation. Other work has suggested that cell transformation
may occur after a small number of events, possibly
two o r three. although in some instances (for example,
retinoblastoma) recessivity at a single locus (i.e.. twoevents) may suffice. In the case of recessivity at asingle locus. genes of protective effect, now often
called "anti-oncogenic". are turned off. This subject isreviewed in Annexes A and B of the UNSCEAR 1986
Report [U I].
137. In the case of these "anti-oncogenes" there isevidence that after a first mutation at one of these
loci, a somatic recombination event occurs which
replaces the normal gene on the unmutated chromosome with the mutated gene, leading to cell transformation. One recent report from an in vitro study ofyeast cells has shown that radiation may induce
somatic recombination. thus being able to affect boththe initial and the second of these stages.
138. Evidence has accumulated that various carcinogens. including radiation. tend to break humanchromosomes at specific locations. While these "fragile
sites" are not yet well understood, some correspondclosely to known cancer-related chromosomal breaksites, for example, known rearrangement points or
oncogene locations [YI]. However, it is not clear
whether radiation causes cancer in ways different fromother carcinogens.
139. Several studies have shown that mouse cells
may be transformed by the application of chemical carcinogens such as N-methylnitrosourea andbenzo(a)pyrene [G7, M2 1. Z I]. This activates the

N-ras and H-ras oncogenes, and in one case [ZI] thetransformed gene is due to a guanine-to-adenine(G-A) nucleotide substitution (a point mutation). In adifferent study. the c-K-ras oncogene was activated by
gamma radiation, which also caused a G-A substitution [G6]. These findings suggest that. at the oncogene
level. the carcinogenic effects of radiation are at least
similar to, if not identical with, the effects ofother carcinogens. The studies cited involved different
tumour sites, s o that more direct comparisons are
difficult.
3.

Does radiation induce unique cancer characteristics
at the cellular level?

140. Several investigations have shown that thenormal somatic cells of cancer patients differ fromtheir tumour cells in respect to oncogene activation o rother chromosomal changes. This finding documents
the clonal nature of the tumour and, more importantly,
the specific events involved in the tumour's origin.
Similar studies should be undertaken in radiationexposed individuals where it would be valuable todetermine whether the tumour cells alone manifest thechromosomal or oncogene-related changes attributable to irradiation or whether the normal cells. too,
manifest these changes. In particular, it may be
important to examine affected and normal cells inindividuals exposed in utero, in order t o relate theeffects of radiation to prenatal age at exposure,especially for those individuals exposed early inprenatal development.
141. For many reasons it is desirable to knowwhether the cancer cells produced by ionizing radiation differ cytologically or biochemically from thecancer cells produced by other carcinogens at thesame organ site. A clinically detectable difference
could have uses in screening and in testing. It could
also be valuable in determining which cases of cancer
are due to radiation exposure and which are not; thiswould be useful for epidemiology as well as foroccupational safety. liability and the like. DNA
sequences at certain loci affected by different mutagens
in some experimental systems show characteristic
patterns (e.g.. base changes, deletions), suggesting thatdifferent mutagens have preferential effects at the
DNA level. It has been possible, for some cancers, todetermine whether or not radiation induces similarchanges at the genetic level to those caused by othercarcinogens. Experimental studies of chemical mutagens
on cell lines and the finding of the "Philadelphia
chromosome" in the Japanese atomic bomb survivors
with chronic granulocytic leukaemia (as is observed in
spontaneous cases) suggest no radiation-specific mutational pattern [F3].
142. The available information generally suggeststhat radiation induces the same cellular anomalies a sother carcinogens. Data from Hiroshima and Nagasaki
on breast cancer suggest no differences in histologic
type nor tumour size by age at exposure o r radiationdose [T9, 1141. nor were atypical changes o r residual
proliferative lesions seen in women exposed t o radiation but free of cancer. These observations led

Tokuoka and his colleagues to conclude that "radiogenic breast cancer does not differ histologically fromspontaneously occurring (breast) cancer in Japanesewomen" [T9]. Similarly, Matsuura and his colleagues[M15], in an analysis of the histological types ofstomach cancer seen among the survivors, found nocompelling evidence of a radiation-specific histologicaltype, although there was evidence that the degree ofdifferentiation of adenocarcinomas is poorer in highdose than low-dose groups. On the other hand, acomparison between exposed and unexposed stomach
cancer patients from Japan showed a higher frequency
of better-differentiated tumours in the exposed, whowere also several years older than the unesposed[S35]. Twenty years ago, gastric carcinoma in the
exposed occurred at the same age as in the unexposed.
143. While in all risk groups the lower third of thestomach was the site of most cancers. there seemed to
be an increase in the degree of intestinal metaplasia of
the gastric mucosa with increasing dose [M15. Y2].
The Japanese population in general has been prone todevelop gastric carcinoma in the lower third of thestomach, in areas affected by intestinal rnetaplasia.
This is also characteristic of stomach cancer in highrisk areas of .4ndean Latin America and may berelated to dietary constituents. However. it is conceivable that the stomach as a whole was predisposed tocarcinogenesis by irradiation and that in rhe lower
third of the stomach the normal risk processes wereaccelerated. If this is true, it represents an interacrionwith environmental lactors and will change, as thefrequency of stomach cancer in Japan is changing.
144. An examination of the cytopathology of lungcancers in uranium miners in New Mexico. UnitedStates, suggests that the same array of cell types isobserved in roughly the same proportion as would be
expected [S20]; others have found some differences inp r o ~ o r t i o n ,but most of the usual cell types are seen[C4]. Some malignancies have not yet been shown toarise after exposure to radiation; chronic Iymphocytic
leukaemia and polycythemia Vera, Hodgkin's diseaseand cervical cancer are esamples.
145. In one autopsy series [K17], about 25% of theliver cancers caused by Thorotrast exposure wereangiosarcomas, a tumour type also caused by chemical
agents but which is otherwise quite rare. In this seriesof 29 autopsies of Thorotrast-induced angiosarcomas,
the authors found that the cell types and histopathology were similar to those of angiosarcomasfrom other causes. Thus, while a radiogenic tumour
may be of a relatively rare tissue type, it is not itself
different from a non-radiogenic tumour of the same
type. The presence of the Thorotrast as an internal,
long-term resident in the liver may induce histologicalchanges by means other than simply the radiation
effect.
146. In a series of 180 autopsies of Japanese Thorotrast patients who had malignant hepatic tumours,
Mori et al. [M31] reported a preponderance of
cholangiocarcinomas and especially of haemangioendotheliomas.

147. Biopsies of thyroid cancers from 31 patients
who had been given external x-irradiation have been
compared with biopsies of thyroid cancers from 389
non-irradiated patients. The irradiated patients weresignificantly more likely t o have the papillary type oftumour, with a higher incidence of metastatic lymph
nodes [T13]. While these results suggest that the tissue
types are not unique to radiogenic thyroid cancers.
they may depend on the external source of theirradiation and may not be comparable to thehistopathology after exposure to internal nuclides.
148. A recent study [M34] has found that the
distribution of cell types In radiogenic acute leukaemias
in adult atomic bomb survivors and cervical cancer
patients did not differ from that in spontaneous
leukaemias. In spondylitis patients secondary acuteleukaemias were of all cell types other than chronic
lymphocytic leukaemia.
149. A general conclusion from the available data isthat there is no diagnostic difference between the cellsof radiogenic tumours and the cells of the spontaneous
tumours of the same site. This conclusion is consistent
with the fact that cancer is a mutational disease thatcan be caused by any mutagen.
4.

Causal mechanisms: gene activation or inactivation?

150. As mentioned above, some tumours (especiallyretinoblastomas) are apparently caused by gene deletion, which presumably inactivates necessary genes o r
gene repressor regions of chromosome 13. The result.
if both homologous chromosomes are affected, iscancer. In other tumours, cancer appears to be causedby the incorrect activation of a normal gene. o r theactivation of a mutant version of a normal gene; inthese cases, the tumour occurs in heterozygous cells
and the effect is "dominant" at the cell level.
Oncogene amplification, one of the means by which
oncogenes are activated. occurs in a variety of humantumours including neuroblastomas (where amplification of the N-myc occurs), retinoblastomas [L13],
glioblastomas [L 121, leu kaemias and carcinomas.
Radiation may work in different tissues by inducing
chromosomal translocations, by deleting repressor
sequences, by deleting or inactivating necessary geneso r by causing point mutations in normal genes.
Further studies \rfill be required to identify themolecular nature of the lesions caused by radiation.
151. As noted earlier in the section describing doseresponse models, there is a variety of evidence
suggesting that high doses of radiation can damage
cells to such an extent that DNA-repair mechanisms
are ineffective: apparently, such cells are often sodamaged that they are either non-viable or cannot
replicate. At least, they d o not seem capable of furthertransformation to malignant states. This form of cell
inactivation has been found in several studies. Mole
has argued that high doses of radiation to foetuses
in utero seemingly show this effect [M7], though thishas not been proven directly. Among adults, a relative
deficit has been seen in osteosarcomas in radium dial
workers subject to very high doses [R12]; in breast

tissue irradiated in the course of mastitis therapy [L6],in thyroid cancer after irradiation including "'I
ingestion for hyperthyroidism [DIO. H121; and in thepelvic organs of women who were heavily irradiatedto treat benign gynaecologic disease [W6] and cervicalcancer [B12]. Leukaemia in ankylosing spondylitis
patients demonstrated a similar deficit [D 1 I]. Finally.
the deficiency in breast cancer among women treatedfor cervical cancer [BIZ] may be due to a different
cell-sterilizing effect. Ovaries subject to substantial
irradiation may become deactivated. thus indirectly
protecting the breast from carcinogenic effects. Higherorder terms in dose-response curves may not be trivial
ones. and dose-response estimates should take theminto account: this is increasingly relevant as therapeuticradiation concentrates higher dosages on smaller andbetter-defined tissue areas. On the other hand. therelatively lower dose outside the primary target area
may have the inadvertent effect of generating somesecondary cancers in cells that would have beensterilized by less advanced equipment and techniques.

B.

TISSUE SUSCEPTIBILITY IN CHILDREN

152. Tissues differ substantially in their susceptibility
to radiation carcinogenesis, and the age and sex of the
exposed individual may also affect their responses.
These differences are seen in sites with very low orvery high relative risks for given exposures, in patternsof latency o r the cell types of post-irradiation turnours.
in age and sex vulnerability. and in some aspects of
the age of onset of such tumours. It is enlightening to
examine the relationships between age at exposure andtumour onset and between proliferating and nonproliferating tissues, as well as the life-cycle e\.ents ofspecific tissues as they relate to susceptibility in thattissue.
153. Data on these Special tissue effects come fromseveral sources, including (a) in utero exposure and(b) age at exposure for tissues with marked periods ofproliferation o r development. The special vulnerabilityo r insensitivity of tissues is informative, for i t may
identify the process by which radiation induces cancer
in specific tissues and the special risks attendant on
certain types of exposure. Such knowledge could
refine our understanding of which human subpopulations are more susceptible to radiation effects, relative
to radiation protection guidelines or to medical
therapeutic practice.
1.

Exposures in utero

154. The risks to the irradiated embryo or foetus werediscussed extensively in Annex G of the UNSCEAR
1977 Report [UZ] and again in Annex C of the
UNSCEAR 1986 Report [Ul]. Those findings arebriefly reviewed here, summarizing the best currently
available dose-response estimates and considering how
current data on prenatal exposure relate to the biologyof radiogenic cancer.
155. If cancer is caused by a series of mutational
steps. along with the effects of growth proliferationand promoters, the embryo or foetus should be highly
susceptible t o radiation-induced cancer. The available
data are equivocal at best: indeed. animal experiments
have failed t o find a particular sensitivity [B5. UI].
There are basically only two ways to collect data on
this topic. One is to examine the children of women
irradiated, while pregnant. for diagnostic or therapeutic purposes, and the other is to examine thechildren of women irradiated at the time of the atomic
bombings. T o date, the findings from the two sources
seem contradictory. The findings are summarized inTable 14, which only provides published estimates of
the approximate average relative risks. and does notdirectly reflect the controversial aspects of thesestudies, which will now be discussed briefly.
156. Two large-scale investigations have undertaken
to assess whether the fraction of children exposed to
x-irradiation in utero was higher for children who diedof cancer (generally, prior to age 10-15) than forcontrol children who did not die of cancer. One of thestudies was in the United States and the other in GreatBritain; both have now been accumulating evidence
for about three decades. The first to be reported was
the Oxford survey [S5]. It suggested a radiation effect.
a cumulative relative risk (which was only crudely
correlated to dose) of around 8.25 in the first trimesterand 1.45 in later trimesters. a linear dose-response
pattern, a relative risk that decreased with historictime, and an age-onset distribution with a slightly
higher mean age among cases judged to be radiationinduced than among all cases in the population [S6];the reasons for the latter finding. if i t is other than astatistical artefact, are not evident.
157. This study [SS] has been criticized because theT65 data on the survivors of the atomic bombings at
Hiroshima and Nagasaki exposed in utero, a direct
and prospective set of observations. d o not suggest
such an effect [I I , J I ] and because the British results
apparently conflict with animal data (see [B5. UI]). In
particular, i t has been suggested that various biases
exist in the data. factors that would lead a woman
who was predisposed to bear children prone tojuvenile onset cancers to be more likely to be
irradiated during pregnancy (for example, t o diagnose
problems already manifest in the pregnancy) [D3].
That poor health might predispose one to be exposed
to irradiation was suggested in a study in the UnitedStates showing an excess risk in white. but not inblack children [D3]. The excess risk persisted after
considering sources of bias, which were comparable
between the two ethnic groups: this suggests that theeffect is real in whites. However. the authors propose
an ethnic-specific difference in radiation susceptibility.
for which there is no other basis. making it more
likely that aspects of black-white differences in socioeconomic or environmental conditions are responsible.
158. Stewart and Kneale [KI. K2] have addressed
these issues in several ways. primarily by using MantelHaenszel [M6] multiple contingency table methods t oassess associations between various risk factors. irradiation and childhood cancer. The factors examined
include socio-economic status, birth order of theaffected child, age of the mother at pregnancy andbirth year. They were indeed found to influence theoccurrence of childhood cancer, but a radiation effectpersisted even after they had been taken into accountstatistically [KI]. Stewart and Kneale also contend
that there is a detectable dose effect, that the firsttrimester is a period of high sensitivity, and that theextra x-rayed cases in their survey are indeed radiationinduced.
159. Mole [M7] has argued from data on twins thatthe selection factor was probably not a serious
potential bias. Twins are known to be about five times
more likely than singletons to be irradiated in utero,
but Mole found their post-irradiation risk of cancer tobe basically the same as that of singletons; hence, atleast this particular factor predisposing to foetal
irradiation did not seem to lead to an altered risk.
Twin foetuses are not more susceptible to diseases
than singletons so that their predisposition to be
irradiated may be different from the data on nontwins reported by Stewart and Kneale. On the other
hand, it is curious that twins d o not, overall,
experience more childhood cancer than singletons, as
would be expected based on the greater likelihood of
their having been irradiated [B 151.
160. This was confirmed by an investigation of
32,000 twins in Connecticut, United States, born from1930 to 1969; however, this same study found that thefrequency of x-ray exposure was 2.4 times as high intwins who suffered childhood cancer as i n a fourfold
greater set of matched control twins [H 1 I].
161. The Connecticut study was of twins who hadreceived a dose estimated to range between 0.0016 and0.04 Gy, with a median of 0.01 Gy. After follow-up to
15 years of age, the crude relative risk associated withprenatal exposure was 1.8 (95% C1: 1.4- 1.9), and evenafter adjustment for confounding factors which could
be studied in the sample, the relative risk range was
1.4-1.9. The relative risk for leukaemia was 1.6 (95%
CI: 0.4-6.8) and for all other cancers of childhood 3.2(95% CI: 0.9-10.7). While the magnitude of theconfidence intervals shows that nor all of these results
are significant, the data agree generally with thosefrom the British and other United States studies.
suggesting that the effect is real. even if a radiogenic
cause cannot directly be proven.
162. T65 data from Japan [ I l l reveal no doseresponse pattern in those resident in Hiroshima andNagasaki, although the zero-dose group had a higher
rate of leukaemia than the not-in-city group. Further.
the highest risk group. which had received 0.5 Gy or
more as foetuses. showed no leukaemias. Hence. there
is no evidence for an excess risk. Because subsequent
analyses in Japan have continued to confirm this (andfor leukaemias these analyses now include follow-up
through 1979, i.e., adult ages as well as childhood [I I]),and for other reasons related to various aspects of thedata available to Stewart and Kneale, the findingsof thelatter have come under frequent criticism. Most
trenchant has been Totter and MacPherson [T2], whoshowed that the Oxford su wey's x-rayed control
individuals had not been similar to controls who had
not been x-rayed in regard to confounding social andbiological variables (e.g., social class, birth order andage of mother). and that, therefore. the estimates ofrelative risk derived from these retrospective data.
while valid in regard to the association they show
between various factors, including foetal irradiation.
do not demonstrate a causal relationship between priorirradiation and cancer. These criticisms have received
response [K4, T3]. There arc also problen~swith theeffects-measure and the dose-response data. First,
relative risks of radiation carcinogenesis, for similar
estimated dose. have declined over historical time. forunknown reasons. Second, dose estimates are notdirectly available, and crude, uncertain measures (i.e..
number of exposures) have been used as a surrogate.
163. In sum, these studies habe shown an associationof childhood cancer with prior irradiation but have left
doubts about the nature of the sample. especially in lightof the J a ~ a n e s eobservations. so that one cannot becertain th'at radiation is involved. On the basis of all
the evidence. a selective factor of susceptibility togeneral ill health in the exposed seems unlikely to
explain the result, although limited medical care in
Japan just after the war might account for some of thedifference in the findings [Ill. Another study. in the
United States. by Monson and MacMahon [M8] lends
some support to the general conclusions of Stewart
and Kneale by replicating some of their results. Theseauthors compared exposure in a population sample of
all births with that in a sample of retrospectively
ascertained children who died of cancer. i.e., i t did not
rely on retrospective matching of controls.
164. In particular. the kinds of confounding notedby Totter and MacPherson were considered. but nor
found, in the Monson-MacMahon study. and there is
no proof of better access to medical care for thosedestined to develop post-natal cancer, as Totter and
MacPherson hypothesized. Thus, while there areproblems with these studies, they suggest a 1.4 or 1.5
cumulative relative risk of prenatal exposure, with noreliable data on dose-response patterns. The relativerisk of solid tumours is slightly. but not significantly,
less than that of leukaemia. A study in Finland [S7]disclosed a comparable leukaemogenic effect. but it
was not statistically significant. Other studies withsimilar findings include [D3], [M9] and [St%]; twosmall surveys [C3, 011 reported no increase but were
not large enough to exclude a 40% excess.
165. Several other factors are of interest. The greatest
effect in the Steivart and Kneale survey seemed LO
have been in the first trimester, and the discrepancy
between their data and the atomic bomb data has
been attributed to the greater cell-sterilizing effect ofhigh, early prenatal doses [M7] or to radiationinduced immune deficiencies (e.g., [I I]. [K3]. [K5] and[UI]). However, there was an excess of overallmortality i n Japan only in those who had been
irradiated in the third trimester of their gestation [K6],but these children had no excess cancer [Ill, and these
are the foetuses most likely to survive irradiation. A
bias does not seem likely. therefore, in the Japanesedata. Monson and MacMahon [M8] showed that the
only radiation excess was in those leukaemic individuals
who had been irradiated in the third trimester of theirgestation. Hence dose-effects or gestational-age-effects
are difficult to show or to assess, and no unmistakable
pattern has been seen. I t is also of relevance that dogs
d o not show the specific trimester effect. Thereremains the possibility that concomitant sources ofvariation, and not irradiation, produced the cancers.
These problems are discussed in detail in the UNSCEAR
1986 Report [Ul], which concluded that there was no
firm evidence of a trimester effect.
166. Another relevant question is whether these data
afford a basis for inferring a genetic susceptibility toradiation carcinogenesis. Such a susceptibility might
be expected. or is at least plausible, given the known
genetic susceptibility to perinatal cancers such as
retinoblastoma and Wilms' tumour. Kneale and Stewart[K3, K5] found a correlation between childhood
diseases and cancer in those who had been x-rayed,perhaps indicating susceptible genotypes. The fact that
this was not observed in those who had not been
x-rayed does not offer strong support for a genetic
hypothesis; instead, it suggests that the irradiation
may have had an immunosuppressive effect (but. see[L18]). Genetic susceptibility would be difficult todemonstrate, however, if such genes are rare and theprobability of cancer, even in those individuals. issmall.
167. The BElR 1980 Report [C4] concluded that
there was probably a cumulative relative risk of 5.0
for a first trimester exposure and 1.47 for later
trimester exposures. with the increased risk appearing
as tumours prior to 12 years of age for leukaemias and
10 years of age for solid tumours. The risk was
estimated at 15 excess fatal leukaemias per 10.000
exposed children per PYGy. and 28 excess fatal
cancers of other types. These estimates must be viewed
circumspectly for a number of reasons. including(a) the lack of clear effect of gestational age on theoccurrence of leukaemia and the small effect for othertumours in the study by Monson and Machdahon[M8]; (b) the fact that these authors found only a
1.06 relative risk in recent data for solid tumours;(c) the declining radiation risk o i t r time observed in
the Oxford sun-ey; and (d) the finding of later cancer
risk in survivors. now adults, exposed in utero inJapan [Y8]. Finally, although there had appeared to
be a linear dose-response relationship at least down todoses between 20 and 25 mGy [S5], this, too, is now
suspect, for it was not found by Monson and
MacMahon [M8] and the Knealr and Stewart estimate
was based on heterogeneous data in which exposures
were not accurately known.
168. While it is not strictly classifiable as an in utero
exposure, the exposure of a mother prior to conception may also provide information about radiation
cancer risks. A considerable amount of work has been
done in animals along this line (see [B5] and [UI]),
but only a little in humans. The human data [GI, S8,
S9, U l ] have shown a significant excess of malignant
tumours among the offspring of individuals irradiatedprior to conception (even prior to marriage [S9]),though the effects are not large. The relative risks areabout double the expected cancer rate. Again, thesedata are not consonant with data on the offspring of

exposed parents in Japan. Here, within a cohort of
52.725 individuals followed prospectively. 50,689 ofwhom have individual T65 dose estimates. 36 deaths
were attributed to leukaemia through 1979, of a totalof 3.552 deaths [I 1, SZZ]. The frequency of death due
to leukaemia is not functionally related to the sum of
the parental exposures: indeed. Ishimaru found thestandardized relative risk of the offspring of parents
collectively receiving 0.01 Gy or more of gonadal
exposure to be 0.8. Ten leukaemia deaths wereobserved where 11.9 had been expected [II]. Therewas, moreover, no indication of an increase in any of
the solid tumours of childhood [S22]. These studies
have, of course. relatively low discriminatory power; it
was estimated. for example. that 23 cases of leukaemia
would have had to have occurred among the 16.713
offspring born to exposed parents for a radiation
effect to have been demonstrated.
169. I t is appropriate to summarize the conclusions
offered by the UNSCEAR 1986 Report [U I]. The lackof an effect on early childhood cancers even after
higher doses in Japan is a ground for considerable
caution in interpreting the positive effects from the
medical irradiation studies, especially in light of themany possible confounding or biasing factors. In asimilar way, the fact that early post-natal irradiationin Japan showed carcinogenic effects only many years
later (agreeing with other data on post-natal radiation
effects), whereas the medical series showed theireffects soon after birth, raises serious radiobiologica1
problems if both observations are strictly the result ofradiation. The doubts are enhanced by the absence ofserious effects i n animal experimental data. Also, theconstancy of relative risk values for many cancer sites
in the medical series is at variance with other data thatsuggest site-specific effects. Finally, haematopoietic
stem cell differentiation does not occur during the firsttrimester of foetal development, so that the excess
leukaemogenic effect in first trimester irradiation isdifficult to understand.
170. I t is patent that the existing data cannot resolve
the question of pre-natal irradiation with clarity ormuch confidence. However, it would be prudent toassume that pre-natal irradiation does have an effect,
especially with regard to leukaemogenesis. If pre-natal
irradiation is rcduced or largely replaced by ultrasonography, thc problem may become less critical, but
it would be incorrect to assume that this reduction or
replacement will be an immediate. world-wide phenomenon or that accidental or industrial pre-natal
exposures will not occur. Thus, it is important tocontinue to collect data on this point.

2.

Exposures in childhood

171. The age at exposure to radiation may have a
profound effect on the susceptibility of the individual
to the induction of cancer. especially in those ages thatare known to be characterized by high rates of stemcell proliferation. One of the most obvious of thesecases is exposure in childhood. While in a sensechildhood is a continuation of the in utero growth anddevelopment (which would make childhood experience
merely an extension of the in utero experience), in fact
there may be different sensitivities in childhood andin utero.
172. There are several sources of data on childhood
exposure, but four predominate: (a) children exposedto therapeutic radiation to treat other primary cancers;(b) children exposed for the treatment of noncancerous diseases: (c) children exposed to radiationfrom the atomic bombs, to fallout from nuclear
weapons tests or to accidental discharges from nuclear
power reactors; and (d) female children whose breasts
were exposed to radiation in childhood and perimenarchial ages. These groups may not be comparable
directly, because the first group is largely composed ofindividuals with a genetic predisposition to cancer.
The groups will be considered separately. althoughrisk summaries for the cancer-treated group and allother groups will be presented.
(a) Children exposed to radiation for I reatmen1of primary cancers

173. Though the number of such cases is small,because childhood cancers are infrequent, second
primary malignancies have occurred in children who
received radiation for the treatment of an initialcancer. These populations are of interest because they
contain a high fraction of children who are geneticallysusceptible to cancer. These individuals may be
distinct from the general population of children. They
are all, however, children in whom actively growing
tissues had been subjected to high doses of radiation.
174. There have been two major studies of the riskof second primary cancers in children irradiated forcancer: one. b) Li and colleagues. who used data fromthe United States National Cancer Institute [LI. LZ];
and the other, a survey of data from the United States.
Ital). Federal Republic of Germany. Canada, England.
France, and the Netherlands, known as the Late
Effects Study Group [MlO. M28. T4, T17]. Bothstudies suggest a 15+ relative risk of a second cancerof any site (i.e.. pooling data on all primary sites andcounting all secondary sites). with a 3-12% or morecumulative probability of cancer by age 25. About
68% of all second tumours in the Late Effects Study
Group survey developed in the field of the original
irradiation. The median latency time was I0 years. but
only 5 years for second tumours not associated withradiation. Retinoblastoma and nevoid basal cell carcinoma patients. however, had a reversed latency
pattern. Good dose-response information is generally
not available from these data.
175. Tables 15 and 16 provide basic data from theLate Effects Study Group [MIO. M28, TJ]. These
Tables show two concentrations: (a) that of second
tumours in patients originally treated for tumours ofgenetic origin, i.e., children probably genetically susceptible to cancer; and (b) that of primary tumours insites known to be radiogenic (haematopoietic, bone).
The presence of a primary tumour may imply that thechild is especially radiosusceptible. Second tumours
were frequently associated with radiation in children

known to be genetically susceptible to cancer: of
96 second tumours in such children. 42 (44%) wereradiation-associated [M28]. The expected rates werebased on the United States Connecticut Tumor
Registry, although the cases were international. Hence.
while the qualitative conclusions seem sound andagree with what is known genetically and biologically.
the details of the results may not be precise.
176. In a study of the leukaemogenic risk posed bytherapy in these children. it was found that the use ofalkylating agents was associated with elevated risk
while the use of radiation therapy was not [T18],
consistent with the findings of other studies summarized
in this Annex.
177. In a detailed study of bone sarcomas i n the Late
Effects Study Group, Tucker et al. [TI71 found thatamong the 9,170 children in the analysis, the relativerisk of bone sarcoma was 133 (95% CI: 98-176). There
was a 20-year cumulative risk of 2.8%. or 9.4 cases per
lo4 PY. A comparison was made between 64 of thesechildren for whom detailed treatment data wereavailable and 209 children who had not developedbone cancer by the time of the study. The radiotherapy relative risk was 2.7 (1.0-7.7). after meandoses to the bone site in question estimated to be
27 Gy: there was a sharp dose-response gradientreaching a relative risk of 38.3 with doses above 60 Gy
but decreasing above 80 Gy, and an overall excess
relative risk of 0.0006/Gy. No excess risk was detectedwith doses under 10 Gy. Eighty-three per cent of thetumours were within the field of radiation. Osteosarcoma had the highest relative risk value, followedby chondrosarcoma.
178. An investigation of 64 cases of second cancers
in children in the Federal Republic of Germany
found mainly osteosarcoma. thyroid cancer, and acutenon-lymphocytic leukaemia (ANL); 36 of 50 irradiatedchildren manifested their second tumour in theirradiated field: a separate chemotherapy effect was
not seen [G 141.
179. Overall. these studies indicate that the general
range of absolute risk per unit dose of a variety of
second tumours is within about a single order ofmagnitude and much less than, for example, thevariation in absolute risks for a comparable set of
adult-onset tumours. Solid as well as haematopoietic
tumours resulted from this irradiation. and theyaffected many organs. Although interpretations basedon heterogeneous data collected retrospectively from awidely dispersed group of hospitals must be guarded,i t is probably safe to assume that there is a generalradiation-induced risk of second tumours in children.
180. To determine whether orthovoltage (140-500 kV
peak range energy) or megavoltage (10 M V energy)
therapy is safer, a study was made of 330 children in
Minnesota, United States, who had been given megavoltage therapy [P16]. Only second tumours arising
five or more years after irradiation were considered.
and all children known to be genetically susceptible
were excluded. The 30-year cumulative risk of cancer
was 9.6%; this is somewhat less than the orthovoltage

risks [Ll]. Nine of 14 second tumours were within theradiation field; five children had received chemotherapy
as well, and two tumours developed outside theradiation field in these children. Thus, the apparent
radiosusceptibility in children treated for primarycancer cannot be ascribed solely t o chemotherapeutic
effects o r to genetic susceptibility.
181. In the Late Effects Study Group osteosarcoma
study [T17], mega- and orthovoltage therapy had
similar risks. There were also comparable risks following chemotherapy in these patients, but the radiation
was shown to have risks independent of chemotherapy.
183. Table 17 provides details of the cancer risk
following irradiation for three cancers of which asubstantial fraction are known to be familial (retinoblastoma. Wilms' tumour, Ewing's sarcoma). Most of
the subsequent tumours are sarcomas. especially in
irradiated bones: however, carcinomas can arise inheavily irradiated epithelial tissues, as the Wilms'
tumour data disclose. The general range of risk is
1-3% at 10 years post-exposure, rising to 15-35% ormore after 30 years, based on life-table methods ofcalculation. One can assume that virtually all of thein-field tumours were radiogenic: but the spontaneous
rate in these patients is also quite high, sometimes
nearly as high for all sites combined as for theirradiated field. Hence, radiation interacts with hostsusceptibility. perhaps causing it to be expressed in thespecific target field.

(9

Trearment-for retinoblastoma

183. Retinoblastoma is an embryonal tumour of theretina, usually occurring at, or shortly after, birth. It iseasy to diagnose and is restricted in age, largely
because i t arises in a tissue where mitosis ceases atabout the time of birth. Though it is a rare tumour, its
epidemiological importance has motivated several
studies of patients in major referral centres. One of theinteresting facts about this tumour is that approximately
25% of cases are of a heritable kind; this is detectable
either because the initial presentation is with bilateral
and/or multifocal disease or because other family
members are affected [Vl]. Epidemiological and molecular data have shown convincingly that this heritableform of the disease is attributable to the inheritance ofa single damaged gene region on chromoson~e 13:
retinal cells which then suffer a somatic mutation at
the same region on the homologous chromosome are
malignantly transformed. The tumour cells are clonal
descendants of the first transformed cell.
184. Osteosarcoma is a tumour to which genetic
retinoblastoma patients are known to be at high risk
as a second primary malignancy [F2, VI]. Studies
consistently show that about one third of the second
primary tumours in these patients are osreosarcomas;
the remainder consist of soft-tissue sarcomas, brain
tumours, leukaemias, and melanomas. Osteosarcomas
may occur in the irradiated field, but will spontaneously
occur in distal. non-ocular sites not subject to radiation
therapy and in non-irradiated patients. While othermalignancies are seen in retinoblastoma patients,
about 80% of all second tumours occurring later inchildhood or early adulthood are osteogenic sarcomas.
At present it seems that these cancers result from theproduction of a second mutation in a n exposed
osteoblast. The osteoblast becomes homozygous forthe chromosome 13 gene deletion, just as the retinal
cell does. leading to the neoplasm [D4, D19. H18].
This could even occur in individuals who d o not carry
the familial retinoblastoma gene [Dl91 and is being
seen in some other radiogenic second tumours (osteosarcomas of the orbit [S41]). Because osteosarcoma
occurs even in non-irradiated bones, bone growth a n ddevelopment must involve the same genes involved in
the development of the retina. The concentration of
osteosarcomas in these patients during childhood andearly adulthood shows that the tumours occur during
the normal cell proliferation periods for this tissue. It
is now known that these tumours are generally causedby somatic recombination, leading to cellular homozyosity for the deleted or inactivated gene.

185. Family members of retinoblastoma patients
who d o not themselves manifest that disease seem tobe somewhat more susceptible to other cancers than
the general population, although the reasons for thisare a t present unclear [C5, S123. There are no data onradiation effects in such individuals as yet.
186. A Japanese study of 2,609 cases of childhood
cancer has found roughly similar results [T12]. Seventeen of 50 second cancers were in retinoblastoma
patients, and most were related to radiation therapy.
Of all second tumours, haematopoietic, bone, andthyroid made up the bulk. Thus the pattern is present
in all ethnic groups that have been studied to date.
187. In several general studies, the risk of radiogenic
second primaries has been estimated to be 1-15% in
20 years of follow-up [A8, F2, L1, T4, VI]; since thepopulation risk of an osteogenic sarcoma of theorbital area (or even of the skull) is very low. theradiogenic risks are well over 100 times the baseline
risk in most estimates. Current dose rates are 35-60 Gy,
using megavoltage equipment: this has been reported
to reduce the risk to 1-29? (see [F2] and [Vl]), which
is lower than the risk associated with orthovoltage
equipment. It is not clear whether there is a cellsterilization effect.
188. In retinoblastoma. not only genetic susceptibility
but also concurrent chemotherapy must be considered.
The literature is consistent in finding that almost all
independen1 second tumours have been observed infamilial cases [A3, D15, F2, VI]. The effect of
combined therapy is discussed in section V.C. where itis shown that an excess risk is experienced, at least in
genetic cases [ D 153.
189. Two studies warrant special discussion [A3,S26]. Abramson et al. [A31 followed 693 patients withbilateral, presumably heritable, retinoblastomas a n d
18 patients with unilateral retinoblastomas. These
data are summarized in Table 18. Although previous
estimates from this series on the risk of second
tumours have been between 10% and 15%, they did not
fully account for the variable length of follow-up. If
the time-specific incidence rates are computed, usingthe number of new cases divided by the number ofindividuals not yet affected up to the time of followup, time-specific cumulative risks can be calculated
and a life-table cumulative incidence obtained. With
this method, Abramson et al. found a mean latency of
10.4 years. For individuals undergoing neither radiation (or with second tumours outside the irradiatedfield) nor chemotherapy (and yet surviving, having
been treated by enucleation alone), the incidence oftumours was 10% after 10 years, 30% after 20 years,
and 68% after 32 years.
190. For all patients, the risks of second tumours
were considerably higher. After 10 years, the risk was
projected to be 20%; after 20 years, 50%; and after 30
years, 90%. This is much higher than reported in otherinstances, at least partially because of the method ofcomputation which accounts for differential follow-up
and at-risk periods. These results need to be confirmed. Tumours that developed outside of the radiation field (or in non-irradiated individuals) had
significantly later ages of onset than those in the field.
191. By comparison. the Late Effects Study Group
sample of retinoblastoma patients exhibited a 14%
cumulative risk after 20 years [T17]; this group
included a mixture of heritable and spontaneous cases,
which may account for some of the difference with theAbramson study. It found that the relative risks ofsecond bone cancers following primary therapy forretinoblastoma were similar to those following comparable therapy for other childhood cancers, presumably
because the baseline bone cancer risk is higher in
pa~ientswith retinoblastoma than in patients withother types of childhood cancer. That is, rrtinoblastoma patients have higher baseline osteosarcoma
rates, so that a larger numerical excess number ofcases produces only a modest relative risk.
192. Dose effects have been estimated in a general
way for the Abramson study data. Thirty-sevenpatients received orthovoltage therapy only, withdoses ranging from 3.5 to 260 Gy. Thirty-five received
betatron radiation (3.5-120 Gy). Fifteen received combinations of these with some other miscellaneous
treatments. Life-table analysis showed that the risks ofsecond cancers following one course of betatronradiation (3.5-4.5 Gy) were not different from thosefollowing multiple courses (70-90 Gy). Similarly.
patients treated with orthovoltage doses of less than
110 Gy had the same life-table risks as patients treatedwith more than I I0 Gy.
193. In the second study [S26], Sagerman showed a
2.5% risk of second tuniours for patients receiving
60 Gy. 5.5%. of those receiving up to 110 Gy, and 32%
for those receiving more than 110 Gy. The variability
in follow-up times and the fact that those patients
receiving higher doses had longer follow-up complicate
the interpretation of these results. Lower doses havebeen used more recently, and hence have shorter
follow-up times. The life-table methods of Abramson
et al. did not demonstrate a difference related to dose.
Hence, it is not clear how much dose reduction,
fractionation or energy level of the therapy affects therisk in retinoblastoma patients.

194. A study of 882 retinoblastoma patients in
Britain reported results that were qualitatively similar
but that, quantitatively, showed less risk [D 151. In thisseries, 30 second malignant neoplasms were seen. The
results are presented in Table 19. Twenty-six of thesecond tumours occurred in the 384 patients withgenetic retinoblastoma; using life-table methods toaccount for differential follow-up times, the risk of asecond tumour was estimated to be 8.4% after 18 years(6.0% for osteosarcoma alone). Of these 26 tumours,
12 had developed outside the radiation field (a risk of
3.0% after 18 years), all of them osteosarcomas (2.2%
among those with neither radiation nor chemotherapy.
i.e., the baseline risk level). The British population
risk of osteosarcoma by age 18 years is about lo-', sothat the relative risk in genetic retinoblastoma was 200(95% CI: 50-500).
195. Within the radiation field. where second turnours
are probably radiogenic, the risk in the genetic cases
was 6.6% after 18 years. Average doses were 35-40 Gy.
with little variation. While the radiation effects inthese data are not dose-specific, they do indicate thenature of the risks. The follow-up period was shorter
than that reported by Abramson et al. [A3]; otherwise, the difference in risk is probably due to different
efficiencies i n the ascertainment of secondary neoplasms. Whether the true actuarial risk is as high as
Abramson et al. suggest, or somewhat lower, retinoblastoma patients are obviously at very high risk of
secondary neoplasms.
196. A brief report by Koten et al. [K27] has given
an estimate of 19% for second tumours after 35 years
in patients in Holland. This is intermediate between
the other studies.
197. All of these children were irradiated at or nearbirth, that is, at about the same age, so there are nodata on the effect of age at exposure and no effort has
yet been made to project the lifetime risk, although
the two major studies d o offer some indications. In
Abramson et al. [A3], the cumulative incidence curvein those without radiation effect (but who are genetically susceptible) is slightly concave upward frombirth to age 32, the maximum number of years offollow-up. The curves for tumours inside and outside
the radiation field show similar shapes through age 25,
after which the data are sparse. If this finding iscorrect, then radiogenic turnours are occurring at
about the same ages as spontaneous tumours in thesechildren, as is the case with radiogenic adult-onset
carcinomas generally (as will be seen below). The
cuniulative increase rises non-linearly with age offollow-up. suggesting at least crudely that a multiplicative risk projection is more applicable than an
additive projection, again in agreement with most
adult cancer patterns. The non-linear cumulation ofrisk is also apparent in the study by Draper [D15],
although less detail is given. As shown in Table 19, theabsolute life-table probability of second cancers rises
by a factor of two in the years 12-18, relative to theincrease in the 12-year interval 0-11. This is true forradiogenic as well as non-radiogenic second tumours.
198. It should be stressed that retinoblastoma patients
constitute the only significant group of human beings

in which the carcinogenic process can be observed,
after radiation, in exposed cells in which (a) radiation
is in a sharply delimited area and can be comparedwith the same area without irradiation and the rest of
the body; (b) the cells at risk are effectively haploid in
regard to cancer risk; and (c) all exposed individuals
are of essentially the same age. The subsequent
projection effect should differ in ways that are
informative relative to multi-stage models. because
only one second stage is needed for cancer t o occur inthese individuals. It would be useful to know how theeffect of cell sterilization. which must occur in the
periocular region after intense irradiation, manifests
itself in regard to (a) the dose-response relationshipand (b) the probably smaller number of carcinogenic
events .ieeded to take place as a consequence of
irradiation.
(ii)

Treatmenr for Wilms' rumour

199. There has been considerable work, mainly by Li
and colleagues (e.g., [L3]), on the risk of a second
neoplasm after radiation treatment for Wilms' tumourof the kidney in childhood. After nephrectomy,
patients receive radiotherapy to any areas that might
be the site of further tumours or potential metastases,
usually the renal fossa, elsewhere in the abdomen. orin the thorax. In 487 patients and 4,255 person-yearsof observation, Li et al. observed 1 1 second tumours,with latent periods ranging from 7 t o 34 years. Most
patients were given orthovoltage therapy with average
doses of 25 to 30 Gy to the abdomen; other sites
received varying doses. There was a second tumour in
2.8% of the patients. Nine of the second malignancies
were solid tumours and occurred in areas that had
been given 6-40 Gy. One was in a non-irradiated area.
There was one case of acute myelogenous leukaemia.
The cumulative risk of a second tumour was 18% (SE:6%) in 34 years after diagnosis of Wilms' tumour.
200. The relative risk of radiation itself was not
estimable (i.e.. was not finite), since no case occurredin the 75 non-irradiated patients. Another study has
yielded similar results, with 2.3% of cases having asecond tumour [SIO]. A third study reported a variety
of sites for second tumours, including the thyroid,
gastrointestinal sites, and bone, all with relative risks
over 80 [T4]: leukaemias were increased 13 times.
Many of these sites, e.g.. the thyroid, are unlikely tohave been in the intended irradiated field. and theauthors d o not report radiogenic cases separately.
Wilms' tumour, too, may be heritable in a large
fraction of cases. Its controlling gene region, alongwith the gene for insulin and the H-ras-l oncogene(rat sarcoma), is on chromosome 1 1 and, as is true forretinoblastoma, somatic homozygosity at the relevanrloci may be sufficient to produce the disease.
(iii)

Trearmenrfor Ewing's sarcoma

201. Ewing's sarcoma is a form of bone cancer,
typically treated by local irradiation and chernotherapy.
Lately, long-term sunvival rates have improved. andseveral studies have demonstrated a substantial risk of
secondary osteosarcomas in the irradiated field [G2,S11, T4]; there may also be a risk of leukaemia [T4].
These patients received 44-55 Gy. followed by a

10-15 Gy boost to a reduced field, over a six-weekcourse of administration [Sl I]. Patients receiving
orthovoltage radiation were ordinarily treated withoutchernotherapy, whereas those receiving megavoltage
radiation had combined therapy. The increase in risk
is consistent for all studies. A dose-response of 7.2 cases
per lo4 PYGy and a cumulative risk of 35% over
10 years have been estimated [SI I]. There also seems
to be an increased risk associated with combined
therapy, i.e., newer modalities may have increased therisk of secondary malignancies. The evidence suggeststhat bone tissue is susceptible to carcinogenesis if it isirradiated before o r during the adolescent growth
spurt.
(iv) Trearmenr .for Hodgkin's disease202. Some information exists on the risk of second
tumours after irradiation in childhood for the treatment of Hodgkin's disease. Although data from thetreatment of this malignant disease in children arelimited, the radiosusceptibility of certain tissues. specifically, bone. haematopoietic. and thyroid, has beenreported [T4]. However, in children treated withradiation alone. solid second primary tumours haveoccurred, leukaemias occurred only when chsmotherapy or combined radiation and chemotherapy had
been given [M28]. This is consistent with findings inadult Hodgkin's patients. There was no indication of afamilial susceptibility to Hodgkin's disease in these 40
children. Dose information is not available.
203. T o summarize, the evidence from children
irradiated to treat a primary cancer shows very highsusceptibility to second cancers and promises to be
informative concerning the nature of the genetic
changes caused by radiation and their relationship to
carcinogenesis. However, since these children areprobably not generally representative of the whole
population, these results are not useful for estimatingrisk coefficients o r for risk projection for the general
population.
(b)Children exposed ro radiation for treatmentof benign conditions

204. There have been a multitude of uses of irradiation
for the treatment of benign conditions in childhood.
The exposures in question primarily involve (a) thehead and neck, to treat tinea capitis (scalp ringworm)[M 13. RI, R22. S161: (b) the thymus. to treat what
was thought t o be a pathologically enlarged thymus[H 1. S141: (c) the neck, to treat tonsilar and nasopharyngeal conditions [S15]: and (d) various sites, but
especially the head and upper body. to treat haemangiomas (benign superficial tumours usually present shortly
after birth) [LIO].
205. The tumours induced by these exposures areprimarily leukaemias and cancer (as well as benign
lesions) of the thyroid. Risks of these tumours
attendant on exposure of the head and neck inchildren are summarized in Table 20. At doses of lessthan 1 to about 8 Gy, the absolute risk of radiogenic
cancer varied from <O.1% at 10 years to about 8% a t
30 years after irradiation for malignant neoplasms ofthe thyroid a n d was much lower for leukaemias. Onestudy IS271 has reported an increased incidence ofbasal-cell skin cancer in tinea capitis children; risk
rates are difficult to calculate because of the complex
ascertainment of cases, mixed ethnicity. and other risk
factors, but among white children, there is an increase.
Some aspects of this study are discussed in thesections on host factors and on the interaction ofirradiation with environmental factors. Other cancers
have been reported as well: brain and parotid tumours
have arisen in small but excess numbers in the tinea
capitis series and bone sarcomas have developed inchildren treated with radium for bone tumours.
/i)Thjlroid and thymus exposures

206. The thyroid gland is susceptible to radiationinduced cancer, especially when exposure occurs in thefirst two decades of life. The effect of internal
irradiation in children exposed to "'1 in the MarshallIslands, where a special age effect was not seen, will be
discussed later. The risk coefficient estimate frommany studies is consistently in the range of 1.6-9.3 cases
per lo3 PYGy [C4] in mean doses which ranged from0.09 to more than 10.0 Gy (see [S13], [S38]) inchildhood exposures. These values are based on thymus
irradiation [HI, 514, S381, on tonsilar x-irradiation[S15], head and neck exposure [M13]. and on thefollow-up of the tinea capitis patients [RI, S161, as
well as on the Japanese data. A summary estimatebased on data from North American childhood
exposure to under 15 Gy was 2.5 cases per lo4 PYGy
for exposure under age 18 when both sexes werepooled [N53. Animal da:a and the Japanese atomic
bomb experience suggest about a twofold higher
susceptibility for childhood exposure (under age 18)[N5]. There is a marked excess of cases in females, ingeneral 2-3 to 1 [N5, S131, uniformly across manystudies; this ratio is similar to the sex ratio in
spontaneous cases and does not indicate a particularradiosusceptibility in females [S 131.

children in the population around the city of Rochester,
New York, United States [S38]. In the latter instance,a cohort of about 2,650 children irradiated from1926 to 1957 and 4,800 sibling controls were followed
for about 30 years. The doses ranged from 0.05 to
I I Gy, with 62% having received less than 0.5 Gy; themean was 1.2 Gy. Those who had received higher
doses were treated earlier in the time period and hence
have a longer follow-up. The dose-response data aresummarized in Table 21. Recently, the pathology of
75% of the reported benign thyroid nodules wasstudied, and many were reclassified as non-neoplastic,
thus sharpening the dose-response estimates. Almost
all of these children had been irradiated in their firstyear of life. In many ways. this makes the cohort
similar to that of the retinoblastoma patients (whoexhibit no excess of thyroid cancer following radiationof the orbit). The relative risk, after 29 years offollow-up, was 49.1. based on sibling controls. and the
SMR was 44.6 (based on New York Stare cancer ratedata); for benign thyroid adenomas the relative risk
was 15.0. These values are significant at much lessthan the 0.001 level. They also show the sensitivity of
the relative risks to the choice of controls.
210. Figure I indicates the dose-response pattern. An
additive model yielded 3.46 k 0.82 excess cases per
lo4 PYGy; the sex difference was marked with risks of
5.25 per lo4 PYGy for females and 2.05 cases per
lo4 PYGy for males, which is similar to estimatesfrom other studies. In Japan. exposed persons underage 19 showed a value of just over 2.1, with a sex ratio
of about 2.9 (derived for all ages) [W5]. The doseresponse pattern fitted a linear model (P < 0.0001).
not improved by adding a quadratic rerm. The
authors also fitted a relative risk model to their data,
based on the Cox regression method. This fitted well(P< 0.00001) with a linear dose term (not improved

207. Several other studies of cancer after miscellaneous
exposures of the thyroid have reported similar results[B6. C4, D5, M!2]. Jewish children may be especiallysusceptible [C4, S13, S14. W1 I]: when matched tocomparable non-Jewish children, the relative risk has
been at least as high as 3.5 [S14, Wll]. Whether this is
an artefact of the exposure regimen or is due to otherfactors is not certain.
208. Because spontaneous thyroid cancer is quiterare, it is likely that most of the observed tumours areradiogenic. The bulk have been of the papillary type[C4], and there appears to be a latency period of atleast 5 years [C4, S131, perhaps with a peak excess risk
about 20 years later [C4], though excess risk has been
seen to persist up to 40 years after exposure [S15,S381. Consistent with studies of specific radiation
exposures, a retrospective examination of female
thyroid cancer patients (i.e.. ascertained because of
thyroid cancer not because of irradiation) showed anincreased risk with radiation and with younger age at
exposure. a relative risk of 16.5 overall. but 42.2 for
exposure at less than 20 years of age [M 141.
209. The best dose-response data come from Japan[W5] and from a study of the thymus-irradiated

0f
0

I

I

I

2

4

6

I
8

THYROID DOSE (Gy)Figure I. Thyrold cancer lncldence In relation to thyroid dose.
[S381

by adding a dose-squared term), and the relative risk
estimate after exposure was 1.58 times the prevailingrisk. Data for benign adenomas were similar, both
qualitatively and, to a great extent, quantitatively; therelative risk was 1.44. Figure I yields a risk coefficientsimilar to the figure from Japan, for lower doses, but
in the Japanese data the risk falls after about 3.5 Gy.
2 1 1. This study [S38] also allowed a dose-fractionationassessment. Such data are rare in general, and the results
are summarized in Table 22. In sum. the low-dose per
fraction group had higher risks per Gy, which is notconsonant with the decreased effect of dose fractionation that has commonly been theorized. The results
were the same for adenomas (not shown in the Table).
Thus. neither the number of fractions nor their dose
was protective.
212. Finally, Shore et al. [S38] examined the projection effect in this cohort. The excess in thyroid cancer
began 5-9 years after irradiation and seems to havecontinued even after 40 years of follow-up (i.e.. inpatients irradiated in the 1920s). However. there
appears to have been a slight decrease in the excess
after about 25 years (although adenomas continue toincrease). The mean latency time was 29.3 years, withsomewhat shorter latencies (27.4 years) for thosehaving received the highest doses. The Japanese dataalso show a continuing effect after at least 35 years[W5]. These data follow the age-specific incidence
distribution of spontaneous thyroid cancer in adults.
which reaches a peak in early adulthood and changes
relatively little thereafter.
213. This study agrees generally with the Japanese
T65 data [P4] in suggesting a linear dose-response
pattern for thyroid cancer in irradiated children (aswell as adults). Data from tinea capitis patients are
similar in this regard, although the slope appears to be
steeper. Japanese data [P4, W5] suggest a higher risk
in childhood than adulthood. In North American
children having received doses in excess of 15 Gy,
however, a reduction of effect appears to occur,
presumably as a consequence of cell sterilization [N5].
214. Although these thyroid neoplasms are of therelatively benign papillary type (and radiation effects
include purely benign nodules as well) they may
eventually pose a serious risk. Thyroid neoplasms ofwhatever aetiology can become life-threatening, andthe mortality after 25 years of follow-up is about 7%[NS]. Thus, the risk in children may be substantial,
and further time may be necessary to assess its actuallevel.
215. As was discussed briefly earlier, there has been
speculation on whether radiation-induced thyroid
cancers differ from naturally occurring thyroid cancers.
It has been found that radiogenic thyroid cancers,
somewhat more often than their naturally occurring
analogues, tend to be of the papillary type, and tohave metastatic lymph nodes [T13].
216. Some concern has been expressed about whether
the apparent excess in the exposed individuals is afunction of the detailed follow-up to which many ofthem were subjected. However. a radiogenic excess of
thyroid cancer may also have been reflected even at
the population level. In a study in the state ofConnecticut, United States, based on its tumour
registry, an excess of thyroid cancer was correlatedwith the childhood time period during which these
exposures occurred [PSI. In several instances. the risk
has continued to be elevated as much as 35 years after
exposure, so that the lifetime excess in thyroid cancers
may be more substantial than the very small anduncertain excess in the first decade or so after
esposure.
(ii) Leukaemia as a general ourcome in e-vposedchildren
217. At present. the evidence for excess leukaemia in
exposed children comes largely from two sources:
children exposed in Hiroshima and Nagasaki andchildren exposed to treat various benign conditions of
the head and neck. specifically of the thymus andscalp (tinea capitis). The Japanese data are reviewed
in section 1II.B.Z.c.
218. Studies of children with scalp irradiation totreat tinea capitis [Rl, R22] have produced results inaccord with the Japanese studies. The relative risk oftumours of the head and neck was 3 in a matchedcase-control study of 10,833 cases in Israel, and forleukaemia. specifically, 2.3. The marrow dose wasabout 0.3 Gy. leading to an increase of 0.9 excess
leukaemias per 10' PYGy. There was also a clear
increase in brain tumours. Mean follow-up time was
26 years. Children of less than 10 years of age who
were irradiated had higher risk than those exposed atolder ages. Latency for leukaemias was 9.3 years. No
other causes of death were elevated. Other studies
have found comparable results [A4, M13, S16].
219. In a study on thymus-irradiated children there
was a relative risk of leukaemia of about 3.1 [HI],though a dose-response relationship could not be
estimated.
220. There are no precise estimates of the doseresponse risks of leukaemia in children. The general
range of risk for single or short-duration exposures
combining data from all ages, over the 25-year risk
period following irradiation was estimated in the
BEIR 1980 Report to be between 0.01 and 2.2 excess
cases per IOVYGy, or 0.25-55 cases over the 25-yearrisk period [C4].
221. Approximate risk coefficients from [RI] can bederived as follows. Ron and Modan report 10 leukaemia
cases in 10,842 irradiated children and seven in 16.241
non-irradiated controls. They report that the sexadjusted risk of leukaemia was 4.0 cases per lo4 inmales and 6.0 per lo1 i n females. These persons were
followed for an average of about 22.8 years, so thatthe number of excess cases was 0.18 per 10' PY in
males and 0.26 per 10' in females. At an average doseof 0.3 Gy, this corresponds to 0.60 male and 0.87 female
cases per 10' PYGy. These are crude estimates whichassume that age is not a material factor. so that all
person-years of observation are equivalent. They agreeroughly with the BEIR estimates. Because the results
are not statistically significant, only the mean estimate
is given, with no confidence interval.
(iii)

Exposure of rhe cenrral nervous sysrem

222. The Israeli tinea capitis study [Rl, R22] has
found an excess of brain cancers, with a relative riskof 2.5 (95% CI: 0.9-7.4), with males appearing to be
more susceptible. The dose to the brain was 1.2-1.4 Gy
to the upper layer and 0.95-1.2 to the layer 2.5 cm
below. The risk coefficient estimates, in excess cases
per lo4 PY, were 2.3 for irradiation less than four
years of age, 7.5 for five to nine years, and 3.2 for ages
above 10. Another study of irradiated children has
produced a risk coefficient estimate of 2.9 1 2.4 brain
cancers per lo4 PYGy from five to 22 years after
exposure [Ll I]. No significant increase in intracranialtumours has been seen in Japan among any of the agegroups [S23].
(iv) Exposure o f the skin to rrear haemangioma andorher skin disorders
223. Many children were irradiated to treat haemangiomas, in general in visible areas of the skin, fromroughly 1910 to 1960. Treatment was by 226Ra
implants. Over 20,000 of these patients have been
followed in Sweden [F12]. Among 10,000 of thesepatients [LlO], 75 cancers occurred during the registry
period 1958-1979. Only 55.6 had been expected, basedon the same registry and a national birth record
system, yielding a relative risk of 1.35. Although thiswas a prospective investigation in that a cohort was
identified as being at risk and compared with thenation as a whole, cases were ascertained retrospectively
from a registry. and some cases may have been
overlooked. A preponderance of tumours of thecentral ncrvous system, breast, and thyroid was found[LlO, H221, confirming both the radiosusceptibility ofthese sites and the reliability of the data. Furthermore,
the frequency of birth defects among the mothers inthis study was close to that expected, suggesting that
this was a representative cohort. The occurrence of
thyroid malignancy supports other studies and indicatesthat over-screening bias is not the only reason that
excess thyroid tumours have occurred in other children
given radiation to the head and neck area.
224. There has been widespread use of radiation(generally of "soft" x rays) to treat acne in adolescents.
Some of the doses were administered with coneshielding, to protect the thyroid and other areas;others were administered without such shielding. Data
from the United States thus far provide no evidence
that this use of radiation has led to thyroid or othercancers [G8]. The doses were fractionated, and thepatients were generally 16-18 years of age or older.
when the thyroid appears to be less radiosusceptible
than in early childhood.
(c)Children exposed ro atomic bombings and fallour

225. Several groups of children have been studied
who were exposed to radiation caused by the detonation of nuclear weapons. The best documented are thechildren exposed in Hiroshima and Nagasaki and thechildren exposed in the Marshall Islands (the latter

were primarily exposed internally, to I3'I). Three othergroups have also received some attention: namely,
children exposed to radioactive fallout from [hedistant atmospheric testing of weapons, children
exposed to accidental discharges from nuclear power
installations, and children exposed to relatively elevatedlevels of cosmic radiation by virtue of living on the
Colorado plateau in the United States or at similar
altitudes; the last-mentioned children have been studied
only cursorily, e.g., all of them lived in industrializedcountries and none lived at elevations as high as theAndean altiplano or the Tibetan plateau. The cancer
risks resulting from these exposures are consistent
with the risks from other exposures (reviewed above);
there is a susceptibility to leukaemia. to thyroid
cancer. and, in a special and only partially understoodsense, to breast cancer (see below). In fact, theleukaemia risk has been satisfactorily studied only inJapan: other studies of it remain controversial.
226. Thyroid. The risk of thyroid cancer has alreadybeen reviewed in connection with other exposures. andsome of the Japanese findings have been given. In
Japan, about 3.6 additional incident cases per lo4 PYGy
were seen among females exposed before 20 years ofage, as contrasted with one additional incident caseamong males in these same years. There is mounting
support for a lessened susceptibility in those over
20-30 years of age at the time of the bombing [B5, P3.
P4]. In the Marshall Island cohort, a group of 250
individuals that has now been followed for 30 years,
the only substantial risk is that of thyroid cancer due
to ingestion of I3'I, I3'I etc., with doses estimated to
be 7-14 Gy in young children and perhaps 20 Gy in
infants (< 1 year) [C5. C6]. No tumours were detectedin the first 10 years of follow-up. Only one case ofleukaemia has been seen. While there have been casesof benign thyroid nodules, it is uncertain how muchexcess of malignant thyroid cancer has occurred. Only
papillary cases have arisen, and the relative risk of thenon-metastatic carcinomas has been 0.82 for individuals exposed before 10 years of age and 3.94 forthose exposed after this age (computed from [C5]).
The risk shown in Table 20 is 1.8 per lo4 PYGy forthe children: curiously. this study is unique in findinga smaller risk in younger children, but this could be
artefactual. The thorough search for thyroid anomalies
has led to the surgical removal of most benign cases,
perhaps sparing some individuals the risk of developing thyroid carcinoma. Furthermore, the long
duration of the excess risk for this tumour means that
increased risk may continue to reveal itself.
227. In an investigation of thyroid malignancy inchildren exposed to atomic testing near the Nevada
test site, United States, there was an excess of cases
relative to expectations based on data for the whole
United States, but no excess relative to expectations
for neighbouring states [23].Sample sizes were small,and it was concluded that the numbers of exposedchildren might not be large enough, given current risk
estimates for thyroid cancer, to demonstrate excess
risk from nuclear-testing fallout.
228. The most recent report on the population of the
Marshall Islands [H32] has found an inverse relation-

disappeared by about 1959; that is. after 15 years or so[03]. The latency time is shortest in exposed children,
i.e., it is inversely related to age at exposure [I7]. Most
cases were of acute leukaemias, and these showed themost age-dependent subsequent risk; chronic granulocytic leukaemias showed very little age-dependence[I7]. The subsequent risk can be fitted adequately to alog-normal distribution [I7].

ship between the prevalence of thyroid nodules andthe distance from the BRAVO explosion to the atollof residence at time of exposure. The results suggest a
linear dose-response relationship and an increase in
the risk estimate by 33% to 11 cases per lo4 PYGy.
229. Finally, a recent case-control study in Japan
has found that irradiation of the head, neck, or chest
in infancy to doses of 0.0002-0.4 Gy was the only
identifiable risk factor for the occurrence of thyroid
cancer in teenagers [Y7].

231. At a dose of I Gy. the relative risks for children(< 19 years) and adults have been estimated to be 6.2
and 3.3. respectively [PIS]. Overall relative risks (i.e..
for all doses > 1 Gy and all ages > 15 years at thetime of the bombing) are 31-33 [S17]. The risk
coefficient for Japanese children has been estimated at
2.8 additional cases per lo4 PYGy (T65 kerma). with alower risk in those exposed between ages 10 and 19[F3]. This finding is similar to that for adults, exceptthat the cell types in children have been of the acutelymphocytic and the acute and chronic granulocytic,
which are typical of spontaneous childhood Ieukaemias.
The highest sensitivity seems to have been for chronic
granulocytic leukaemia.

230. Leukacmia. The leukaemia data from children
irradiated by the atomic bombings have recently beenreviewed [e.g.. C4, F3. PIS]. Where i t had once beenthought that the distinction between Hiroshima andNagasaki would be informative with respect to thedifferent RBEs of high- and low-LET radiation, it
now appears that there is little useful data in that
respect, owing to the revision of the dose estimates. In
Japan, the most informative data are the contrasts inrisk after exposure between the 0-0.09 Gy and the> I Gy groups, under age 10. Figures 11 and 111 show
the general risk pattern quite clearly for children andfor adults (from [B24], based on T65 doses). The
latent period is brief, beginning 3-5 years after
exposure and reaching a peak 7-8 years later [F3],after which time the excess risk levels off: subsequentstudies have shown that significant excess cases

232. For leukaemias in children exposed at less than
10 years of age, sex ratios were 0.76 (M/F) for
doses < 0.1 Gy: 1.90 for doses 0.1-0.99 Gy: and 3.71
for doses > 1 Gy. For children 10-19 at the time of thebombing, the respective values were 1.05, 10.32 and

0

0-10C
W

a
ul

Ln

x

I

I-

"

1

1950 1954

2
a
W

-

I-

4

20

1958

1962

1966

1970

1973

01950 19k4....................................
i9!iu 1962

19d6

1970 19j4

above 50 AT8

above 1 Cy........ 0-0.09 G y

Figure II.

Cumulative deaths from leukaernia, 1950-1974,per 1,000persons alive In 1950,for varioue
age groups at the time of the bombings (ATE).
tB241

........

UI

0

R e l a t i v e risk (>1 Gy / 0-0.09 Gy)(deaths per 106 PY)

Absolute r i s k

I

I

10

20

I

30
AGE ATE

I

I

I

40

50

60

"

Figure Ill. Absolute and relative risks 01 leukaemia by age at the lime of thebomblngs, 1950-1974. average for both Hlroshlma and Nagasaki, T65DR doses.
18241

0.84 [CJ]. However, the background rates are higher
in males, and the relative risk is not statisticallydifferent between the rwo sexes [P15]. an argument
favouring a multiplicative projection model.
233. There is no excess of childhood cancers otherthan leukaemia and breast cancer in these children.
Evidence is now available on their later adult experience.
but to date there are no new adult-onset tumour risks
clearly identified with childhood exposure, with the
exception, perhaps, of stomach cancer (4.7 cases per
1 O4 PYGy) [S 17, W5].
234. Most of the controversy in the United States on
distant nuclear fallout exposures has centred on its
possible leukaemogenic effect. Comparisons have been
made for all childhood cancers and separately forleukaemias, based on mortality data for counties withhigh and low exposure before, during, and after
fallout periods. I t has been argued that the data
supported an excess in the high-exposure areas ofsouthern Utah [L4], which excess was correlated intime with the period of exposure to fallout and which
was not evident in low-exposure areas. This interpretation has been criticized, in particular because thedata are not compatible with a simple radiogenic
effect; rates in different areas over these time periods
do not vary simply as a function of exposure.
suggesting that other factors are involved (e.g.. [B6].
[L5] and [RJ]). Reviewing a broader set of data, Landet al. [L5] argued that in southern Utah the leukaemia
rate has been lower than in other parts of the UnitedStates in years prior to the exposure. Further, there
was a deficit in juvenile cancers at the remaining sites
in the exposed area.
235. On the basis of Utah-wide data on fallout, Beckand Krey [B7] have contended that the suggested lowdose area in northern Utah actually received higher
mean doses. so that the gradient in risk described by
Lyon et al. [L3], even if correct. does not correspondto exposure. Johnson [J2] used a large interview studyof Utah Mormon families to argue for a very large

excess in cancer (at all ages) at known radiosusceptible
sites. Because of problems with its methodology. theJohnson study has not generally been accepted asvalid. In a study, which attempted to determine if
Johnson's results could be correct, Machado et al.
[M20] restricted their analysis to a small area ofsouthern Utah. In the proper time period following
exposure to fallout. 1955-1980, there was a small
excess number of leukaemias with onset at ages 0-14
(RR = 2.84 for exposed children, much less thanfound by Johnson) [M20]. There was also an excess ofcases at all ages (RR = 1.42). Machado et al. estimatethat the doses were between 0.001 and 0.021 Gy, sothat small effects, at most, would be expected.
236. There may. accordingly, be a small increase in
the rate of leukaemias in these exposed children,
although more accurate estimates of dose in otherparts of Utah might reduce the size of this effect.
However, since southern Utah rates were about 35%
higher than expected from the rates in the UnitedStates as a whole, at least some of the increase isprobably real. The individual doses are not known. so
a dose-response analysis is not feasible.
237. Analysis of leukaemia mortality rates in the
United States through the period of atmosphericnuclear testing has suggested patterns \vhich areconsistent with fallout effects [A18]. States wereclassified according to the level of exposure based on
the assessment of strontium-90 in COW'S milk samples
in 1959-1960, in human bone in 1966-1967, and in
total diet in 1964-1965. The leukaemia rates during
1950-1976 were correlated with exposure in statesclassified in high, intermediate and low exposuregroups. The pattern of leukaemias showed a 5.5-year
latency and a 15-year plateau, and were only of theacute and myeloid types. consistent with what is known
from other studies of radiation-induced leukaemiasin children. There was also a consistent nation-wide
pattern of these types of childhood leukaemias, andno other exposures to radiation or other agents
could be identified by the author to account for+this. The estimated risk coefficient was 6.46 0.16
excess leukaemia deaths per lo4 PYGy. The author
reviews other data on childhood leukaemia. arguingthat his risk estimates are consistent with those,further supporting a fallout-related explanation.
238. Recently, two preliminary surveys of the frequency of cancer among young people living near
nuclear power installations in the United Kingdom,
specifically at Dounreay and Sellafield, reported anincrease in leukaemia [G 19. H261. Since the estimatedradiation doses in the vicinity of these plants seem too
low to account for the increase, other studies were
initiated. One of these addressed the situation at
Dounreay [D23]. These authors conclude that theirfindings weigh heavily against the hypothesis that theincrease had been due to radioactive discharges fromthe plants, unless the doses to the stem cells fromwhich childhood leukaemia originates have been grossly
underestimated. Cook-Mozaffari and her associates
have undertaken a far more comprehensive study ofmortality in the years 1959-1980 in the vicinity of allof the nuclear installations in England and Wales[C 191. Their findings are succinctly summarized in[F14). Briefly, there was no evidence of a generalincrease in cancer mortality near nuclear installationsin the 22-year period. Leukaemia in the age group0-24 years may be an exception, however: standardizedmortality rates for lymphoid leukaemia increased withincreasing proximity to an installation. In Local
Authority Areas where at least two thirds of the
population resided within six miles of an installation,
relative risks were invariably greater than I, ranging
from 1.12 (British Nuclear Fuels Limited, Capenhurst,
not statistically significant) to 3.95 (Amersham, statistically significant at the 5% level on a one-sided test),
a s compared with Local Authority Areas not in thevicinity of nuclear installations and selected to have asimilar urban-rural status and population size.
239. Over all installations. the relative risk forleukaemia within the six mile distance was 2.0. Since
the individual exposures are unknown, no doseresponse estimate was possible. The investigators
noted that it was not clear whether the effect could be
d u e t o a general confounding of other environmentalo r socio-economic factors. One of these may be theventing of pesticides into the air when the cooling
towers were cleaned. Although it is known that thesubsequent risk of leukaemia among inrlividuals exposed in the first two decades of life is substantiallyhigher than among those exposed later in life, basedo n the Japanese experience and a linear dose-responsemodel, a doubling of the risk would imply a dose ofhundreds of mGy which seems unlikely given present
estimates for exposures within a few miles of a nuclear
installation. Thus, while the risk observed may be real,
it cannot be accounted for on the basis of the doses
received.
(d) Exposure of rhr female breasr in childhoodand or perimenarchial ages

240. In general. radiogenic breast cancer follows thenatural age distribution for this tumour, suggesting
that, as they d o with spontaneous breast cancer, otherhost factors, specifically the endocrine and cell proliferation status of the exposed breast tissue. modify
the susceptibility and latency of radiogenic breast
cancer [B6. H6, T6]. Data on age at exposure areavailable from women receiving chest fluoroscopies
for pneumothorax monitoring in New York [L6. S I],
Massachusetts [D8] and Canada [H6]: from women
treated for mastitis in Massachusetts [B3. L6]; fromwomen treated for benign breast disease in Sweden[B8]. and from atomic bomb survivors [TI. T6].
241. These data consistently disclose a declining
relative risk of cancer with increasing age at exposure.
and a markedly high relative risk for exposure inadolescence and young adulthood. For individuals
under age 25 at exposure. there is a latency period ofat least 15 years, and excess risk persists for 40 years
or more [H6]. A linear model gave the best fit in theJapanese [T6], New York, and Massachusetts series[H6], but a quadratic model fir better in a combined
analysis of the Canadian fluoroscopy data [H6]. Except
in the case of the Japanese study. the young womenordinarily received courses of treatment involving
several ( I - 10) exposures and a total of about 1.5-2.5 Gy
to the breast. With the possible exception of a large
Canadian study (to be discussed later. in the section
on adult breast exposures), the evidence does not
document a fractionation effect [B6]. The absoluterisk is in the range 3-8 additional cases per l V PYGy
[B6. T6] based on a linear model. with higher values
having been found in women who were younger at thetime of exposure. Women irradiated at the time of
their first pregnancies were especially vulnerable [B6].
Because the Japanese women who were less than
15 years old at the time of the bombing are only now
reaching the ages when breast cancer becomes mostconlmon, it is not yet possible to derive satisfactory
lifetime dose-response estimates.
242. Several major findings have recently emerged
from Japan [P15, T6]. In corroboration of the studies
reviewed above. an elevated risk among women aged
10-19 at the time of exposure has been clearlyshown. The relative risk for women who received I Gy
when they were under the age of 19 has been
estimated to be 2.5 1 ( 20.75). compared with a relativerisk of 1.45 (f0.24) for exposureover that age in theextended Life Span Study (LSS-E85) using the T65DR
dose estimates [P15]. At present. the data are notcompletely consistent with respect to the level of riskfor post-menopausal exposures, and further studies ofthe exposed cohorts are needed. The most importantresult may be the finding that women under age 10 at
exposure exhibit an excess risk ([T6. T7, T141; see
Table 23). The excess is related to dose, but did notappear until this cohort reached the ages at whichbreast cancer normally arises, consonant with previous
age-onset results. These are higher relative risks thanobserved in any other age group having received
comparable doses. Absolute risks are high at ages
10-19 [T6], though they seem roughly comparable toages < 10 [T13]; that is, childhood may be the peakyears for susceptibility. The Japanese findings are
summarized and discussed in more detail in section
III.C.4 on adult exposures. Breast-tissue susceptibiliiybelow age 10 has also been seen among infants
irradiated for thymus enlargement [HI91 and inchildren irradiated for other primary cancer [L 121.
3. Tissues apparently not susceptible toradiation-induced carcinogenesis
243. There is accumulating evidence that certain
tissues, generally those involving non-proliferating
cells, are relatively non-susceptible to radiation-induced
cancer. In children, cancer caused by radiation isrestricted commonly to the white blood cell and boneforming tissue and to the thyroid. Except for breastand perhaps stomach there are not much specific data
in regard to solid adult cancers. However, the indications from the most recent Japanese (DS86) datasuggest a high general susceptibility, expressed at thenormal adult ages for carcinomas [S49]. Children
surviving irradiation to treat childhood cancers may incoming decades reflect risk at a variety of irradiatedsites.
244. The information presently available thus suggeststhat if there is an effect of radiation in childhood forother sites, the result will be similar to that found in
the breast. in that excess cancers will arise at roughly
the same ages at which they do naturally. If thisoccurs, then a variety of tissues may be shown to besusceptible to radiation in childhood, but perhaps
without an unmistakable excess susceptibility due tothe young age of the exposed tissues. This would
provide an important contribution to our understanding of radiation carcinogenesis and of the tissue
biology of epithelia.
4.

teristic patterns to the expression of that risk. Tumour
types arise at ages that are typical of the spontaneous
childhood tumours of the same sites, but exposure inchildhood also appears to generate tumours that are
typical of adults and that appear in the usual adultages rather than in childhood. There are indications in
the case of second tumours following retinoblastoma
treatment that a multiplicative projection model may
apply. as i t does in the case of most adult tumours;
data from other sources are at present still too sparseto reach any general conclusions.
247. With the exception of the Japanese data. thestudies on childhood induction of cancer following
ionizing radiation provide convincing evidence that
there are effects, but they do not provide risk
coefficients useful in lifetime risk projection for adulttumours.

C. TISSUE SUSCEPTIBILITY IN ADULTS
248. It is to be expected that age is a critical factor in
determining the radiation risk, since childhood is aperiod of tissue generation and, for many tissues,
differentiation. The question is, how different issusceptibility in the tissues of adults?
249. The bulk of our knowledge of dose-response,
age and projection patterns after adult exposure
comes from three studies: women treated for cervicalcancer, patients (mainly men) treated for ankylosing
spondylitis, and the Japanese exposed to the atomic
bombings. These studies will be presented in detail inchapter V1. In this section, their results and those of
the remaining literature will be summarized in thecontext of the biological issues involved.

Summary of exposure effects in children

In summar). the experience of children who
have received substantial doses of ionizing radiation
demonstrates the susceptibility of the thyroid, bone,bone marrow and the breast. The bulk of the children
who have been successfully treated by radiation forcancer initially presented with tumours characterized
by a large heritable component. From observations onsome of those children who received neither radiation
nor chemotherapy, it can be seen that they are
obviously more prone to develop cancer than normalchildren. In general, certain sites are susceptible, andthe evidence is now clear that this has to do with generegions expressed in both the tissue involved in theoriginal primary tumour and in the tissue of thesecond tumour, particularly in the case of secondary
osteosarcomas occurring in treated retinoblastoma
patients. Individuals with the hereditary form of thistumour are known to develop osteosarcomas awayfrom the irradiated fieid or in the absence of irradiation. There is also evidence that other relatives ofsome retinoblastoma [C5, S 121and rhabdomyosarcoma[S50] patients are at excess risk of cancer of various
types at a number of organ sites.
245.

246. Current evidence, though not conclusive, suggeststhat children are susceptible to the induction of mostcancer types by radiation, and that there are charac-

250. As was seen with juvenile exposures, there may
be biological differences between tissue types of adults
relevant to their radiosusceptibility. The assessment ofradiation effects must be made in the context of the
exposed populations that are available for investigation. Most adult exposures occur as a result oftreatment for disease; such individuals may not bebiologically representative of the population at large,
either because they are genetically different or because
their disease itself changes their susceptibility toradiation. This is likely to be especially true ofindividuals irradiated for the treatment of cancer
itself.
25 1. Two principal sources of possible non-representativeness are important in the interpretation of cancer
induction in irradiated cancer patients relative toother adult cohorts. First, i t is known that a fractionof any population is genetically susceptible to cancer,
e.g., cancers of the colorectum and the breast. Second,most cancers are thought to result from specificenvironmental exposures [D13]: cancer patients may
not be representative of their population in terms of
their history of exposure to such risk factors. To theextent that this is true, their tissues may already havebeen partially affected by these risk factors. Comparing
their post-irradiation experience with that of their ageand sex-matched peers may not be an appropriate way

to estimate the effects of radiation. Evidence on thispoint will be given later.
252. There are important informative cohorts ofadults who were initially exposed for other diseases,
including tuberculosis, mastitis, thyroid anomalies.
benign gynaecological problems, conditions requiring
diagnostic x-ray examinations, and ankylosing spondylitis. It is difficult to know, however, if these patientsare random representatives of their populations; there
are indications that some, at least. are not. Their risk
should be compared with that of the most representative possible unexposed groups.
253. Several other cohorts of individuals, in effectrandomly selected from their populations, have been
exposed to large doses of radiation, and they arenaturally the most reliable sources of data on thesusceptibility of normal adults. They include occupationally exposed groups (radiologists, radium dial
painters, miners, nuclear workers) and individuals
exposed to nuclear testing or to the atomic bombingsin Japan. To gain information on the biologicalaspects of radiogenic cancer, it must be determined if
these groups have different experiences.
254. As essential as it is to consider separately therisk for individuals who may be susceptible toradiation carcinogenesis and the risk for those whoare probably more representative of their population,
it is equally essential to consider the risk in terms ofthe nature of the tissues exposed to radiation. There
are different tumour groups in this regard. The first ishaematopoietic tumours following irradiation of thebone marrow and osteogenic tumours. The risks here
are unique. Due to the widespread distribution ofactive bone marrow:. such tumours have been observed
following many diffcrent exposures. The second groupis nerve and connective tissue tumours, where tumoursthat occur in normally dividing cells should be
differentiated from those in non-dividing cells. The
third and largest group of adult tumours is carcinomasof epithelial tissues, which tissues have life-longpatterns of cell division and specialization.
1.

Adults exposed to radiation for treatmentof primary cancers

255. Relatively little is known on a population basis
about the risk of radiogenic second tumours in the
many adults who have been exposed to treat a
primary malignancy. To date. most of the evidence
has been derived from investigations of the consequences of radiotherapy for cervical and ovariancancers. for Hodgkin's disease and non-Hodgkin's
lymphoma and for the tumours of childhood reviewed
earlier. There has also been one large general study ofsecondary leukaemias in cancer patients.
256. Second tumours in adult cancer survivors may
take the form of local solid turnours in the irradiatedfield, if cell sterilization has not been excessive.
Radiogenic sarcoma has been observed to arise fromthe area of skin, or the underlying fascia, i n an
irradiated area or even from a radiation ulcer (e.g..

[B20]). Second tumours may also be systemic ones
such as leukaemias, presumably caused by a transformation of the cells in exposed bone marrow.
Finally, second tumours sometimes occur at remotesites; whether such tumours could be radiogenic, e.g.,
due to scatter, is essentially impossible to determine.
257. Since many cancer survivors treated by radiotherapy were also treated by chemotherapy. it isnecessary to ascertain what portion of the secondcancer risk is due to the chemotherapy or to aninteraction between the two modes of therapy. Thiscan be difficult. Alkylating agents have a highcarcinogenic potency; they are delivered in large
doses. and most of the body is exposed. Radiation is
locally delivered, in general. Interactions will beconsidered in chapter V.

258. In the case of leukaemia following radiotherapy
for lymphomas, it is presently difficult 10 differentiate
between truly radiogenic second cancers (i.e., leukaemias) and leukaemias that have been caused by theconversion of an initial lymphoma cell to leukaemic
form; this has been suggested to be a normal stage in
the natural history of lymphon~as, although somestudies reveal that it is not [e.g.. BIO]. Molecular
genetic methods may be able to resolve this issue if theoriginal lymphoma cells have specific genetic markers
for which one could screen the subsequent leukaemia
cells.
259. Only a minority of irradiated patients develop
radiogenic second tumours. The relative risks areoften rather small. especially for cancer patients whoare elderly and have fewer years of life during rvhich
to be at risk.
(a) Trearmenr for Hodgkirj 's disease260. One of the most intensively studied groups ofadult cancer survivors, in terms of risk of second
cancers, is that of persons treated for Hodgkin's
disease. While the treatment modalities varied, theyoften involved radiation to affected lymph nodes. In
some patients. no other therapy (or only surgery) was
carried out, but in the majority of long-term sunlivorsof Hodgkin's disease, chemotherapeutic agents werealso used. The results of several studies are reviewed
here [B9, B10, Bl1, B37, C7. C8, G4, P121; [Bll] is asummary of results reported to 1984.
261. The most notable second cancer in these patientsis leukaemia, specifically, acute non-lymphocytic
leukaemia (ANL), although solid lumours and otherleukaemias have also been observed. In the manystudies reported, the results are similar. X-ray therapy
alone does not seem to be a risk factor for theleukaemias. and it may or may not be a risk factor forsolid tumours; evidence on the latter point is conflicting, and since the latency period is longer than forleukaemia, there may not yet be sufficient data on
long-term survivors.
262. Boivin and O'Brien have analysed data pooled
from seven reports of second-cancer risk after treatment
for Hodgkin's disease [B37]. After radiotherapy, therelative risk values for solid tumours were as follows: allsites. 2.2; bones and joints, 20.0; soft tissues, 18.3; nonHodgkin's lymphomas, 8.1; melanomas of the skin, 6.7;
buccal cavity and pharynx, 4.1: nervous system, 3.6;
respiratory system, 2.5; and digestive system, 1.8.
Unlike for leukaemias, no elevated risk of solid
tumours was found in the chemotherapy-only group.
possibly because the studies had shorter follow-up
times.
263, Chemotherapy has been strongly associatedwith subsequent tumours and with the special risk ofacute non-lymphocytic leukaemia; combined therapy
appears to lead to an increased risk based on theinteraction between the radiation and chemotherapy.
However. support for an excess effect of x-ray therapy
is weak [BI I]; the re1atil.e risk of combined therapy
versus chemotherapy uithout radiotherapy was slightly,
but not significantly. lower (125 vs. 136) in one seriesof patients from the United States [BIO, BII]. andthere was no interaction effect in another [C7].
Briefly. there is little evidence for a radiation hazard
relative to secondary acute non-lymphocytic leukaemia
in treated Hodgkin's disease patients. These data aresummarized in Table 24.
264. It is appropriate to note that effective chemotherapy is relatively recent and that in the past, with
only x-ray therapy available. survival was not sufficient
to provide much information. Data are accumulatingthat may permit the statistical isolation of the independent effect of chemotherapy, but this urill not be
feasible until some years at-risk have accumulated.
There are no systematic dose-response data as yet.
265. The cumulative relative risk of acute nonIymphocytic leukaemia due to chemotherapy of various
types is high, sometimes in the hundreds: for otherleukaemias it is about I0 a n d for solid tumours, about
3-3; individuals older than 40 at treatment are athigher relative risk than those who ivere younger, asomewhat unexpected finding [C7, G4]. The risk ofsolid tumours appears to be increased about 3-1 times
by combined therapy. In a study of United States
patients, Boivin and Hutchinson report that the riskof a solid tumour was 1.8, relative to the expected
number, for those with no intensive therapy (raising aquestion about the appropriateness of the expected
rates), 2.1 for radiation only, 1.8 for chemotherapy
alone, and 3.3 for combined therapy [BIO]. After alatency period of 10 or more years, the relative risks
were statistically significant only in the case of theradiotherapy-only group, for whom the relative risk ofsolid tumours was 25 (95% CI: 8.1-58.4).
266. A n increased risk of acute non-lymphocytic
leukaemia has been seen in children treated for
Hodgkin's disease [T4]; however, there was no case inchildren treated with radiotherapy alone [M28]. While
it is conceivable that individuals with Hodgkin's
disease have a natural proclivity to develop leukaemia,
the evidence suggests that leukaemias occur after
chemotherapy and in all stages of Hodgkin's disease,but very rarely in the absence of chemotherapy [BlO,Bl I , G4].

267. A recent study of Hodgkin's disease patientstreated with chemotherapy and radiotherapy at theUnited States National Cancer Institute has beenreported [B35]. As had been found in other radiogenic
leukaemia studies. the excess risk in this small series of
192 patients was expressed in only a small window oftime, in this case from three to 1 1 years. Of course, suchsecond tumours, all acute non-lymphocytic leukaemias.
were only observed in survivors of the original disease;moreover, the authors did not isolate the effects ofradiation therapy from those of chemotherapy. Twoother studies appear to confirm this report [P12, T191,
although there are reports of elevated risk in comparable groups for a period of up to 20 gears [KX].
268. Recently. another indirect risk of treatment of
Hodgkin's disease has emerged. In a study of female
patients in Houston, Texas. United States. cervicalconditions resulting from infection by human papillomavirus were found to be considerably more prevalentthan expected in a general population of the sameages. A twofold to fivefold increase in the risk ofcarcinoma in situ and of invasive carcinoma of thecertix and anogenital region is seen in these ufomen[Kg]. Although this has not been reported in other
Hodgkln's disease series, the connection is plausible
but will require longer follon-up to be ascertained(this study entailed a detailed retrospective review ofPapanicolaou tests of the patients over many years).
In an immune-suppressed individual, vulnerability tohuman papilloma virus infection appears heightened(paragraph 302); this infection progresses over a
period of years, in some individuals to carcinoma[Kg]. I t is not possible, from the available data, toidentify radiation effects independently, because mostpatients received combined therapy.
(b)Treatmenr for cervical cancer

269. Cervical cancer is commonly treated by externalbeam therapy and/or by the implantation of intracavitary radium sources in the vagina and the uterus
for extended periods of time. In the cohorts that havebeen studied, radiotherapy has usually involved two
36-hour applications of 2.6 lo9 Bq of radium. followed
by 20-70 Gy from external beams delivered in 2-Gy
fractions over several weeks [BIZ]. Both orthovoltage(200-400 kV cobalt-60) and megavoltage (2-33 blV
photons from betatrons o r other devices) externalradiation have been used, with a typical dose being
20-70 Gy to the pelvis, delivered in fractions of several
Gy over a 4-8 week period. Risk analysis was initially
carried out by classifying the tissue sites into threegroups based on general level of dose. The greatest
dose is received by the entire pelvic area and thelateral lymph nodes; other heavily exposed organs
include the bladder, rectum, endometrium, colon,
ovaries and bone. The kidney, gallbladder, stomach.
pancreas. and liver are exposed to an intermediatelevel of radiation. Finally, remote sites such as the
buccal cavity, lung, breast, brain, salivary gland a n d
thyroid receive little radiation. Nearby sites have dosesin the tens of Gy: intermediate sites. 1-10 Gy, andremote sites, tenths of G y [B12].
270. The largest study of second tumours in cervicalcancer patients is the International Radiation Study ofthree groups. Of 5,146 second cancers. at most 5%(162) were attributable to the exposure to radiation.
Pelvic irradiation with high doses seemed to be
associated with some increased risk of cancer to the
exposed organs. including the bladder. rectum. bone.
connective tissue, ovary. small intestine and kidney.
The risk of bladder cancer was also increased inwomen with similar diseases who had not been
irradiated; however, the relative risk increased, overtime post-exposure. only in the irradiated group,suggesting a radiation effect [B12]. The risk of cancerof the uterine corpus was consistently below expectedlevels. Figure IV provides the probabilities (relative
risks) and confidence intervals for various second
cancers in irradiated women at least one year after
irradiation.

Cervical Cancer Patients (IRSCCP) [B 12, D9]. Over
182.000 women from eight countries (Canada, Denmark. Finland. Norway. Sweden. United Kingdom.
United States and Yugoslavia) have been followed fromthe time of diagnosis of cervical cancer. Over 1.3 million
person-years of observation have accumulated, including 623.798 person-years to women who were treated byirradiation and 178,243 person-years more than 10 years
after irradiation. The average follow-up was 7.6 years. A
high fraction of cancers was confirmed histologically.
a n d it is believed that the participating registries wereable to ascertain the vast majority of cancers that
occurred; data from the separate registries and detailsof the investigation are reported most fully in [D9].
Since most other studies of cervical cancer have as
their subject the same individuals included in [D9],only the latter results will be reported in detail.

272. The risk of leukaemia was elevated in these
data. but the elevation was similar for exposed andnon-exposed. The dose to the bone marrow is estimatedto have ranged between 3 and 15 Gy. and hundreds ofradiogenic leukaemias would have been expected.
However, fewer than 100 were observed. suggestingthat cell sterilization was an important factor. The
relative risk of non-lymphocytic and acute leukaemias
was small. 1.4 (95% CI: 1.1-1.8). and may reflect lower
levels of exposure at more remote marrow sites, where
cell sterilization was not important. In one of thestudies of which the IRSCCP series was composed

271. In addition to classifying the sites according to
distance (close, intermediate or remote) from theradiation source, the IRSCCP study divided thewomen into those with invasive cancer who weretreated with irradiation, those with invasive cancer
who were treated without irradiation, and those within situ cancer of the cervix treated without irradiation.
Relative risks for women followed more than 10 years
are given in Table 25 (the table contains data fromanother study. to be discussed below). Interestingly,
the pattern of relative risks was similar among the

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SHALL I N T E S T I N E-a-

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LEUKAEMIA
t.lULTIPLE HYELOMA

Figure IV.

r

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0.1

0.2

0.5

1

2

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0.1

0.2

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RELATIVE R I S K

RELATIVE R I S K

COHORT SERIESCASE-CONTROL SERIES

5

10

Reiallve risks of malignancy at rpeclfled slter after radiotherapy for cervical cancer bared on a cohort series [El21 and acare-control rerler [838].

[S34], doses to the marrow of about 7.8 Gy did yield arelative risk of 2.5 for leukaemia: however, although
the sample base was 25.718 women, this was not
significant. Leukaemia was slightly elevated in theSurveillance, Epidemiology, and End Results (SEER)
programme patients studied in the United States by
Curtis et al. [C8], and the relative risk of leukaemias
in another large case-control study in the UnitedStates [B26] was 2.3 (95% CI: 0.2-24.4).
273. To understand this apparent leukaemia deficit
better. a case-control study of leukaemia in a sampleof the IRSCCP patients has been done [B36], using
individual patient records from 196 leukaemias and
750 matched controls (cervical cancer patients notdeveloping leukaemia) to estimate the doses to each of
14 skeletal components of bone marrow. Using amarrow-component-weighted dose-response function,
the best-fitting models included a negative exponential(cell-sterilization) term. Linear and quadratic terms,
relative to the effects at low doses, could not be
distinguished statistically in this study, although thelatter yielded higher risk estimates at low doses andwere preferred by the authors. This suggested to theauthors that in therapeutic doses. cell killing is
responsible for the deficit in leukaemias noted above.
The risk of chronic lymphocytic leukaemia (CLL)(RR = 1.03) was not elevated. but the overall relativerisk for radiogenic leukaemias was 2. l(90% Cl: 1 .O-4.3);
risk increased until 4 Gy, with a 0.88% excess relativerisk per 0.01 Gy, and at 1 Gy the relative risk was
1.88, based on the linear term of the dose-response
function. If the exponential term is included, therelative risk at I Gy reduces to 1.7 in this study.
Women treated over age 55 experienced no excess
risk. The difference between the relative risk in thissample and the relative risk of 2.3 for the entire cohort
was attributed to increased sample sizes in the more
recent study [B36]. The estimated excess number ofcases per lo4 PYGy was 0.48..
274. The authors [B36] concluded that this analysis,
incorporating both cell sterilization and local marrow
exposure considerations. not only explains the deficit
in leukaemia in the IRSCCP group relative to othergroups receiving smaller mean doses (e.g., women
treated for benign gynaecologic problems and atomic
bomb survivors) but also provides an estimate of the
maximum leukaemogenic effect of radiation. This is arelative risk of about 5; doses sufficient to generate
greater re!ative risk values will, by virtue of the cellsterilization effect, fail to do so. Radiotherapy was
judged to be a much weaker leukaemogen than chemotherapy.
275. For unknown reasons, colon cancer occurred atsimilar rates in irradiated and non-irradiated women.
This was unexpected, since other studies (e.g., [ D l I]
and [S3]) have found evidence for radiogenic coloncancer, and the rapidly dividing cells of the mucosa of
the colon should be susceptible to radiation. However,a study of Swedish patients, while revealing excess
cancers of the bladder, endometrium. ovaries. andrectum, also did not find an excess of colon cancer
relative to the general Swedish population [P17]. On
the other hand, there is a report of teenagers sterilizedin German concentration camps during World War I I
who are now manifesting colon cancer in areas
surrounded by radiogenic tissue damage [R15]. The
lack of excess colon cancer in cervical cancer patients(at a statistically significant level) could be the resultof cell sterilization [B12]; however. rectal cancer wasincreased in the same IARC series only among
irradiated women. implicating the therapy [BIZ].
Since non-irradiated cervical cancer patients exhibiteda risk pattern similar to that of those who were
irradiated. other interacting factors must be suspected.
276. There was no excess of cancer of the stomach.
pancreas or kidney, all of which organs had received
intermediate doses in the IRSCCP patients. The
results for pancreas and kidney are not surprising,
because in other major series these sites were nothighly susceptible. However, the stomach received
substantial doses and would have been expected toshow elevated risk.
277. For organs receiving low levels of exposure, no
excess risk was seen other than to the lung and oralcavity. Younger as well as older irradiated women
showed a reduced risk to the breast, for which theauthors offer the explanation that radiation-ablationof the ovary has a protective hormonal effect: however, the effect was also seen in women irradiatedpost-menopausally [B12].
278. The deficit in uterine sarcomas- is interesting.
because an excess of such tumours occurs in women
irradiated for benign gynaecologic disorders (seebelow): the deficit in the cervical cancer group may be
due to a higher proportion of the women having
undergone hysterectomy as part of their cervicalcancer treatment, leaving fewer women at risk ofuterine cancer [B12]. Excess risk to the uterus has
appeared in a study in China, where 8,704 women
treated for cervical cancer received 5.5-12 Gy to theuterus; in this group, 12 uterine cancers occurred fiveto 19 years after exposure [Y4].
279. Smoking-related sites (lung, oropharynx. bladder,oesophagus) have shown elevated risk in the IRSCCP
series. Some excess was also seen in patients not
irradiated. There nlay be an interaction between
smoking and other factors to produce cervical cancer(see section V.A).
280. The IRSCCP study population has been used
for a case-control study [B38] to provide more precise
relative risk data than is possible with the moreheterogeneous total cohort. The case-control study
included 4.200 patients with second cancers for which
histological confirmation was possible and 10,200
matched controls (patients without second cancers).
These relative risk values and estimated excess cases
per lo4 PYGy are shown in Table 26 [B38]. Details of
the dose-response patterns are provided in the original
study [B38] but are too extensive to be given here; theresults are broadly consistent with the fullcohort
study [B12, D9].
281. In the case-control study of the same series[B38] it was found that the dose-response patternincreased with dose, even for high doses, for mostpelvic organs other than the colon. Indeed. rectal,
bladder, uterine, vaginal and ovarian cancers all
showed dose-response increases up through doses inexcess of 100 Gy. These tissues should also haveexperienced a cell-killing effect, as indicated for thecolon, and the fact that they did not casts some doubt
o n the explanation of the lack of colorectal cancer
excess in this series.
282. Figure IV presents comparisons of the relative
risks based on both the whole cohort and the casecontrol analyses of the cervical cancer series. There
are some substantial, difficult to explain differences.
highlighting the importance of using appropriate
control o r referent data.
283. A prospective study in Japan of 1,572 women
treated with radiotherapy for cervical cancer (1,478
cases) and ovarian cancer (94 cases) revealed eightcases of leukaemia (five non-lymphocytic, one acutemonocytic, and two chronic myeloid leukaemias)
where 0.45 would have been expected, based on therates for the general population [M26]. The period of
follow-up ranged from six to 20 years. The relativerisk was 11.2. The average mean marrow dose was
1.2 Gy, and the absolute risk coefficient was 0.45
excess cases per lo4 PYGy to the bone marrow. Fourof these individuals were in a high-dose-rate grouptreated with both a linear accelerator and remote
afterloading using radium, and a fifth had beentreated with the linear accelerator alone.
284. In a subsequently published series from Japanof 19,384 women with uterine carcinoma of whom
12,729 had been given either radiation alone (4,310) orradiation combined with surgery (8,419), statisticallysignificant increases in leukaemia and cancer of therectum were observed [A14]. The relative risks were
3.9 and 2.9, respectively.
(c)Treatnzent for ovarian cancer

285. Two groups of patients from the United States
initially affected with ovarian cancer have beenstudied by Reimer et al. [RI I]. In all. 45.903 personyears of risk were observed, with a mean initial age of
56 years. Patients had been given varying treatments.
There was a n overall relative risk of cancer of 1.4; therelative risk was 1.5 in the irradiated patients and 1.1
in non-irradiated patients. Sites included the endometrium, colon. bladder, breast and haematopoietic
system. In the first two years of follow-up, the risk
was greatest for endometrial cancer. Since the rates ofhysterectomy were not known for the computation of
expected and observed rates, this finding may be
spurious. However, the uterine corpus of post-menopausal women is known to be susceptible to rapid
carcinogenesis after the administration of exogenous
hormones (e.g. [S29]). Reimer et al. found a nonsignificant excess of breast cancer, raising the possibility
that other hormonal or therapeutic factors interactingwith treatment may be involved. Their data aresummarized in Table 27. Values given in the table are
relative risks. The study reported relative risks after
less than two years, 2-4 years, 5-9 years and more thannine years of follow-up, but there were no tlme
patterns. The relative risk values were roughly constantfrom two to 9+ years, which is too soon after
exposure to draw meaningful conclusions about projection effects. Dose information was not available.
286. In one of the groups, the non-irradiated patients
had a relative risk of 0.3 of developing leukaemia, butirradiated patients had a corresponding risk of only
1.3 (not significant); however. in the other group, who
had been given chemotherapy only, the relative risk
was a significant 9.3 (95% CI: 5.2-15.3). In 1,399
ovarian cancer patients, Greene [G3] evaluated therisk of subsequent acute non-lymphocytic leukaemia
as a function of treatment. In women treated byradiation alone. no acute non-lymphocytic leukaemia
occurred; in those treated with both radiation andchemotherapy, the relative risk was not different fromthat in women treated with chemotherapy alone(combined therapy: RR = 120.95% CI: 44-261: chemotherapy: RR = 100. 95% '01: 37-218) [G3].
287. Greene also reported an excess of colon, but
not rectal, cancer after at least five years of follow-up,
whereas, as noted above. in the cervical cancer group,
rectal cancer was significantly elevated but coloncancer was not.
288. Lymphoma and bladder cancer were increased
only in the- irradiated group. No excess of leukaemia
occurred in one of the series: however, in the other.
there was a total excess of leukaemias (acute nonlymphocytic leukaemias), with RR = 171.4. Most ofthese cases had received radiotherapy. but all had also
received chemotherapy. This study [G3] was the firstreport to raise the possibility of a causal role forradiation in bladder cancer and in lymphomas in
ovarian cancer patients.
289. Another large study (9,726 cases) from theUnited States [C8] found the following relative risksof leukaemia: 10 for radiotherapy with no known
chemotherapy and 9.5 for chemotherapy, both significant at the 1% level. When only acute non-lymphocytic
leukaemia was considered, these relative risks were evenhigher (2 1.1 and 22.2, respectively). These results are
not consistent with the minimal radiation effects in theabsence of chemotherapy in other studies describedearlier, and there is at present no clear explanation
for the difference. However. chemotherapy is used
increasingly t o treat ovarian cancer and radiotherapy
decreasingly; therefore, the estimation of the cancer
risk from radiotherapy may be more relevant toradiobiology than to practical problems in humanhealth. The Japanese investigation of cervical cancer,
cited earlier, reported an excess of leukaemia in a
population of 1,572. of whom 94 had ovarian cancer[h126]; whether this suggests a special risk only, o r
mainly, in the small subset cannot be determined
adequately.
(d)Trearmenr for breast cancer

290. In a series of second breast cancers in women
irradiated for a primary cancer of the breast, Hankey
et al. [HI31 found no significant evidence of aradiogenic risk to the second breast (from scatter) but
did find a relative risk of 3.2 for all second primarybreast cancers, when compared to the overall population. For breast cancer patients treated only withsurgery, the relative risk was 1.2-1.4, perhaps reflecting
a generally elevated susceptibility of patients with a
primary breast cancer. This study involved a five-year
follow-up of 27,175 patients in the state of Connecticut.
United States. In a comprehensive study of theConnecticut Tumor Registry for the period 1935-1982.
Harvey and Brinton [H20] found the relative risk of asecond tumour to be 2.0 (95% CI: 1.9-2.1), comparedto 1.5 (9% CI: 1.5-1.6) for women treated without
radiation; 20 years after irradiation the two risks
became equal (at RR = 1.7, based on the Connecticut
population). The relative risk for a second breast
cancer was 3.9 for irradiated and 2.8 for nonirradiated patients. Relative risk values for othersecond tumours are given in Table 28; the treatment
data refer only to initial treatment, and there may besome false negatives. Note that an excess of chronic
lymphocytic leukaemia was reported; this is notthought to be a radiogenic tumour and suggests thatthese results may confound other sources of variability.
291. Among 14,000 British women treated between
1946 and 1982, 194 developed a second tumour in thecontralateral breast more than one year after the
initial diagnosis [B28]. There was no evidence forradiation induction in the second breast, based on acomparison with a matched control group.
292. In another study of initial treatment for breast
cancer [C8], the relative risk of leukaemia associatedwith surgical treatment alone was 1.0, for radiationonly 1.7, and for chemotherapy alone a significant 3.8(Table 29). The risk for radiation alone, when all typesof leukaemia were considered. was not significant, but
the relative risk for acute non-lymphocytic leukaemia
alone was 3.7 (95% CI: 1.6-7.2); compared with thesignificant RR of 6.7 (95% CI: 4.5-32.3) for acute nonlymphocytic leukaemia following surgery or chemotherapy. The latency period suggested a causal effectof the treatment to the authors, because the excess risk
did not occur until at least three years after irradiation(but, the same was true of the chemotherapy-onlygroup). Patients with local disease had no excess
leukaemias. but patients with regional stage disease
exhibited relative risks of 2.7 for all leukaemias and 5.5
for acute non-lymphocytic leukaemia. The regionallocal distinction was found for chemotherapy as well asradiotherapy. As this finding had not been reported inany previous systematic examination of breast cancer
patients, the authors suggest that unreported chemotherapy could have occurred, though there may besome radiogenic effect [C8]. No dose-response data
were available for these patients.
293. A study of 1.359 Japanese breast cancer patients
showed a 1.29-fold higher risk of second cancer inpatients without a family history of cancer. but with afamily history of breast cancer the relative risk was 3:
a radiation-associated relative risk of 1.62 was observed,
but no increase was associated with chemotherapy
P31.

294. A small number of the survivors of the atomic
bombing of Hiroshima and Nagasaki have developed
more than one primary cancer [M 16, R6]. Specifically,
three women have been identified, all of whom
initially had breast cancer and subsequently developed
a second malignancy. All had undergone radiotherapy.
Two developed acute granulocytic leukaemia, one
four years after radiotherapy and the other eight years
after; their estimated atomic bomb doses (T65DR)
were 5.94 and 3.64 Gy, respectively. The third woman(atomic bomb dose 0.31 Gy) developed cancer of thelung beneath the treated breast some eleven years afterradiotherapy. While it is probable that the carcinomaof the lung was radiotherapeutic in origin, it is mootwhether the two cases of leukaemia were attributable
to the therapy or to the atomic bomb exposure.
However, the time that intervened between first andsecond malignancy was in both cases consistent with aradiotherapeutic origin, and the treatment doses had
been high.
295. A study undertaken in the United States of
8.483 women has found a significant excess of acute
myelogenous leukaemia after irradiation for breast
cancer, but not in those not irradiated [FI 11. Many ofthese cases had also received adjuvant chemotherapy.
The post-irradiation risk was 1.29 0.5% after 10 years.

+

2.

Adults exposed to radiation for immune suppression

296. Total-body immune suppression has been induced
in numerous patients to treat leukaemia or Hodgkin's
disease. to prepare the patient for a bone-marrowtransplant following the eradication of leukaemia or
to prevent host-versus-graft disease in recipients ofkidney transplants. The treatment effects have been
discussed above. The use of a bone-marrow transplant
to replace leukaemic immune system cells has beensuccessful in up to 60% of cases with acute myeloid
leukaemia, and, to date, only two second malignancies
have been noted [B14, L8, T83; doses range between
about 7 and 12 Gy. It is too soon to summarize therisks associated with this treatment. for there are as
yet few surviving patients. However, one report has
shown a 2% risk of second malignancies. over 2-5 years,
in individuals treated with total body irradiation [T8].
Complicating these results is the fact that somechemotherapy before or accompanying the irradiation
has probably been given to these patients.
297. Some credence is lent to these estimates of risk
by Greene et al., who have scrutinized individuals
treated for non-Hodgkin's lymphoma (NHL) [G3,G9]. Among 517 patients, in whom marrow dose
could be estimated, there were nine acute nonlymphocytic leukaemia cases observed where essentiallynone (0.08) had been expected, a relative risk of 105(95% Cl = 48-199). This was after 2,203 person-yearsof observation. a mean age at diagnosis of 43.4 years
and an average of 4.3 years of follow-up. For total
nodal irradiation, the relative risk for acute nonlymphocytic leukaemia was 28.0, and for total-body
irradiation, 7.0, both significant. Greene et al. foundsuggestions of a correlation between cumulative radiation dose to the marrow and relative risk of subsequentacute non-lymphocytic leukaemia, independent ofchemotherapy effects, but the numbers were small andno dose-response pattern could be derived from thedata.
298. In this study, the relative risk after combined
chemotherapy and radiotherapy was 6.0, also significant (p < 0.05). Controlling for chemotherapy, there
was still a n increasing acute non-ly mphocytic leukaemia
risk with increasing cumulative bone marrow radiation
dose. which was significant (p < 0.005). The relativerisk was 8.1 for doses greater than 7 Gy, compared todoses less than 7 Gy. When acute non-lymphocytic
leukaemia patients were compared to a fourfold larger
set of non-Hodgkin's lymphoma patients without
subsequent acute non-lymphocytic leukaemia, a risk
coefficient of 0.03 additional cases of acute nonlymphocytic leukaemia per lo4 PYGy was estimated.
299. It may be that the lower doses generally givent o treat non-Hodgkin's lymphoma patients had produced acute non-lymphocytic leukaemia, whereas thehigher doses given to treat Hodgkin's patients has hada cell-killing effect and produced no acute nonlymphocytic leu kaemia.
300. These patients received total-nodal, hemi-bodyo r total-body irradiation or some combination thereof,
exposing large volumes of marrow to a relatively low
a n d fractionated dose, with single doses of about
0.1 Gy given over a period of months and totalling a
few Gy. Hodgkin's patients, by contrast, typicallyreceive 2 Gy per day, administered over a period ofweeks and leading to a cumulative dose of tens of Gy[G3] with substantial cell sterilization, which may
explain the absence of radiogenic acute non-lymphocytic
leukaemia in them.
301. Danish patients treated for Hodgkin's disease
and non-Hodgkin's lymphoma had the following
combined relative risks of developing acute nonIymphocytic leukaemia: 8.4 within 10 years of initial
treatment and 8.9 thereafter [S39]. Other patients inthis registry developed an excess of lung cancer(RR = 1.8). female breast cancer (RR = 2.1). andbladder cancer (RR = 2.6); the Connecticut Tumor
Registry did not find an excess of bladder cancer, but
did confirm breast and lung cancer, along withthyroid and buccal cavity cancer [C14].
302. Patients immune-suppressed for renal transplant
seem, like Hodgkin's patients, to be susceptible toinfection by human papilloma virus and hence to arisk of cervical and related tumours [Kg, S21]. inthese studies, the effects of irradiation and of chemotherapeutic immune suppression cannot be separated:in any case. the effects are not dose-dependent,
because the result is not a directly radiogenic cancer
but a susceptibility to cancer clearly produced byunrelated agents.
3.

Leukaernogenesis in cancer radiotherapy generally

303. Curtis et al. have reported the results of asurvey of 440.000 patients in the United States treated
for all types of cancer [C8]. They assessed the risk ofleukaemia. specific to type of treatment administered
for the primary cancers. A significant excess ofleukaemias in general and of acute non-lymphocytic
leukaemia specifically, for those patients given chemotherapy (Table 29). is described. Relative risks associatedwith exposure to ionizing radiation in the absence ofchemotherapy were inconclusive: small. non-significant
excesses were observed for cancers of the mouth.
stomach. rectum, larynx. lung, connective tissues.
breast, endometrium, ovary, prostate, testis, bladder.
kidney and renal pelvis, and for multiple myeloma.
The excess risk of bladder cancer associated withradiation for primary ovarian cancer agrees with theresults found in the study of ovarian cancer patients
discussed above [RI I]. The overall relative risk ofacute non-lymphocytic leukaemia among patients
receiving neither radio- nor chemotherapy was 1.2(not significantly different from 1.0); the corresponding risk was 2.5 with radiation and 4.5 with chemotherapy, both significant at the 1% 're~~el.
All of theelevated risk was due to acute non-lymphocytic
leukaemia. These patients may develop increasing
relative risks with time, and solid tumours may also
arise. Studies in the Connecticut Tumor Registry[C14] showed an increase in leukaemia after radiotherapy for cancers of the uterus o r ovary, butchemotherapy as a joint cause was not examined indetail.
304. Although only three (3.95) of the tests shownin Table 29 were significant at the 5% level. the overall
result (not shown) was significant at p < 0.01 in both
radio- and chemotherapy groups. Hence, the resultsd o not appear simply to be statistical artefacts ofmultiple testing.
305. A case-control study of radiation-induced leukaemias in cancer patients has recently been reported. basedon United States tumour registries from the states ofCalifornia. Connecticut, Kansas, and Massachusetts[B26]. Cases consisted of individuals with two cancers,
the second being leukaemia occurring more than one
year after the diagnosis of the first tumour, andcontrols consisted of those with no second tumour.
Controls were matched on sex, age at first diagnosis,
site of first cancer, and survival after first tumour
diagnosis; matching was 2 to 1. Chronic lymphocytic
leukaemia was considered separately from all otherIeukaemias. which were pooled. This study involved
166 chronic lymphocytic leukaernia second tumours.
232 second leukaemias. and 781 controls.
306. As chronic lymphocytic leukaemia has not yet
been shown to be a radiogenic tumour, it served as adata quality control. The relative risk of chronic
lymphocytic leukaenlia after radiotherapy was 0.7.
that is, there was no significant difference from unity.
For all other leukaemias collectively. the relative risk
was 1.6 for all irradiated sites and 2.4 for only trunksites. Both values are statistically significant. Among
specific-site cancers, those of leukaemia after breast
and uterine corpus were elevated, and in this and allother regards the results are similar to those of otherstudies of radiation of active bone marrow in adults.
Results after cervical cancer were positive, with
RR = 2.3. but not significant. No dose data wereavailable, and no information about the nature of theradiation treatments was given.
307. Study of the Danish tumour registry has foundrelative risks greater than 1 for acute non-lymphocytic
leukaemia following initial irradiation to treat for headand neck cancers (RR = I . 1 ), genital cancers (RR = 1.9).
female breast cancer (RR = 2.7) and lymphoma(RR = 8.4) [S39]: with the exception of lymphomas
and breast cancers, for which the relative risk was 2.3.
the risk for acute non-lymphocytic leukaemia 10 years
after irradiation was not significantly different from
1.0.
308. The question of whether an interaction exists
between radiation and chemotherapy in leukaemogenesis is of importance [see also G3, G9]. The
incidence of excess acute non-lymphocytic leukaemia
in Hodgkin's and non-Hodgkin's lymphomas is similar,
implicating combined therapy or just chemotherapy
with alkylating agents. Data from ovarian cancer
patients, though inconsistent, suggest that chemotherapy is responsible. but those from non-Hodgkin's
patients suggest an interaction. In the non-Hodgkin's
patients, whole-body or broad tissue exposure iscommon, but the relative risks of acute non-lymphocytic leukaemia following total-body or nodal irradiation are both elevated (7.0 and 28.0, respectively). The
results of the general study [CU] were inconclusive
regarding radiation but agreed with other studies inshowing a marked chemotherapeutic effect. Good
dose-response data are not available from thesegeneral cancer-treatment surveys.
4.

Adults exposed to radiation for treatmentof benign conditions(a) Haenlaropoietic risslre309. The haemaropoietic system, or some portion ofit, is in the field of most radiation exposures. Thissystem is actively mitotic throughout life and, with its
own process of differentiation and cell division. ishistologically distinct among tissues. I t also behaves
epidemiologically in a different manner from othertissues in regard to radiogenic cancer, in which respect
it is similar only to bone cancer after brief exposures[C4]. Despite the sometimes negative findings of theabove-mentioned studies on the effects of radiotherapy to treat cancer, where doses are often high,the haematopoietic system is highly vulnerable toradiation carcinogenesis. There are relevant haematopoietic data from most cohorts exposed to radiation;
the results are remarkably homogeneous and permit a
fairly unambiguous characterization of the risks.
3 0 Leukaemia. The bulk of our information comesfrom Japan and the British studies of ankyiosing
spondylitis patients. who received only short-term
exposures. Before reviewing these data. the results ofother exposures, in particular, those which occurred
over long time periods. will be summarized. These
results come from Thorotrast patients. from other
patients given radium-224, from women exposed toradiation to treat gynaecological disorders, fromradiation workers and from radium dial painters.

3 11. Thorotrast (thorium dioxide) is an alpha-emitterthat was used from about 1930 through the early
1950s for a variety of diagnostic roentgenographic
purposes. Two series of European patients have been
followed in detail and have shown an excess of
haematopoietic tumours [K 16. M251. In one, involving
3,772 Portuguese, Danish, and German patients [M25].
the total cumulative whole-body dose was determined,
30 years after treatment, to have averaged 2.7 Gy
following the use of 25 ml of Thorotrast, on average.
The first appearance of leukaemias was eight years
after treatment, with cases continuing at least to 1978.
If, in fact. acute granulocytic leukaernia ( A G L ) can be
induced at all by high-LET radiation. the small
number of acute granulocytic leukaemia cases seen inthis group of patients may be an indication of cellsterilization having occurred. Conjectures about thedose-response relationship in this and similar instances
must be guarded. however, because of the wasted dose
and the concentration of the isotopes in bone marrow.
The long period of excess risk expression is notinconsistent with the results from single-exposurestudies of radiogenic leukaemias, because the emissions in bone-resident nuclides persist indefinitely.
312. In another series of over 5.000 German patients[K 161, exposures ranged from 0.5 to 4 Gy after similar
Thorotrast dose levels. While the commonest resulting
cancers were those in the liver (see paragraph 403).
there were 27 leukaemias instead of the two thatwould be expected. The shortest time to appearance ofleukaemia was five years, Most of these tumours werereticulosarcomas.
3 13. The effects of "'ll, a beta emitter. used to treat
hyperthyroidism, d o not appear to include leukaemia[H 12, H 141.
314. Radiologists who entered their profession
between 1920 and 1939, had an increase in leukaemia,
but those entering thereafter have shown no effects[C4, M181. The doses received are difficult to estimate,but probably range from 6 Gy for those entering in
the 1920s to 2.4 Gy for those entering in the 1930s.
The extended time of exposure did not reduce the risk
below that observed after single high-dose. highdoserate exposures [M 181.
315. Some cases of leukaemia have been found inradium dial painters [C4, P191, but it is not obvious
whether there has been a significant excess. Also not
yet established is the possibility that these individuals
have experienced an excess of myelomas. The data arereviewed in [RIO]. One difference between the excess
leukaemias associated with "'Th and the apparent
absence of leukaemia after exposure to 226Ra and224Ramay be the length of time that the individual is
exposed. The reasons for this difference require
further study.
316. Table 25 shows that excess leukaemias wereobserved in several groups of women treated forbenign gynaecologic disorders [W6]. In the benign
disease patients, the risk of leukaemia declined as
doses to the pelvic marrow increased. In a series from
Massachusetts, United States. [B 121, the latency period
was similar to that in the Japanese survivors and thespondylitics; however. the numbers were quite small.

317. Detailed studies of the projection effects inJapan will be presented in chapter VI of this Annex;
however, the T65 data on the Japanese atomic bomb
survivors [Life Span Study (LSS)] and the British
ankylosing spondylitis patients have been compared aswell as analysed jointly [Dl 11. based on the data
described in [K7,S3 I]. The relative risks for leukaemia
are given in Table 30. In both studies, the firstmanifestation of excess risk occurred within five years
after exposure; the relative risk rose thereafter, andpersists for at least 40 years [S49].
318. If one eliminates those survivors under 15 yearsof age at the time of the bombings and focuses on therisk within the first 20 years after exposure. therelative risk in the spondylitics (3.37) is much less thanthat in the Life Span Study group (13.50). Darby et al.
[Dl 1, DZO] showed that in this restricted subset there
was no trend in relative risk with age at exposure, ineither group. There was no evidence in either study for
an increase in chronic lymphatic leukaemia. There wasno significant difference in relative risk between males
and females in either study.
319. Age-specific relative risk models were fitted by
Darby et al. [Dl 1, D201. For both groups of exposed
individuals, the best model had the relative risk
declining with time since exposure. In Japan. an ageat-exposure effect occurred, but it was due solely tothe presence of individuals under 15 years old at thetime of the bombing. The rate at which relative risks
for acute leukaemias declined with time since exposure
was a function of age at exposure. but the limited dataon chronic leukaemias do not support such a difference.
Figure 111 shows that there is a sensitive period for
exposure under age 10, after which relative risk isroughly constant.
320. In Muirhead and Darby's analysis of model
fitting to cancer data [M36, M371, in which theankylosing spondylitis and Hiroshima data werestudied separately. the constant relative (but not theconstant additive) risk model was found consistent
with the ankylosing spondylitis data; however, theconstant additive (but not the constant relative) risk
model provided a satisfactory fit for the Japanesedata. Intermediate models provided somewhat betterfits to both series, although not statistically significant,but the best-fitting parameter values for those models
were markedly different for the two sets of data.
321. There are dose-response data of a general kind
for women irradiated for benign or malignant gynaecologic conditions [W6]. Table 31 provides relative risksof leukaemia as a function of total pelvic marrow doseand mean marrow dose from several studies. In supportof the cell-killing argument, raised earlier to explain
the level of leukaemias in cervical cancer patients, i t
appears from these data that higher local doses areassociated with lower relative risks of leukaernia.
322. Figures I1 and V provide a graphic summary of
the relationship between single doses (or short-term
exposures) and leukaemogenesis; Figure V has beenused frequently to summarize the leukaemia findings
in Japan. It is based only on the Japanese data [I71and on earlier dose estimates. The pattern has
persisted in recent reports from Japan [03, P6], but athorough analysis of the revised dose estimates (DSS6)
is not yet available. For all acute leukaemias pooled.
there is a distribution of excess cases which is afunction of age at time of exposure. The younger theage at exposure, the shorter the latency. These
patterns have been fitted empirically to a log-normal
distribution.

I ALL FOfU4S OF LEUKAE11IAI

ACUTE LEUKAEMIA( CHRONIC GRANULOCYTlC LEUKAEHlA

0

5

10

15

20

AGE ATE?5YEARS AFTER EXPOSURE
Figure V. Schematic reprerentatlon of the relationship between
age at the time of the bombings and time of occurrence ofleukaemla In Japanese atomic bomb rurvlvors receiving morethan 1 Gy.

tm
323. Figure V shows that for chronic granulocytic
leukaemia. there is less variation, with age at exposure.
in the projection pattern following radiation exposure[14, 15, 161. Excess risk virtually disappears after about
20 years [03, P63. As with acute leukaemias, a lognormal distribution adequately fits the chronic granulocytic leukaemia data. Chronic and acute leukaernias
may have a similar pathobiology, but they differ in theabsolute effects produced by a given exposure level. sothat the two types of tumour should not be consideredjointly. The most recent data from Japan suggest that
there may be some residual excess risk, even 40 years
after exposure [S49].
324. Figure VI provides a different view of the T65
Japanese data, comparing them with the relative risk
for leukaemia in the spondylitics from Darby et al.
[D I I]. Two variables were modelled. age at exposureand time since exposure. Interaction between these ismodelled by standardizing each in terms of the other.
The figure shows no apparent trends in susceptibility

40

ANKYLOSING S P O N D Y L I T I S S E R I E S

L I F E SPAN STUDY Sk!PLE-A l l types of leukaemia(above 1 Gy / 0 - 0 . 0 9 Gy)
A l l types o f leukaemia
Acute leukaemia

-

-

40

-g 2 0 a 10-> 5 +

5 20
7

cz
w

u

>

c'
4

4
W
2

-.--..-*-..'....,

@
.

105-

2
W

a

P:

I

I

cZE

I

25-

1

30-

1

45-

I

55,

1

I

<15

1:-

1

25-

I

35-

I

45-

I

55+

AGE AT EXPOSURE

AGE AT EXPOSUREYEARS 5 1:;CE EXPOSUREYEARS S I N C E EXPOSURE

AGE I T OBSERVATIOti

AGE AT OBSERVATION

Flgure VI. Relative rlsk of leukaemia in relation to age at exposure, tlme slnce exposure, and age at observation for the ankylosing
spondyiltls serles and for the Llle Span Study sample (T65DR doses). Lines marked wlth clrcles are lor unadjusted data. Lines
marked wlth squares are adjusted by Including a llnear trend In log (relative rlsk) with tlme slnce exposure In the model. For theplotted polnls, tlme slnce exposure has been chosen so that the lnltlal point coincides with the unadjusted value.
[Dl11(RR) with age at exposure, other than the excess
susceptibility in those under age 15 (children) in
J a p a n , discussed above. Darby et al. found evidenceof a linear trend in log RR with time since exposure.
so the data were analysed both including and notincluding this trend (see figure). In neither series wasthere evidence that the rate at which the excess risk
declined with time since exposure was a function ofage at exposure.
325. Relative risk is higher in the Life Span Series,
even after eliminating childhood exposures; this could
be due to cell-killing in the spondylitics o r to theeffective amount of marrow exposed. The difference
between acute and other leukaemias can be seen in
Figure VI; when adjusted for a trend in time since
exposure, the pattern of relative risk for acuteleukaemias differs substantially from the unadjusted
pattern. The most recent spondylitis data [D21] showthat leukaemia excess R R does not disappear completelyby 25 years after exposure.

326. I t should be kept in mind that the point ofreference for the discussion in this section is the
exposure of non-cancer patients in view of thepossibility that cancer patients are more cancer-prone
than the population at large. Indeed. the regularpattern of effects seen in non-cancer patients is lessperceptible in patients treated for cancer. In particular.
individuals irradiated for leukaemias and lymphomas
have not consistently manifested leukaemia as asecond radiogenic cancer [G3].
327. Mulriple myelonta. Multiple myeloma remains
one of the most enigmatic candidates for the list ofradiation-induced malignancies. The Japanese atomic
bomb survivors have been studied in regard to
multiple myeloma by Ichimaru and colleagues [HS.
121. Data were based o n 29 cases occurring in the
period 1950- 1976. The age-standardized relative riskincreased with absorbed dose in the bone marrow,with no differences between cities or sexes. Based on
the T65 doses, the excess risk estimate is 0.48 cases per10' PYGy. As in other series, latency is 15-25 years.
with a long-lasting period of excess risk (at least
30 years). A longer latency after younger ages at exposure follows a carcinoma-like pattern. The spontaneous incidence of multiple myeloma increases with
about the 5-6th power of age, which is similar to the
behaviour seen for carcinomas.
328. Darby et al. [ D l l , D20] found evidence ofelevated myeloma risk in their combined analysis. An
increase in risk has also occurred among radiologists
who entered their profession since 1930 [M18], andthe Hanford radiation workers, as well as otherexposed cohorts, appear to have experienced a small
excess of multiple myelomas [C 10. G 12. H 161.
329. Many chronically exposed occupational groups
were reviewed by Cuzick [CIO]: nuclear workers.
radium dial painters, uranium millers and miners andradiologists. The overall relative risk is between 1.4
and 2.9. Multiple myeloma was also more common inradiation workers in the United Kingdom. based on a
recent study of the Sellafield nuclear workers [S54].
though not in another of the employees of the United
Kingdom Atomic Energy Authority [B22].
330. Cuzick [ClO] reviewed the effects of diagnostic
and therapeutic exposures on the induction of multiple
myeloma. The exposed groups included Thorotrast
patients. spondylitics. and groups exposed during
fluoroscopy or for treatment of gynaecologic disorders. Results were similar: although many studies
yielded confidence limits that included a value of 1.0,
there was. overall, a small increase in the relative risk.
about 1.6 (range 1.1-3.3).
331. Cuzick also assessed the relative risk according
to type of radiation to determine if the effects ofinternal alpha-emitters (radium dial painters, Thorotrast patients and nuclear workers) had been different
from those of gamma-emitters or x rays (atomic bomb
survivors, radiologists, nuclear workers. spondylitics,
fluoroscopy patients and gynaecologic therapy
patients). His summary is given in Table 32. Uterine
cancer patients are an exception to the pattern ofexcess risk, and for them the risk is higher with highLET internal emitters than with low-LET sources.
332. The IRSCCP cervical cancer study [B12] foundonly marginal support for an excess of multiple
myeloma; however, the general deficit of leukaemiasin this group, attributed to cell sterilization. may be
imporrant. Both leukaemias and myeloma are B-cell
diseases, as are some cases of chronic lymphocytic
leukaemia. which has never appeared to be radiationrelated.
(b) hbn-dividing tissue333. Many tissues in adults are con~posedof cells
that do not normally or frequently divide. These
include muscle and the neuronal tissue of the brain
and central nervous system (CNS). As reviewed
earlier, tumours of the central nervous system are
known to occur following exposures of the head andneck in children; rhabdomyosarcoma may also occur,rarely. as the second tumour in retinobiastoma orother childhood cancer patients. However, some ofthese tissues are still growing in early childhood. andit would be worthwhile to determine whether normallynon-dividing tissue is radiosusceptible.
334. In general. spontaneous adult-onset tumours in
non-dividing tissu; appear to be very infrequent. The
most recent comprehensive reviews of radiation carcinogenesis. including the UNSCEAR 1977 Report, have
either ignored radiogenic cancer at these sites orjudged it to be rare or even absent [B6. C4]. Heavily
irradiated parts of the central nervous system, excluding
the brain, in ankylosing spondylitis patients havemanifested excess cancer, although this finding isbased on only four cases (0.5 expected) in 14.000
patients. two of which may already have been present
at the time of irradiation [S28. S3 I]. The spinal cord isheavily irradiated in such patients. The paper by
Smith et al. [S31] appears to be the first substantial
report suggesting that these tissues are radiosusceptible. In the atomic bomb survivors. there is asimilarly elevated relative risk of cancer associatedwith heavy irradiation of the spinal cord and nerves[S23]. suggesting that the data in the spondylitics may
be reliable. he cell type of these cancers was not
given [S23. S28, S3 I].
335. Other individuals who may have received heavy
doses to'the central nervous system include the radium
dial painters, who did not. however, experience anincrease in brain tumours [RIO]. Swedish patientstreated with '"I for hyperthyroidism exhibited only aslight, non-significant excess (cell type not specified)[H 141. Radiation workers. including radiologists. haveshown similar results [e.g., M18].
336. A case-control study in Los Angeles. California.
United States, of women irradiated for medical anddental diagnostic purposes found a relative risk of 4.0
for all forms of meningiomas after exposure under theage of 20 and of 2.1 for patients irradiated before
1945. both of which values are statistically significant.
The majority of tumours arose after age 50. The
authors think that there is an early age susceptibility,
although these women, albeit aged less than 20, were
not all irradiated as children [P 181.
337. In sum, many individuals have received irradiation to considerable areas of muscle. nervous. andother connective tissue. The fact that tumours have
only rarely arisen in these areas is in general agreement with the requirement that a tissue be mitotic to
be radiosusceptible. If it can eventually be shown thatradiation induces mitosis, or if these tumours are
actually in mitotic cell types (e.g., glial cells), radiation
may increase tumours in these tissues proportionately
to their natural incidence. However, these tumours are
so rare naturally in adults that it is difficult to detect asmall increase from the available data.

(c) Dividing non-epithelial tissue338. While much of the nervous and connective
tissue of the body is not normally mitotic in adults,
this is not true of all tissues. Notable exceptions are
glial cells and the cells involved in the remodelling of

bone. These divide. at least in response to stress or to
demands for repair. As has already been noted, thesetissues are radiosusceptible in childhood, and osteosarcomas and neuroblastomas of various kinds areamong the most consequential childhood tumours.
339. The data on risk for actively dividing mesenchymal tissue are strongest, and clearest for cancers of
the tissues in the periosteum, i.e.. osteosarcoma andother bone cancers. Indeed, ionizing radiation is the
only welldocumented risk factor for such cancers.
340. There are, basically, three different kinds of
exposure for which data on bone cancer exist: persons exposed to bone-seeking radionuclides, internallydeposited, often of high-LET alpha-emitters; persons
exposed to high doses of external irradiation; andadults irradiated to intermediate doses during a single
exposure in Hiroshima and Nagasaki. Internal emittershave been of two types, long and short half-life
isotopes, with differing epidemiological results.
341. Individuals receiving exposure to bone-seeking
internal emitters include watch dial painters whose
mastoid and other cranial sinus epithelial linings were
exposed to radon decay products and whose bones
were exposed to '26Ra and "8Ra and patients who
were given radioactive x-ray contrast medium (i.e.,
Thorotrast). Underground miners, who are exposed toradon gas. have not exhibited an excess of osteosarcomas. There is much literature on this subject
from animals (see Annex B of the UNSCEAR 1986
Report) [UI]. Osteoblasts are the most common cellsof origin of osteosarcomas. The internal high-LET
alpha-emitters, ?"Ra and 22%a, are among the bestdocumented radiogenic causes of bone cancer. Radium224, a short-lived isotope, emits radiation on the surfaceof the bone where the active target cells are located,
whereas '26Ra, a long-lived radioisotope, is distributed
more evenly throughout the bones, and its emissions
are more effectively shielded from these cells.
342. Radiogenic osteosarcomas tend to occur in thesame locations of the skeleton in which spontaneous
osteosarcomas occur, especially near the epiphyses of
rapidly growing long bones: risk is highest in the knee
joint and lowest in the vertebrae. Even with highspinal doses, there has been only a single vertebral
osteosarcoma in 14.000 ankylosing spondylitis patients[E3]. Bone sarcomas have been observed in individuals
first exposed to 224Raat ages ranging from 2 to 56 years[M22].
343. The effects of exposure to long-lived alphaemitting radioisotopes is largely known from theexperience of the radium dial painters and otherindividuals totalling about 3,000 in number; this work
is summarized in [R 101. An excess of osteosarcomas invarious bone and head/sinus carcinomas has been
observed; for example, Polednak and his colleagues[P19], in a study of 634 women who worked in theradium dial painting industry' from 1915 to 1929,
observed 22 deaths from bone cancer where only 0.27
had been expected on the basis of age/time/causespecific death rates for United States females. Most, if
not all, of these cases were probably due to radiation,

since the tumours are otherwise quite rare and thealpha-emitters provided continuous exposures. The
excess occurred over an extended time. from seven to
59 years. The radioisotopes z26Raand ?I6Rahave long
half-lives (1,600 and 6.7 years. respectively) and areremoved slowly from the bone. I t is not possible toquantify the latency period of these tumours in ternms
of time after exposure, since the exposure wascontinuous. In such individuals exposure is notmeasured in terms of Gy but in terms of Bq, theinferred total systemic activity; however. the rota1
exposure of the bone ranged from about 0.1 to500 Gy. In 2.135 patients injected with Thorotrast,
which contains 232Th.a long-lived alpha-emitter, there
were three bone cancers when one had been expected.
Tumours of the sinuses of the head in these individuals
may be due to the presence, for appreciable amountsof time, of radon gas (222Rn)in the sinuses [e.g.. R131.
344. The experience with persons exposed to shortlived alpha-emitters is different, because the exposure
can be dated and the dose and dose-response relationship more easily quantified. The most important
cohort is a group of 898 German patients given
injections of 224Ra to treat ankylosing spondylitis,bone tuberculosis and other diseases [M22]. These
individuals experienced an increase in osteosarcomas.
with onset from 3.5 to 25 years after the initial
injection, which is very similar to the onset observedin radiogenic leukaeniias (Figure VII). Such an early
onset period contrasts with the continuing occurrenceof bone cancer after 226Raexposure; presumably theshorter half-life makes the 224Raexposure more like abrief exposure. All ages were affected.
345. The mean dose to these patients was 11.0 Gy inchildren. administered over 11 months, and 2.05 Gy in
adults, over six months. The distribution of induction
times was the same in adults as in children. As noted
earlier, this is not consistent with causation being afunction of the number, or proportion. of actively
dividing cells, which should be greater in children.
346. Unlike in groups exposed to radioisotopes
having longer half-lives. there have been no sinus(paranasal, mastoid air cells) cancers in this group.
This may be due to the fact that the decay products of:"Ra do not include long half-life gases [M22].
347. The RElK 111 Committee attempted to summarize
the dose-response pattern, and their table of risks
is reproduced as Table 33. Original dose-response
patterns, developed by Rowland, were modified toremove exponential terms of the form exp(-cD)
because these were nunmerically close to 1.0 [C4]. Bothlinear and quadratic forms have been given because it
was judged impossible to differentiate confidently
anmong the models based on the available data. For
protracted exposure to alpha emissions from Z24Ra,
Mays and Spiess have estimated 200 bone sarcomas
per lo4 PGy of average skeletal dose. They estimated aratio of 7.5 for the effective endosteal dose to a given
level of average skeletal dose; based on this, the risk
coefficient is 27 per lo4 PGy, as shown in the table[C4, M221. As most of the risk experienced by theseries of patients given 224Rain the Federal Republic

I

....

- Bone sarcomasI

YEARS A F T f R IRRAOl AT I O N
Figure VII. Bone sarcoma incidence in radium-224 patients and leukaemlas in
the atomic bomb survivors. The distribution of appearance times is remarkably
simllar for leukaemias, following prompt radiation, and for bone sarcomas,
following relatively brief radium-224 irradiation.
[M221

of Germany seems to have passed, this estimate
should be close to the final risk for this series [M22].
Dose-response curves are difficult to conipute becauseof the different types of radiation involved in exposedcohorts, but linearity cannot be excluded [C4].
Thomas and McNeill have fitted dose-response
patterns for bone and head sinus cancers to a modelwith cell-killing:
RR = ( I+bDc)(0.5)U'd

348.

where b. c and d are constants to be evaluated in
fitting the model [TI I].
For bone cancer, these authors developed arelative risk estimate based on data from the watch
dial painters and the radium-injected patients in theFederal Republic of Germany. They estimated theabsolute excess risk to be 6.4 per 10' PY and MBq(2.36 per lod PY and pCi) from exposure to long-lived
226Raand 228Ra, where PY are counted after a fiveyear post-initial-exposure latency period and the doseis in terms of systemic intake. For short-lived 22'Ra.
the estimates are 1.8 cases per lo4 PYGy for juveniles
and 1.0 for adults, measured in terms of skeletal dose.
The authors found some evidence for non-linearity andcell-killing. These data are summarized in Figure VIII.
The highly curvilinear nature of the dose-effect relationships should be noted when deriving risk coefficientsin the low dose range.
349.

the environment. In radiation exposures, unlike many
chemical exposures, the protective normal mechanisms,
such as buffering layers of mucus, are ineffective.
Epithelial tissues are all characterized by layers of stem
cells, which normally divide throughout life to produce
the differentiated functional cells that are the basis of
the organ systems. The number of stem cells, their

RADIU!.1 D I A L PAINTERS..----.

0.04-

Linear exponential[ion-1 inear
exponential

Ln
Y
CT

,
0.03u

=-

L

a
w0.02CW+
4=0.01 x

I-

5
0
0.1

0.4

1
10
SYSTEMlC I N T A U ( M B ~ )100- TMOROTRAST PAT IEllTS,d-"----

Juveniles

0 Ad"] t su

r 0.3Y-u,0 . 2 d350. F o r head carcinomas the authors used a 10-year
minimum latency period and found that a linear
model with cell-killing fit the data best. They estimatedthe risk of additional cancer deaths to be 5.4 per
lo4 PY and MBq ( 1.98 per 105 PY and pCi). The doseresponse pattern fitted by them is given in Figure IX.
(d) Epithelial tissue
The epithelial tissues form the interactive
surface of the respiratory. digestive, genito-urinary andsecretory systems. As such, these tissues are theexposure interface between the inside of the body and
35 1.

5

r
4
2

2 0.1

-

-

3

U

10

1

100

AVERAGE SKELETAL DOSE ( G Y )Figure ~ 1 1 1 . Bone sarcomas In radlum-exposed penons In
relation to systemlc Intake or average skeletal dose.

[T111other biases. However, trend analyses with respect toboth age and time since exposure are significant at
p < 0.000 1 [C4]. Tumours arose in irradiated areas ofthe scalp in 41 of the 2,200 irradiated children, manyof whom had multiple lesions, but in only threecontrols [S27].
355. A study of Czechoslovakian uranium miners
has shown a relative risk of about 4.6 for skin cancers,
primarily basal cell cancer of the face; alpha-radiation
doses are estimated to have been about 1 Gy [S30].
However, since alpha penetration to the basal cell
layer is doubtful, this finding is not universally
accepted [R7]. A recent study of six groups ofCzechoslovakian miners, updating the earlier data.
has again confirmed an excess of basal cell carcinomaof the skin in uranium (but not in coal) miners [S5 I].
SYSTEIlIC INTAKE (MBq)
Figure IX.

Death rates from head carcinomas in radium dial
painters.
IT111

architecture. turnover rates and metabolism differ fordifferent organs, providing different size targets forradiation. In addition, epithelial tissues may be
stimulated to divide or grow by a variety of agents,
including hormones, irritation, cell damage and so on.
Despite these differences, i t would be valuable, fromthe standpoint of biological knowledge, to determine
whether any generalizations can be made about thesusceptibility of epithelial tissues.

(0

Skin

352. As a large and widespread epithelial organ, theskin is irradiated during most radiation exposures. yet
the data on radiogenic skin cancer are fragmentaryand inconclusive. That an effect exists has been known
since shortly after the discovery of x rays. However.
expected rates are difficult to determine since reportingis unreliable and skin cancers are not usually fatal.
Most reports have centred on individual cases rather
than on larger populations. The Japanese data reveal
no radiation effect. and there are no estimates of risk
available from diagnostic or therapeutic thoracic
exposures. Occasional studies report excess cases, but
the doses have usually been over 10 Gy.
353. The relative risk of skin cancer for radiologists
in the United States has been between 2.4 and 3.3 overthe past 65 years [M 181. Exposures have varied greatly
over this period. In a series of about 2,200 children
irradiated for tinea capitis. the relative risk was 7.1[C4. Si6, S271, and a relative risk of 5.4 was found inchildren who were thymus-irradiated [H 1 , C4]. Other
studies of skin cancer following various types ofradiotherapy have found similar results.
354. Table 34 provides data on the relative risk ofskin cancer among whites exposed to treat tinea
capitis, in terms of age at exposure and time since
exposure [C4]. The expected numbers of cases were
derived from national data from the United States;
given the unreliability of such data for skin cancer, theexcess could be attributable to closer follow-up or

356. A total of 6.405 patients treated for benign
diseases of the head and neck in the Netherlands wereascertained 19 to 48 years after treatment. Thirty skintumours in 21 patients were diagnosed, and a doseeffect relationship of 40 carcinomas per lo4 PYGy wasestimated [V4].
357. Dose-response patterns have not been accurately
estimable for radiogenic skin cancer. If any conclusion
is warranted, it is that the skin is susceptible toradiation, but that excess cases are not common,
especially at doses of less than 5-10 Gy. There is noapparent plateau after which risk subsides. Since skincancer is rarely fatal, is often not reported and isassociated with exposure to sunlight [S27] and otherfactors, it is difficult to generalize about the latency
period. In the tinea capitis series, the latency appeared
to be 20 years or more [S27], and the risk persisted forat least 45 years ([C3]; see also [V4]).
358. Doses in the tinea capitis series were 3-6 Gy[S27]. From the tinea capitis and the thymus-irradiatedchildren, the BEIR I11 Committee estimated risk to be
1.02 and 0.44 excess cases per 10" PYGy, respectively[C4]. However, several chest-fluoroscopy studies havereported fewer cases than these estimates predict. This
deficit may suggest a non-linear pattern, e.g., athreshold, but satisfactory or comprehensive risk
estimates for radiogenic skin cancer do not currently
exist.
359. In a study of the "soft" x-rays (Grenz, or Bucky,rays) used in Sweden to treat a variety of dermatologicalconditions in 14.237 patients from 1949 to 1975.
Lindelof [L 15, L 171 found a RR of 1.45, significant at
the 5% level, of non-melanotic skin cancer. Malignant
melanonia was not elevated (RR = 1.07).

(ii)

Breasr360. In this century, large numbers of women havereceived irradiation to the chest to treat a variety of
medical conditions. Among these arc chest fluoroscopy administered to follow the progress of artificial
pneumothorax treatment. radiotherapy for various
non-malignant breast disorders. including post-partum
mastitis, and the radiation received by the atomic
bomb survivors.

361. Although there are difficulties in estimating
doses and in other aspects of these studies. risk
appears consistently to increase with increasing dose
and to decrease with increasing age. The bulk of theinformation suggests that the dose-response pattern islinear, although one Canadian fluoroscopy series has
obtained a better fit with a quadratic model [H6].
Radiogenic breast cancers occur at the same ages atwhich breast cancers occur naturally: elevated risk
appears to persist throughout life, after an initiallatency period. Latency is rather long (> 10 years): it
may also vary, being an inverse function of age at
exposure. I n general, cases of exposure at postmenopausal ages have not been studied in numbers
sufficient to allow a reliable assessment of effects. andthere may be a decreased susceptibility with increasingage [TlJ]. However, elposed Japanese of this age
have a relative risk of 3.1 [L6, T6. T14]. The
possibility of a cohort effect, associated with theincrease in breast cancer in Japan since 1945. should
be considered. As discussed earlier. it has now beenshown that exposure at ages below 10 leads to a
substantial risk of breast cancer.
362. The details of the relative risk of breast cancerfrom incidence data collected in Hiroshima andNagasaki for the period 1950-1980 are summarized inTable 35 [T14]. .A trend of increasing susceptibility
with decreasing age, within a given dose level, can be
seen. Figure X shows the decrease in relative risk withincreasing age at exposure. for the 0-0.09 and the0.51 Gy (T65) groups [TIJ].
363. The Japanese results can be compared withthose of two other studies from the United States. a
Massachusetts tuberculosis fluoroscopy and a Rochester
series of post-partum mastitis patients [B2. C4, L6,
S47]. Howe has also reported fluoroscopy data frommost provinces in Canada [H6]. Total relative risks.
for doses from 1 to 4 Gy. are consistently between 2
and 3, with values of 4-6 for those exposed at younger
ages. At doses higher than 4 Gy, most studies have
only small samples; however, the largest of these has
found a relative risk of 14.6 at high doses [H6].
Incidence data from Japan suggest a corresponding
relative risk of about 4 [W5], indicating perhaps thatsurvival from breast cancer depresses the true relativerisk estimated from mortality data. Relative risk datafrom these four study populations are summarized inTable 36. Table 37 provides details on relative, as well
as absolute. risk differences for three of the major
investigations, subdivided according to age at observation and age at exposure; the similarities in the
different data sets can be seen.
364. A recent case-control study of breast cancer
following irradiation to treat tuberculosis in Denmark
has found no significant increase [S53]. U'hile thestudy was too small to rule out an effect. it was large
enough to confirm that other studies in the literature
are not underestimating the risk. A similar negative
result. and interpretation. has also been reported by
Davis et al. [D27] based on a study in blassachusetts.
Doses were smaller than in other series (0.66 Gy) andthe average age at exposure higher (28) than in otherstudies.
365. Acute post-partum rnastitis patients have no%
been followed for up to 45 years. with an averageiollow-up time of 29 years [S47]. Relative to controls
and female siblings of patients. rhe R R value forbreast cancer in the irradiated breast, age- andinterval-adjusted, is 3.2 (906 CI: 2.3-4.3). The riskincreased by 40% per Gy with an essentially linear
dose-response except for a diminution at doses above
7 Gy, with no fractionation effect. A multiplicative
projection model was a better fit than an additive one.
and the RR did not change with time since exposure.
366. The absolute risk in Japan has been estimatedto be between 3.0 and 4.0 ? 0.7 cases per 104 PYGy.
with a pattern that is roughly linear and no inter-city
difference [T9. T141. Risk coefficients in the various
fluoroscopy and mastiris series range from 6 to 8.5
cases per lo4 PYGy [CJ]. As previously noted, withthe exception of the Nova Scotia series, these data areconsistent with a linear dose-response pattern (seeFigure XI and Table 38). The New York mastitis datafor uni-lateral breast exposure suggest that doses of
4-14Gy have a cell-killing effect [B2, C4. L6].
tiowever, for bilateral breast exposure. even at higher
doses (in some instances tens of Gy) no downturn inthe dose-response curve was observed. The fluoroscopy
series, especially in Nova Scotia. were highly frac-

AGE ATB
Figure X. Relatlve rlsk of breast cancer In atomlc bomb survivors for the 0.5
or more Gy relallve to the 0-0.09 Gy done group (T65DR kerma doses).
[TI41

MASSACHUSETTS(670)

BREAST DOSE ( G y )BREAST DOSE (Gy)

I

,

u

NOVA SCOTlA FLUOROSCOPY(6340)#j0,I& 300a?

5 200-mEU

u '00U
W
Z

- 0A
rC

a

u

BREAST DOSE (Gy)

ibo

2b0

3b0

4b0

tIU>!BER OF FLUOROSCOP l ES

Flgure XI. Breast cancer incidence in relation to radiation dose in atomic bomb
sunivors (T65DR doses), mastltis patients,and fluoroscopicstudies in Massachusetts
and Nova Scotla.
[B21

tionated, and this may make a difference at highdoses. Mastitis may also have its own biologicalrelationship to breast cancer after irradiation [L6].

,367. Besides the slight indication of non-linearity athigh doses in [S47], the other exception to a simple
linear model is from a record-linkage study of datafrom nearly all of Canada. A pure quadratic model
appears to fit these data best. though a linearquadratic model fits almost equally well [H6].The
departure from linearity is evident in the lower
reiponse per unit dose bf women in the Canadianprovinces other than Nova Scotia, where the doses
ranged up to much higher values [H6]. In Nova
Scoria, the patients were examined in the anteriorposterior position (facing the x-ray tube) whereas in
the other provinces the patients were mainly examinedin the reverse position, resulting in doses per fraction
about 20 times smaller. The absolute risk on a linear
basis in the range 0-2 Gy, which contains the major
fraction of the cancer cases, appears to be about threetimes smaller for those provinces than for Nova Scotia
alone. Based on the evident lack of excess cancer forthe lower dose range (0 to 0.99 Gy) in the Canadianstudy as a whole [H6]. this factor would be considerably
greater at low doses. This one series contributes thebulk of the data above 4 Gy. Howe argues that
because in other instances high-dose information isrelatively sparse. and because it is in the high dose
range that non-linearity is expected to be mostapparent, a linear-quadratic model is the prudent
model to adopt in the establishment of breast-cancer
dose-response patterns [H6].

368. Two studies have examined the possibilities ofsynergism between several other risk factors in women
irradiated for post-partum mastitis [B30. S371. These
factors include family history of breast cancer, late ageof parity, oral contraceptive use. menopausal hormone
use and various ovarian-related factors. Women withbenign cystic breast disease and those irradiated at thetime of their first childbirth were at increased risk, butother women were not.
(iii) Lung

369. Most of the exposures to the breast or chestalso involve the lung, and there are several cohorts ofindividuals who received internal exposures specificallyto the lung. principally underground miners who
inhaled radioactive radon gas. Exposures to the lungfrom therapeutic radiation have been experienced bypatients with ankylosing spondylitis. These and theother groups have experienced most of the kinds of
exposures needed to understand the radiosusceptibilityof the lung. In particular, the miners were exposed tomoderate doses of high-LET radiation over long time
periods, the atomic bomb survivors were exposed to asingle dose, and the radiotherapy patients received
fractionated. moderate-to-large doses over a shorttime period.
370. There appear to be no risk differences between
males and females, after accounting for the effects ofsmoking. Most of the available information, however,comes from males; data on both sexes come primarily
from Japan and clearly suggest no difference exceptthat which is due to smoking [S49].

371. Relative risks from exposures to brief external
x- and gamma-irradiation are 1.2-2.0 [K7, S28, S31,
W5]. In the miners, who had variable levels anddurations of exposure to inhaled alpha radiation.
because relative risks are dose- and duration-dependentand because there may be interaction between the
exposures and smoking, this aspect of the data will be
discussed in section V.A. The mining data come fromuranium miners in Czechoslovakia [S19, S511, theUnited States [C20. I1 I. S20] and Canada [C4. G10,
H 15, M 191: from Swedish metal and Canadian gold
miners [A9, D 12, E l . M19, R5, R7]: and from a few
other reports [C4, R7, T I 1. T201. Thorotrast patientswere exposed to thoron (120Rn) gas, also an alphaemitter, as a n exhalant; these patients manifest an
excess of lung cancer (40 cases vs. 34 expected) after
doses ranging from 0.3 to 14 G y [K16]. The smoking
habits of these patients do not differ from those of
the general population of the Federal Republic of
Germany.
372. Radiogenic lung tumours appear preferentiallyin the epithelium of the upper bronchial tree, unlike inexperimental animals given radioactive inhalants o r
intratracheal instillation. One mechanism for theupper bronchial effect of natural exposures to radon
daughters is the adsorption of the free-ion fraction,that is, ions not bound to dust particles (see Annex Gof the UNSCEAR 1977 Report [U2]), Most datasuggest that the cell types do not significantly differ
from those in non-radiogenic lung cancer [C4, C12,
S20].
373. The ages of onset of radiogenic lung cancers are
similar in general t o those of spontaneous lung cancer:
there is little evidence for excess risk before age 35[C4]. This suggests that the latency period is afunction of age at exposure; however, not all of thedata are consistent. The minimal latency period has
usually been at least 10 years, roughly independent ofage at exposure in spondylitis patients and in Swedish[R5] and Canadian miners [C4]. In other mine studies
and in the Japanese atomic bomb survivors, latency
has been dependent on, and negatively correlated
with, age at exposure: early exposure has led to longer
latency and, perhaps as a result of increased years at
risk o r increased years at observation, higher absoluteo r lifetime excess risks. The data from the UnitedStates are not entirely clear. In one study of Colorado
miners (where dose rates may have been higher thanelsewhere), there was a shorter latency period in
exposed smokers than in non-smokers, but doses may
have been overestimated due to the way in which
exposures were sampled [C4, R5]. Moreover, thefollow-up times for individuals initially exposed atyounger ages may be insufficient. Excess risk is known
to persist for at least 50 years after exposure began.
374. The overall data suggest that the relative
biological effectiveness (RBE) of alpha-radiation to
the lung relative to gamma-radiation, is 20, although
there is much uncertainty in this estimate, largely
ascribable to the difficulty of converting data on
WLM to absorbed doses in G y [C4]. A reference
conversion is 6 mGy per WLM for mean bronchialdose and usual conditions in mines [I 1 I]. This resultsin unit risk of 1.0 per lo6 PY-WLM corresponding to
1.67 per lo4 PYGy.
375. Thomas and McXeill have fitted the doseresponse dara to additive and multiplicative models
for exposure to alpha-emitting radionuclides [TI 1.
T201. Results are provided in Table 10. The models
fitted were linear cell-killing models of the form (using
their notation)
R = (a bDc)(0.5)"/*-where a. b, c and d are the parameters estimated fromthe dose-response relationship, fitted by weighted
least-squares. and R refers to both additive andrelative risk (in the case of additive risk, a was set at
0.0. and in the case of relative risk, to 1.0). The second
exponential term models cell-killing effects. .A linear
dose-response is modelled by setting c = 1.0. For
details on the justification of this dose-responsemodel. see [TI 1, T20]. Thomas and McNeill found someevidence of a departure from linearity in the doscresponse patrerns of the mining data (Figure XII).
376. An extensive analysis of lung cancer in miners
exposed to radon daughters has been published.
reporting on results from four studies of six minergroups in Czechoslovakia [SSI]. The lung cancer rateincreased as a function of exposure. Excess risk
appeared about 5 years after the onset of exposure.
peaked at 20 years. and. though excess persisted. it was
no longer significant after 30 years (the approximate
limit of follow-up to date in these subjects). Unlike
some other studies of miners who began exposure
under age 30, there was a detectable excess risk before
age 40. However, relative risks were higher withgreater age a t onset of exposure. The data from theCzechoslovakian uranium miners appear to be essentially complete for group S (miners first exposed
between 1948 and 1957) [S51, K281; the total lifetime
risk can thus be calculated directly without the use ofa projection model, suggesting an average lifetime riskof approximately 4.5 10 * per WLM. Other findingsof importance were: (a) a documented excess oflung cancer at total exposures less than 50 WLM:(b) an approximately additive effect of smoking: and(c) possible evidence for a cell-sterilizing effect at highdoses for small cell lung carcinoma, but not for
epidermoid cancers.
377. Further data on the Ontario miners have also
become available [M40, M421. These too indicate thatthe minimum latency period for appearance of excess
lung cancers after first exposure to high concentrations of radon daughters is 5 years. not 10 years a spreviously assumed. This conclusion is substantiatedby studies of the Eldorado uranium miners in Canada[H25, H3 I]. It also appears that excess lung cancers inthese uranium miners reached a maximum about
10- 15 years after first exposure and decreased towards
zero about 20 years after last exposure [K28. M40,
S51]. The risk coefficient derived from the Ontario
miners study suggests an average lifetime risk of about
1.7
per WLM for miners exposed to 1 W L M peryear from age 20 t o 55.
378. The range of risk coefficients derived fromvarious studies of uranium miners is very broad b u t is

CZECHOSLOVAKIAN URAIIIUM MINERS

COLORADO PLATEAU URANIUt.1 MUERS

Y
ul

ci

->
Y

t

-I
u

a
u
!

CUMULATIVE EXPOSURE (ULM)

CUrlULATlVE EXPOSURE (WLI!)CUMULATIVE EXPOSURE (ULM)

CUMULATIVE EXPOSURE (WLM)k

SWEDISH METAL MINERS
20

5- ATOtlIC BOMB SURVIVORS--

Hiroshima
0 Nagasaki

**..*

Y

- 15 "l

w
Y

2 10+
u
2

s 50

I

1

I

I

1

100

200

300

400

500 600

I

1700

CUMULATIVE EXPOSURE (WLH)

Figure XII.

I

1

2

I

I

3

4

OOSE EQUIVALENT ( S v )Lung cancer risk In five groups of miners and in atomic bomb s u ~ l v o r s(T65DR doses).

IT111

in general compatible with the central value of about
10 excess cancers per 106 PY and W L M (additive risk
model) or ab.out a 1% increase in normal incidence (assuggested in ICRP 50) of lung cancer per WLM(multiplicative risk model). When applied to the adultmale population of North America, these risk coefficients suggest an average lifetime risk of about 3
per WLM for uranium miners age 20 to 55 at the timeof exposure [M40]. Recent data from those studies inwhich most attention was given to reassess exposure
data are compatible with the range of 1.5-4.5 lo-$ per
WLM for adult male miners. as was estimated in
ICRP 32.
379. As mentioned briefly in chapter I, in many
areas of the world houses have been built with or on
materials which contain 2'6Ra from which radon gas isreleased into the air of the living space. Exposure to
the alpha emissions from the radon daughters is apotential risk factor for lung cancer. as demonstrated
in miners, but the risks from exposures in homes have

only recently begun to be estimated. Extensive indoor
survey results are becoming available, but there are, asyet, few studies of the lung cancer risks associatedwith living in such environments for long periods.
380. In an initial study from Sweden, Svensson et al.
reported on a case-control study of the association
between lung cancer and radon in houses in the areaaround Stockholm [S52]. Study subjects had lived in
the area for 30 years o r more. There was a statisticallysignificant relative risk of 2.2 (95% CI: 1.2-4.0). a n d
4.1% of cases in this group appeared to be attributable
to the exposure. There was an indication of a doseresponse pattern, with increasing cumulative exposure,
as seemed similar to results from miners in the UnitedStates and in Czechoslovakia.
38 1. Other data have not shown an effect of domestic
radon daughter exposure on lung cancer. A recent study
by Gjorup and Hansen [G20] compared Denmark to
Sweden. which has 2.1 times the radon exposure levels

in homes. There was no evidence for an excess of lungcancer in Sweden. Potential differences in other risk
factors. such as smoking. were not studied in thisreport.
382. The ICRP issued in 1987 a summary of the risks
associated with exposures to radon [I1 I]. This study
covered the existing literature in detail up to about
1986, and considers many aspects of exposure of thelung to high-LET radiation. Its conclusions andlifetime risk projections are given in chapter VII.
383. The BEIR IV Committee [CZO] has recently
issued an appraisal of the effects of radon exposure.
This report was received too late for review by
UNSCEAR, and only a brief Secretariat review isconsidered here. The BEIR IV Report reviews all of
the high-LET data available to it through 1987. for all
types of exposure, and provides extensive doseresponse modelling and statistical fitting. as well as
lifetime risk projections.
384. After reviewing the literature on radon, theBEIR IV Committee considered the best way toobtain a single numerical estimate of the risk fromradon exposure is with the following equation:r(a) = r,(a) [ I + 0.025g(a)(Wl + 0.5W2)]
where r(a) is the lung cancer mortality rate at age a;r,(a) is the baseline lung cancer mortality in the
United States 1980-1984population; g(a) is a coefficient
equal to 1.2 for ages less than 55 years. 1.0 for ages
55-64 vears, and 0.4 for ages 65 years and over; W , isthe cumulative radiation exposure in WLM from fiveto 15 years before age a: and W, is the cumulative
exposure 15 years or more before age a. This is arelative risk model which accounts for age at risk.
385. The BEIR IV Committee [CZO] considered only
occupational data. On the assumption that the occupational results can be applied to radon exposures inhouses. BEIR IV estimated that 1 WLM per year
would increase the number of lung cancer deaths inboth sexes by a factor of 1.5 with current patterns ofcigarette smoking. Occupational exposures to 4 WLM
per year from ages 20-40 were estimated to increase
the male lung cancer deaths by a factor of 1.6, most of
the cases being in smokers. Note, however. that the
exposure estimates for two of the studies used for the
calculations done by the BEIR IV Committee. notably
the Beaverlodge data [H25] and Swedish iron miners[R5], have been questioned by Frost, and Swent andChambers (see [C20]). I t has also been argued that alarge part of the difference in risk estimates for thegeneral population is due to differences in the assumed
lung cancer rates in the reference populations rather
than to differences in the risk coefficients in BEIR IV[C20] and ICRP 50 [I1 I]. The BEIR IV Committee
modelled the smoking data as interacting multiplicatively with radiation, but acknowledged that a submultiplicative (but not additive or sub-additive) model
was consistent with the existing data.

386. The best data on thyroid cancer are fromchildren irradiated for a variety of conditions: thesehave already been reviewed (paragraphs 20621 6).
Adults have been treated with radioactive iodine for
hyperthyroidism, without showing any documented
excess of true thvroid cancer [C4. H12. H 141. In
adults as in children. the anaplastic, and highly
dangerous, form of thyroid cancer apparently has notoccurred following irradiation.
387. A recent report has examined thyroid cancer in
adults as well as children exposed to fallout from the
Nevada, United States. atomic test site [Z3]. No excess
was observed. and it is apparent that very large
samples would be required to detect such an excess.
The doses received by the Nevada population are in
the range 0-1.5 Gy, usually below 0.4 Gy in adults.
Based on these and other data, including the risk to
the thyroid from external x rays. the authors estimatedthe absolute excess risk to be between one and fourcases per 104PYGy. The BEIR estimate was four
carcinomas per lo4 PYGy, including some occult
carcinomas [C4]. There is insufficient information onwhich to base estimates of the effect of age at
exposure.
388. Two reDorts from Sweden have examined thvroid
cancer in adults and to a smaller extent in children
following the administration of diagnostic amounts of"'I which delivered doses to the thyroid gland of
0.5-1.5 Gy at dose rates of 2-6 mGy per hour [H27,
H281. In the first and preliminary study [H27] theincidence of thyroid malignancies in about 10,000
patients receiving typical administrations of Z MBq wascompared with the expected number of malignancies
computed from the age- and sex-specific incidence in the
Swedish Cancer Registry. Eight cases were found in thepatients after a follow-up of 17 years compared with 8.3
expected. The authors estimated that an excess of atleast 16 would be expected based on risk estimates forsebomb survivor population
adults in the ~ a ~ a n eatomic(external acute low-LET irradiation). This study was
analysed further in a report of the United States
National Council on Radiation Protection and Measurements [N5] which concluded that a risk reduction factor
of at least 3 was applicable to iodine-131 irradiationcompared with high dose rate external irradiation.
Another review of this study is contained in the
UNSCEAR 1986 Report [U I] which points out several
factors which might account for the failure to observe
the predicted excess.
389. The above study has recently been expanded[H28] to 35.000 patients receiving diagnostic '"Iadministrations with a mean absorbed dose of 0.5 Gy.
followed for an average of 20 years. Again theincidence of thyroid malignancies was compared withthe expectation based on Swedish Cancer Registrydata. Record linkage identified 50 thyroid cancers
occurring 5 or more years after the initial "'1
administration compared to 39.4 expected based on
general population rates. Patients who were examined
for a suspected thyroid tumour received the highest
doses and were at the highest risk. Patients given "'1
for other reasons were not at increased risk andneither were those who were observed for 10 years or
more. An expected excess of 41 thyroid cancer cases
was computed from the age- and sex-specific risk

coefficients estimated by the United States National
Institutes of Health, Committee on Radioepidemiologic Tables for external high dose rate irradiation by
x or gamma rays [U4]. The authors concluded that the
thyroid cancer risk from irradiation of the thyroid
gland by I3'l might be up to four times lower thanwith acute external low-LET radiation.
390. An excess of thyroid cancer has occurred inJapan [C4]. The approximate estimate for both cities,
based on T65 doses, is 0.92 male and 2.40 female cases
per lo4 PYGy [C4]. Relative risks have been about 4,
with the excess appearing 15 years after the bombing
and persisting thereafter: whether risk has begun to
decline is not certain. Generally, the adult pattern issimilar to the pattern in children. with latency andsubsequent risk behaving as they do for other adultepithelial tumours. Despite the difference in theabsolute risk of spontaneous thyroid cancer between
males and females, the 3: 1 female to male case ratio is
about the same as that in the unexposed population.
391. A recent summary of thyroid cancer risks issued
by the National Council of Radiation Protection andMeasurements [N5] expressed risk as follows:
Risk=RXFXSXAXYXL
where R is the absolute risk per lo4 PYGy for both
sexes in ethnically similar populations of children
exposed to external x-irradiation after a minimum
induction period of five years. For the United States
population, based on estimates derived from externally
irradiated children, the report [N5] takes this value tobe 2.5. F is a dose-effectiveness factor equal to 1.0 for
external x- or gamma-irradiation and for '321,I3'I and'"I and equal to 113 for ']'I and IZSI.S is a sexcorrection factor equal to 4/3 for females and 2/3 formales, assuming that females are twice as susceptible
as males and that the value R is based on populations
comprising equal numbers of males and females. A isan age-susceptibility correction factor equal to 1 for
exposure at ages under 18 and 1/2 for exposure atolder ages. (If sex-specific R values are used, thenS = 1.0). Y is the average number of years of postexposure risk in the group being evaluated. L islethality, equal to 0.10, assuming that only 1 case in 10
is lethal (this factor is to be used only when estimating
the lifetime deaths due to radiogenic thyroid cancer).
392. The risk can be calculated for any study groupusing this formula. As an example. Table 39 provides
risk estimates for an exposed United States population[N5]. The report of the National Council on Radiation
Protection and Measurements compared absolute andrelative risk models and found little difference inlifetime estimates. This model was also tested against
the Marshallese data, from which direct estimates ofrisk are not reliable, and it gave an adequate fit [N5].

(9Orher epirhelial tissues

393. The literature on lung, breast, and thyroid
cancers has been reviewed separately because, of allepithelial cancers, these are the ones for which the best
data are available. There are, however, many otherepithelial tissues in the body. Data on cancer in thesetissues come mainly from three groups of individuals;

namely, the atomic bomb survivors. the ankylosing
spondylitis patients and women irradiated for malignant
and benign gynaecologic disorders.
394. For many years i t had been thought that someorgans were relatively insusceptible to radiation carcinogenesis. This notion stemmed from the lack of evidence
for a statistically significant excess risk or to the low
background risk of the malignancy itself. I t now
appears that most (indeed, probably all) organs arc
vulnerable to radiation-induced cancer. given the rightconditions of exposure. In Japan, data still do notsupport an excess risk or dose-response for cancers of
the buccal cavity, rectum, pancreas, small intestine,uterus or malignant lymphoma [P15]. These sites mayachieve significance as the exposed cohort passes
through the years of greatest background risk. since inthe last decade several sites not previously thought tobe affected have shown a dose-response relationship.
In patients irradiated for benign gynaecologic disorders, tumours of the buccal cavity. as well as of thekidney and urinary bladder, have relative risks ofabout 2, which are comparable to the relative risk inhigh-exposure Japanese (> 1 Gy) [WS] and in spondylitics (average exposure 2 Gy).
395. In their comparison of the data from Japan andthe spondylitis patients, Darby, Nakashima and Kato
have suggested that there may no longer be any truly
radio-insusceptible epithelial tissues. This opinion isset forth in [Dl 11 and [D20]; the latter contains thedata on which the computations were based. Theirconclusion was arrived at only when the data from thetwo groups were combined and analysed jointly,
increasing the sample sizes sufficiently to show statistically significant excesses. A summary of the risks
based on this joint analysis is given in Table 40. For
example, gallbladder cancer was significantly more
frequent than expected in the combined series than ineither series alone. Darby et al. also described an
excess of central nervous system tumours in their
combined analysis, but see [P15]. This joint analysis
will be referred to in the following paragraphs.
However, it should be noted that these estimates.
while they are the only joint estimates currently
available and the only estimates based on a sample
size large enough to detect significance for some sites,
are based on obsolete doses and a shorter follow-up
than is now available. The estimates have been revised
recently. and while no new joint analysis is available.
the revisions will not reduce the qualitative evidence
for excess risk at the sites reported by Darby et al.
396. In addition to the cervical cancer patients.
several other cohorts totalling about 14,000 women
exposed to pelvic irradiation for a variety of benign
gynaecologic conditions have been followed [B6, C4,
S3. W6]. While these women add information onepithelial sites, they also pose further questions anduncertainties. Relative risk data for them were presented in Table 25. Both radium and x-ray treatments
were involved [B12, D9], and the exposures were
external, low-LET ( x ray) and internal, high-LET[W6]. Doses ordinarily ranged from 20 to 70 Gy,
given in fractions of a few Gy over periods of
4-8 weeks [B 121.

397. In women treated for benign disorders. uterine
sarcomas were increased about eightfold and female
genital and urinary organ tumours about twofold.
Exposure to radiation may lead to relatively advanced.
aggressive uterine tumours when the original reason
for pelvic irradiation is 10 treat a malignant, rather
than a benign, condition [M35]. An elevated risk ofuterine sarcomas was seen in one ovarian cancer series[RI I ] but not in another [C8] nor in the cervicalcancer series [ B 121.
398. The joint analysis of [he Japanese data andthe spondylitis data [Dl I . D20] (see Table 40), serves
to summarize the available literature on a variety
of exposed sites. A multiplicative projection model
describes the combined data reasonably well. Agespecific relative risk is roughly constant as a functionof age once the latency time is over. For heavily
irradiated sites. both sets of data show a positive
correlation between the excess risk and the baseline
prevalence of the tumour (Figure XI 11). This correlation suggests that radiation magnifies processes alreadyat work multiplicatively.

EXCESS

399. In their analysis of the Life Span Study data forthe years 1950-1978. Kato and Schull [K7] concluded
that the mortality experience of this cohort supported
a relative risk model more strongly than the additive
one. This assessment has been further supported by
the more formal adoption of the relative risk model inthe Life Span Study Reports 10 and I I [P15, S39].
Muirhead and Darby reached similar conclusions[h136, M371. The excess deaths from all cancers otherthan leukaemia and bone cancer increase with age atdeath for the same age cohort in proportion to theage-specific death rate from cancers in the populationof all Japan and do not show a constant excess value
by age at death for the same age cohort, as predictedby the absolute risk model.
400. Darby et al. also examined the post-exposurerisk for a pooled series of selected epithelial sites forwhich data are available from both the spondylitis
series and the > I Gy group in Japan [Dl I , D201.
These sites. which the authors referred to as "selectedsites", include the pharynx. oesophagus, stomach,pancreas, larynx, lung, ovaries, skin. and bones. TheyR I S KR E L A T I V E

LIFE SPAN STUDY SAHPLE (above 1 Gy 1 0-0.09 Gy)I

R I S K

LIFE SPAN STUDY SAMPLE (above 1 Gy 1 0-0.09 Gy)

Leukaemia

Lung
Breasta

Stomach
Liver

09

0

I

I

ANKYLOSING SPOt(DYLIT1S SERIES(Leukaemia and cancers o fheavily irradiated sites only)~tomachI

I

ANKYLOSING SPONDYLITIS SERIES(Leukaemia and cancers ofheavily irradiated sites only)
Lung

20
Y

m

1

Leukaernia

54- Leukaemi aSton~acho h0Flgure XIII.

Lung

I

I

I

20

40

60

I

80

Excess and relatlve risks 01 cancers in the Llle Span Study sample (T65DR doses) and in the ankyloslng spondylltis
series lor varlous cancer sites compared to expected population Incidence rates.

[Dl11

also found that the relative risk model describes thedata on the pooled sites.
401. However, the latest report from the ankylosing
spondylitis series [D21] differs somewhat from theother data in regard to epithelial cancers other thancolon cancer. The authors have found that 25 years
after irradiation, the RR values return approximatelyt o normal, contrary to the essentially permanent effectseen in other studies. Age at irradiation did not
significantly affect the subsequent relative risk forthese tumour sites (no patients where such an effecthas been seen were under age 15).
402. The relative risk is higher in females than males
in Japan for many epithelial sites (it is lower forleukaemia). This is shown in Table 41, taken from
Life Span Study 10 (T65). For oesophageal and lungcancer. the difference is probably due to different
smoking habits.
403. Because differences have appeared between theJapanese and spondylitis study, and the doses havebeen revised, one must interpret the parallel analysis
the new dataof Darby et al. with caution:
seem unlikely to change the support for the relative as
opposed to the absolute risk model for excess solidcancer risk, even if the relative risk is found to be afunction of sex. age at exposure. and time since
exposure, as suggested by Muirhead and Darby [M36,
M37]. Similarly, Darby et al. used pooled data todemonstrate escess cancer risk at many sites for whicha n excess could not be documented in either study
alone. This is probably a reliable indicator that thosesites are susceptible to cancer from exposures toionizing radiationow ever,

104. In analysing the available data on these epithelial
tumour sites, especiall!. those of the digestive system, avariety of observations are worth summarizing.
305. Digerriv~sysrenr. Little data exist on salivary
gland tunlours from Japan and the spondylitis series.
partly because of the low exposure levels. Howeler,from the essentially consistent results of eight studiesof medical therapeutic exposures, Land [L 1 I] estimatesthat the absolute risk of salivary gland tumours is
0.26 i 0.06 cases per loJ PYGy after the first five
years post-exposure, with little evidence of an association between response and age at exposure. The data
are summarized in Table 42. Most of these exDosures
are in children. including two tinea capitis series [M13,
S161. and head and neck exposures in five studies [H 1.
54, h l l I, S15, S401, or in middle-aged women treatedwith radioactive iodine [H?l]. In the Japanese data,dose estimation is complex. but the risk is estimated as
0.056 2 0.036 per 104 PYGy for malignant salivary
gland tumours and 0.063 0.035 per 10' PYGy for
benign ones [ 0 4 , T15]. Recent data have establishedthe existence of a dose response for oesophageal
cancer and for stomach cancer, but it is still difficultt o obtain accurate estimates of the lo\ver bounds ofthe effects [03].

common in women. Most of the spondylitics weremen; the gallbladder was given little dose in thecervical cancer patients. There is little statistical powerin the available data. although the recent report [P 151
from Japan estimated a small effect (relative risk at
I Gy about 1.15).
407. The pancreas seems to be of uncertain susceptibility [Lll]. Risk cannot be assessed from theavailable data, and expected rates are complicated byproblems in late and sometimes difficult histologic
diagnosis. In many countries pancreatic cancer is acommon cancer, and one might therefore expect theevidence to be more clear-cut; this is not the case atpresent.
408. Cancer of the small intestine is generally rare,
and it is still difficult to know if there is a radiogenic
effect. The data come mainly from some cervicalcancer patients, but, as noted earlier, both irradiatedand non-irradiated subjects had similar excesses.
Colon cancer has already been discussed in thecontext of the cervical cancer patients. where inconsistent results were obtained. In Japan, mortality data
show an increase in the Life Span Study sample using
the T65 doses [K7,PIS] and the new DS86 doses [Sag].
Only a non-significant increase was reported in the
spondylitics: however, a possible association between
spondylitis and ulcerative colitis casts doubt o n that
result [ D l 11. Rectal cancer seems to be a consequenceof exposure to ionizing radiation, but a dose-response
pattern is not estimable and the dose may need to be
more than 1 Gy to produce a detectable effect.
409. Genito-rcrinarjq sysrcm. The mortality data fromJapan still d o not support a dose effect for uterine o r
uterine cervis cancer. and the evidence comes almost
esclusively from those women irradiated for gynaecologic disorders. The only evidence of the inducibilityof prostate cancer comes from the Nagasaki Tumour
Registry; considering all cases, including those discovered only at autopsy, the absolute risk is 2.1 cases
per lo4 PYGy based on a linear model [LI 1, W5].
This has not been confirmed. a1 least as yet, in themortality data [S48]. Prostate cancer is a disease ofadvancing age, and most cases are not discoveredclinic all^^ and would not be reflected in mortality data.
Land speculates that a small radiogenic risk would beeven less detectable in the much higher backgroundprostate cancer rate in Europeans and North Americans[LI I].
410. A recent study in Japan [TZI] has shown astatistically significant dose-response pattern for bothmalignant and benign neoplasms of the ovary, with alatency period of at least 15-20 years.

+

406. No single data set supports an excess for
gallbladder cancer; the main risk factor for this veryrare tumour is gallstones, which are relatively rare(but becoming more c o m n ~ o n )in Japan and more

4 l I. Some\vhat more detail is available for livercancer after radiation exposure. The liver had been
regarded as being relatively radio-insusceptible. Howel3er. the Japanese data have now revealed a slightincrease in liver cancer. H hen "not otherwise specified"cases are included [P15, S49]. It bears mcntioning thatthe liver is a common site of metastasis for otherradiation-induced cancers. e.g., those of the lung,stomach and breast. and that death certificates will

414. Data are also available from Japanese militarypatients treated with Thorotrast to diagnose war
injuries [M29. M311. In these patients the risk forhepatic cancer was 40.0 relative to a military control
group and 22.2 relative to population-based controls:
the relative risk in both cases was 1.3 (not significant)for other tumours, which included a variety of sites.
After 35-43 years. there have been 50 hepatic tumoursin 254 subjects, a cumulative incidence of 19.2%.
Based on autopsies from these individuals, the meandose rate for the individuals with hepatic cancer was
estimated to have been 0.29 Gy per year. low-LET
equivalent, with a mean total dose of about 9.20 Gy[K18] of this high-LET exposure. after a mean 36.1year latency period.

commonly fail to distinguish between a primary and asecondary malignancy. particularly in the absence of
supportive pathological information. The increasinguse of radioisotopes for diagnostic liver scans or otherradiotherapeutic purposes makes more data available
and also underscores the importance of a betterknowledge of the liver's susceptibility. The best data
come from the Thorotrast patients (indeed. Thorotrast
use was stopped in about 1955, when its liver
carcinogenicity was discovered [M26]). Most cancers
caused by this agent are bile duct carcinomas.
hepatocellular carcinomas or angiosarcomas [C4].
412. Thorotrast data are reviewed in [Cj], anddetails specifically from the Federal Republic of
Germany series are in [K 161. The average dose to theliver from the 25 ml of alpha-emitting substanceinjected was about 0.25 Gy per year; about 65% of theamount injected was deposited in the liver. From these
exposures. the risk estimate was about 300 livercancers per lo4 PGy [C4], projecting c ~ m u l a t i \ ~risketo the lifetime of the exposed cohort of individuals.
For an average of 23 years at risk beyond the first
10 years in this group, the estimated risk rate
coefficient was 13 liver cancers per lo4 PYGy. Complicating this assessment were the conceivable effectsof Thorotrast toxicity, on the one hand, and radiationproduced cell sterilization, on the other. Tumours began
to appear about 10 years after initial exposure. andthe period of elevated risk may have extended beyond
40 years [K 161.

415. Other individuals have been exposed to alphaemitters deposited in the liver. particularly =''Pu. inthe case of nuclear workers. The available data d o notshow an effect but are compatible with an effect nogreater than 10 times that of Thorotrast [CJ].

5.

416. As was noted earlier. studies of the effects ofionizing radiation on adults exposed in the course of
their employment or military service have focusedlargely on radium dial painters and radiologists in the
United States and the United Kingdom or on individuals engaged in nuclear weapons research andfabrication, in the activities of nuclear power stations,in the maintenance and outfitting of nuclear-powered
naval vessels, primarily submarines. or in nuclear
weapons tests. The findings on the radium dial
painters and radiologists have been described elsewhere in this document; this section summarizes thefindings of one large case-control study of radiological
technicians [J5] and of the other studies of occupational, including military-service-related, exposure.

413. The cun~ulativeincidence of liver tumours in
the Federal Republic of Germany series is presented in
Figure XIV, for different liver dose rates measured by
x-ray film and whole-body counter assessment. Because
deposited radioisotopes can be visualized and quantified
on x-ray film, the dose-response pattern has been
estimated for liver cancer. Risk as a function of timesince exposure rises more steeply in the more heavily
exposed [K 161.

/
/

/'

20

Occupationally exposed adults-

Number o f p a t i e n t s : 207
Thorotrast amount: > 20 m l
Mean dose per y e a r : 0.3 Gy---

Nunher of tumours: 237
Thorotrast amount: 11-20 m l
Mean dose per year: 0.18 Gy.......

Number o f turnours: 133
Thorotrast amount: 1-10 rnl

30

EXPOSURE TIME (years)
Flgure XIV.

Cumulative lncldence of liver t u m o u n in Thorotrast patlents.
[K161

417. Jablon and Miller [J5]. in a stud!. ol' 6.5hO
radiology technicians in the United States Arm! in theSecond World War, found no statistically signiticant
differences between them and a control group (6.826
medical, laboratory and pharmacy technologists) withrespect to the frequency of individual sites of cancero r deaths from other causes. More specifically, for
174,500 PY of risk. they observed 12 leukaemia deaths(including one case of chronic lymphocytic leukaemia)
among the radiological technicians and 7 among
the controls ( P = 0.12, one-tailed test). While thedoses are uncertain, their exposures may have been
0.05-0.15 Gy per year, based o n the experience ofsimilar technicians at the Cleveland Clinic (UnitedStates) in 1953. Most of these radiology technicians
did not pursue the same kind of work after they had
left the Army, where their average stay had been lessthan 3 years.
418. Efforts have been made to determine whether
individuals employed in the nuclear industry d o or do
not have increased risks of cancer. In 1978, forexample, Najarian and Colton [N6], in a study of
1.722 death certificates for a variety of workers at thePortsmouth Naval Shipyard (New Hampshire. UnitedStates). found six deaths from leukaemia among the
146 former workers presumed to have been involvedin activities where exposure could have occurred,
whereas 1.1 deaths were expected. A subsequent
retrospective cohort mortality study [R17] of all theworkers at this shipyard failed to confirm the finding.
Among three cohorts, (a) 7.615 nuclear workers (doses
0.01-0.91 Sv; mean 0.03); (b) 15,585 non-radiation
employees; and (c) 1,345 with no measurable exposure.
on whom vital status could be ascertained in 96% ofcases, Rinsky et al. found n o increased mortality for the
exposed groups as contrasted with the other two groups,
nor did they find evidence of a dose-response relationship within the exposed cohort. The standardizedmortality rate (SblR) for leukaemia was 84 (95% CI:
34-174). As is true in many occupational settings.
some uncertainty surrounds the actual doses involved:
for years prior to 1974, the estimates are based on film
badges, but for subsequent years. they are based on
calcium fluoride dosimeters. A study of the employeesof all of the nuclear shipyards in the United States.
government and pritrate, is presently under way. Whileit has not yet reported its findings, the study may
eventually clarify the issue. Similarly. in 1981. Austin
and his colleagues [A161 reported a threefold increasein the frequency of malignant melanoma among theemployees of Lawrence Livermore National Laboratory(United States). Again, a substantially larger, later
cohort study of the workers at Los Alamos National
Laboratory (United States) [A151 failed to support
this. Among 11,308 employees, only six cases ofmelanoma were ascertained where 5.69 would havebeen expected based o n age and sex-specific mortality
rates (SMR = 105). Jn neither of these studies wasevidence presented that the cases had received higher
exposures than other employees.
419. The situation with respect t o the employees atthe Hanford Facility in the state of Washington,
United States, is equally perplexing. Kneale, Mancuso
and Stewart [K20] purported to show that a variety ofmalignancies, including multiple myeloma. are elevatedanlong the workers at this laboratory, but a morethorough and statistically sounder study [GI21 does
not bear out their contentions, although it does find agreater frequency of multiple myeloma than expected.
I t should be noted that even this result rests on threecases. Whether this increase is, indeed. a consequenceof exposure is therefore moot. but multiple myeloma
has been found to be elevated among the atomic
bomb survivors, presumably as a result of their
exposure, and the effect could be real. More recently,
Beral and her colleagues [B22], using standardizedmortality rates, examined the causes of death anlong
39,456 individuals employed by the United Kingdom
Atomic Energy Authority (UKAEA) between 1 January
1946 and 31 December 1979. They found mortality to
be increased for only four causes of death. namely.
testicular cancer (SMR 153: 10 deaths). leukaemia(SMR 123: 35 deaths), thyroid cancer (SMR 122; threedeaths). and non-Hodgkin's lynlphoma (SMR 107;
20 deaths), but in no instance was this increase
statistically significant at the 5% level. The SMR for
myeloma was 83 (95% CI: 36-163). Cumulative dose
estimates are available for approximately half of these
employees; few (84) had received a cumulative dose inexcess of 0.5 Sv. Among the workers for whom there
were dose estimates. prostatic cancer was the only
cause of death clearly related to exposure (SMR 594
for employees with exposures exceeding 10 mSv; four
deaths). A I t h o ~ ~ gthe
h numbers are small a n d theevidence is perforce weak, the data suggest a greaterrisk among workers exposed to tritium than among
workers exposed LO other sources of ionizing radiation(SMR 889; 6 deaths). Beral et al. [B22] estimate excess
mortality for leukaemia and all cancers were 2.2 and10.5 deaths per lo4 PYSv. respectively. Neither ofthese estimates is significantly different from zero, but
at face value they both agree reasonably well with theJapanese and other studies. I t is interesting t o notethat when the UKAEA findings and the Hanford
findings are combined. neither ths increase in prostatic
cancer seen among the former nor the increase inmultiple myeloma seen among the iatrer is any longer
significant [D24]. This suggests that both individual
findings could be due to chance.
420. Possibly the most thoroughly studied of these
special cohorts has been the plutonium workers.
particularly those individuals who were involved inworking with this clement at the time of the Manhattan
Project, when the potential hazard associated with
the inhalation of plutonium particles was poorly
recognized. Some 37 years of follow-up have failed todisclose an increased frequency of any malignancy; thenumber of workers involved is small, but their
exposures were undoubtedly large [V2]. Studies of
plutonium workers at the Los Alamos facility [V3] aswell as of workers at other installations in the UnitedStates [W18] have also failed to find a significantly
elevated risk of malignancy, generally o r sitespecifically. Although the number of years at risk arealready large, these studies continue, and it is conceivable that an effect could still emerge.
421. In 1979, a preliminary report [C16] indicatedthat eight cases of leukaemia had been identifiedamong 3.224 former servicemen who had participatedin the nuclear weapons test code-named SMOKY, oneof a series known as PLUMBBOB, conducted at the
Nevada Test Site. United States. in 1957. Only 3.5
cases would have been expected on the basis of ageand sex-specific population rates (RR = 2.3). Subsequent studies of this same cohort [C17] extended theobservations to the incidence of all types of cancer
and other specified causes of death. No increase inother cancers was seen, but 10 cases of leukaemia(including one of chronic lymphocytic leukaemia)
were found where 4.0 were expected (RR = 2.5).
Similar claims, based largely on scanty epidemiologicalevidence, have since been made for Australian andBritish participants in weapons tests carried out by theUnited Kingdom [K21].
422. Stimulated by these reports, the Medical Followup Agency of the United States National ResearchCouncil launched an investigation of the participantsin five series of tests occurring in the years 1951
through 1957 [R16]. This investigation embraced acohort of 46.186 individuals. A total of 46 deaths fromleukaemia were ascertained (52.4 expected on population rates). No significant excess was found among theparticipants at any test series other than PLUMBBOB
or among PLUMBBOB participants not represented
at SMOKY. The earlier findings of Caldwell and hiscolleagues with respect to the SMOKY test wereconfirmed. No other form of cancer was consistently
elevated; overall. only 1,046 deaths from malignant
neoplasms were identified where 1,243 were expectedbased on population rates (SMR = 0.84). While thedoses of the individuals involved in all of these tests
are poorly known. film badges suggest that the highest
dose received by any one of the participants in
SMOKY who subsequently succumbed to leukaemia
was 0.036 Sv (most received doses of less than
0.005 Sv). At the present, then, there is no consistentor statistically significant evidence for an increase ineither leukaemia or other malignant neoplasms innuclear test participants.
423. Darby et al. [D26], updating the study of Knox
et al. [K21], have summarized the cancer mortality
and incidence among 22.347 men who participated in
the United Kingdom's atmospheric nuclear weapon
tests and experimental programme, and have comparedthese findings with those on 22,326 individuals matchedwith the participants for age. type of armed service,rank (officers and other ranks: socioeconomic classfor civilians), and the date of entry to the study. The
latter individuals were drawn either from among
servicemen who did not participate in the weapon test
programme, or. for the civilians. from the roster of
employees of the Atomic Weapons Research Establishment who had not visited a test location or attended tests
in the United States. Thirty-eight causes of death were
examined separately.
424. Mortality from leukaemia and multiple myeloma
in the participants was slightly greater than would
have been expected from national values. but it was
substantially lower in the controls. However, the rates
of leukaemia and multiple myeloma showed very little
difference between groups characterized by recorded

doses from external radiation. These authors cautiously
concluded "Participation in the test programme did
not seem, in itself, to have caused any detectable effecton the participants' expectation of life, apan frompossibly causing small risks of developing leukaemia
and multiple myeloma".
425. Rinsky et al. [R21] have described the resultsof a case-control study of lung cancer in civilian
employees at the Portsmouth Naval Shipyard (UnitedStates). Their study involved 405 cases and 1,215
controls drawn from the roster of civilian employees
matched on age. year first (last) employed, age at datefirst (last) employed, and length of employment. The
distribution of cumulative radiation doses among thecases differed little from that among the controls savein the percent exposed to 0.01-0.05 Sv where theradiation-related excess was statistically significant.
However. when exposures to asbestos and welding
fumes were taken into account, the radiation-relatedrisks at all levels of' exposure were reduced, suggestinga greater exposure to these factors. This confounds theobserved association between radiation and lungcancer. Analysis of mortality by time since exposure
revealed no pattern of increase as latency increased.
Data on cigarette smoking and socioeconomic status
were not available. These authors conclude that theirstudy does not preclude an association between lungcancer and exposure to ionizing radiation (at the levels
obtaining among nuclear shipyard workers) nor doesit provide evidence in support of such an association.
426. Checkoway et al. [C2 I] have described a historicalcohort mortality study of 6,781 white male employeesof the nuclear materials fabrication plant known as
Y-12 at Oak Ridge, Tennessee, United States, in theyears 1947-1979. Among monitored workers, themean cumulative alpha-radiation dose to the lung was
0.082 Sv, and the mean cumulative external wholebody penetrating dose from gamma-radiation was
0.0096 Sv. Mortality excesses were seen for cancers of
the lung, brain and central nervous system. but not forother sites of cancer nor other causes of death when
the rates among workers were compared either tonational or state rates. No dose-response trend wasobserved for mortality from cancer of the brain and of
the central nervous system. but the rate ratio for lungcancer. based on contrasting workers receiving 0.05 Sv
or more with workers receiving less than 0.01 Sv, was4.60 assuming zero-year latency and 3.05 on a 10-year
latency. These rate ratios are, however, based on only
three deaths and one death. respectively. Thus, theevidence of an increase in lung cancer mortality atthese dose levels is far from compelling.
427. Workers for British Nuclear Fuels at the Sellafield plant have been studied [S54]. Among 14,327
known to have been employed at the plant from
1947-1975. 572 of 2,277 deaths were due lo cancer, 5%:less than expected based on death rates for Englandand Wales (overall mortality was also slightly lessthan expected). Radiation workers had deficits of liverand gallbladder cancers, lung cancer, and Hodgkin's
disease, and excess deaths from myeloma and prostatecancer. Neither excess was significant, and there was
no excess in leukaemias. Dosimetry showed positiveassociations between accumulated dose and death
rates from bladder cancer, multiple myeloma, andhaematopoietic neoplasms. These were significant inregard t o doses accumulated u p to 15 years prior to
the time of death. but not if doses up to two years
before death were included.

6. Exposures to elevated cosmic and terrestrial radiation
428. Although levels of exposure to cosmic radiationvary as a function of altitude, and although somecorrespondence exists between cancer rates and altitude.
there have been few convincing studies to show whether
cancer rates at high elevations are substantially different
from those elsewhere [C4]. Many correlated factors
could explain the data that are available (see [A51 for areview). Studies designed to assess firmly whether
cosmic radiation itself causes cancer would requireprohibitively large samples.
429. A large-scale investigation of background radiation has been undertaken in China [H24, 241, where
cancer mortality levels in a high-background area in
Yangjiang country were compared to those in a control
area with one third the exposure levels. After age
adjustment, there were no significant differences. eventhough chromosomal and other indications of radiation
exposure did differ.
130. A separate study has compared the effects ofradon alpha-exposure in high-background areas ofGuangdong Province of China [H24] with a control
area. High-background area exposures were about
0.38 WLM per year, and control-area exposures were0.17 R'LM per year. No difference in age-adjusted lungcancer rates was found.
3
A study of total background radiation in Japan[US] found an effect only for male liver cancer. Thiseffect fitted a linear dose-response model, but it isdifficult to determine if there were other factors
correlated with background exposure o r if the result is astatistical artefact of some kind, as one due t o multiple
testing. Liver cancer is not usually reported as aradiogenic site, unless doses are also high enough to
induce excess cancer at most other sites as well. In
Connecticut. United States. where there is a tumour
registry and an airborne gamma survey of the entire
state was taken. there was no association between
terrestrial radiation and cancer in the period 1935-1973[W16]. The authors concluded that even a population
currently in excess of 3 million persons is too small todetect the level of excess risk which might be associatedwith the observed level of background radiation.

7. Summary of exposure effects in adults
432. In respect to the radiation exposure of adulthuman subjects (see also [B21]). several generalizations
seem permissible. Regardless of the reason for the
initial exposure. it is evident that (a) a single exposure
can be carcinogenic if the dose is large enough;(b) there is no uniquely radiogenic cancer cell type;(c) though most, perhaps all, of the common cancers

probably can be caused by ionizing radiation, until
now the data have not shown a risk for chronic
lyrnphocytic leukaemia, squamous-cell cervical cancer,
or Hodgkin's disease; (d) the breast, thyroid, and bonemarrow are particularly susceptible; (e) leukaemia,
especially acute non-lymphocytic leukaemia (ANL),
can be produced by radiation: it has a latency periodof less than 5 years, peaks rapidly thereafter and thendeclines, but some excess risk persists for at least
30-40 years: (f) solid tumours have an age-onset
pattern similar to that of non-radiogenic tumours at
the same sites after a latency of about 10 years. For
many sites, the latency period is a function of age at
exposure. In the existing studies, relative risks havebeen between I and 3 for many epithelial sites after
many different kinds of exposures of about 1 Gy: risk
persists for 30 years (for life, in some studies); (g) age
at exposure is the most general host susceptibility
factor. with higher risk associated with younger ages
at exposure; ( h ) atomic bomb survivors and most otherstudy cohorts have yielded comparable results. with a
few notable exceptions, and the latter appear explicablein terms of the exposure regimens used and otherfactors; (i) some individuals may be genetically more
susceptible to radiation-induced cancer than others.
but good data to demonstrate this unambiguously are
Lrery limited.

IV.

HOST FACTORS THAT h1ODIFY RISK

433. There are many biological differences among
human beings that may affect their susceptibility toradiation-induced cancer. These biological variables
are commonly known as host factors. referring to therisk that the exposed individual will become a host to
a tunlour. There are many possible host factors forwhich some data exist. Among these are ( a ) sex:( b ) age at exposure; ( c ) genetic constitution; ( d ) healthstatus: (e) life-style; and (0 ethnicity. Since thepublication of the UNSCEAR 1977 Report. some
information has become available on the potential
role of each of the factors listed.
A.

SEX

434. Current data generally suggest that sex has little
or no effect on radiation carcinogenesis. Tumours in
an irradiated population exhibit a sex ratio very
similar to the same tumours in a non-irradiatedpopulation. There is a strong preference for females inthyroid cancers produced by radiation. but the sex
ratio is similar to that observed for spontaneous
thyroid cancer. S o far, breast cancer following radiation has essentially been found only in females andthis corresponds with the extreme rarity of male breast
cancer. Cancers in the organs usually manifesting
adult onset occur in the typical sex ratios, which formany sites (for example, the lung) show a malepreference and there is no evidence that the radiationrelated relative risk is higher. The male excess of lungcancer is probably a temporary one related to thehistory of smoking habits. Squamous cell carcinomas
and adenocarcinomas of the lung in Hiroshima and.

Nagasaki, for example, seem to develop more rapidly
in males than in females. but no difference appeared
after smoking habits were taken into account [HIO,
K22J. Adenocarcinomas are more frequently slowgrowing than are lung cancers of other histology. The
evidence of a slightly higher relative risk for females
than for males in Japan at many epithelial sites wasreviewed earlier (see Table 41): most of the difference
is probably due to interaction with other sex-associatedrisk factors rather than to a radiation effect.
Radiogenic leukaemia in Japan has a similar
relative risk in both sexes, although the excess risk
per lo4 PYGy is significantly less in females (1.95 inmales and 1.20 in females). Background incidence ofleukaemia is two times more frequent in males. For
other fatal cancers. shown in Table 41, only multiple
myeloma has a higher background incidence infemales; however. thc escess risks are, from a statisticalstandpoint, not significantly different in the two sexes.
Since the background rates are higher in males, therelative risks are s o m e ~ h a tgrearer in females [PIS].
Sex may influence tumour growth and, indirectly,
survivorship.

435.

B. AGE O F ONSET OF TUMOURS IN EXPOSEDADULTS: SINGLE A N D CHRONIC EXPOSURES
1.

Exposure to the atomic bombings in Japan

436. The carcinogenic effects of single exposures ofexternal radiation are known almost exclusively fromdata in Japan. There. the relationships between dose.
age at exposure and age at expression of excess risk
have been studied in detail [K7, P15, S18. S48, S49.
N'53. Because the results have been reviewed extensively
elsewhere in this document. only those facts that relate
to tumour sensitivity as a function of age at exposureand age of onset will be examined here. For mosttumours, there is a decreasing sensitivity with increasing
age at exposure, in terms of subsequent risk of escesscancer. The solid tuniours of aduit onset increase infrequency only at the ages at which they naturally
appear in non-irradiated indi\,iduals. For leukaemia,
the additive risk rises with age at exposure, while therelative risk declines rapidly lvith age over 10 [K7].
Leukaemia. a classic radiogenic tumour with otherspecial characteristics, is usually treated separately. The
characteristic Dattern for breast cancer has alreadv
been discussed in relation to childhood exposures (seeparagraphs 240-242). Basically. all tumour risks seemto decline as age at exposure increases. The same
reports also show the positive correlation between risk
and dose at all ages. There is an unexplained
difference between the data in Japan and uranium
miners. the latter showing increased risk with increased
age at exposure [S5 I].
437. In addition to the fact that susceptibility toradiogenic tumours decreases with increasing age at
exposure, the characteristic latency periods are related
not so much to age at exposure as to the tissue
involved. The leukaemias have the most definite
pattern, with a latency of 2-5 years and a decline inadditive risk after about 25-30 years; a similar pattern

exists for bone cancer. However, the solid tumours ofadult onset have latency periods of a decade or more,
and the excess risk persists indefinitely, probably
throughout life, although this will be determinable
only after the entire cohort experience in Japan is
known.
438. The subsequent risk of cancer fits a multiplicative risk projection model. The delayed latency period,
the persistence of risb: throughout adult years. and theage pattern of excess cases are all consonant withmulti-stage carcinogenesis, as for example. the model
proposed by Moolgavkar [M 1. M2], which posits twostages with selective proliferation of partially transformed cells.
439. Under such a model, increased risk should beseen soon after exposure to a single dose, if (as seems
likely) radiation acts as an initiating agent (see section
III.A.1). H'owever, if this effect is small in thecontrasted groups, the excess risk will not be detectable for some time after it has actually arisen. given
the available sample sizes. I t can be shown that, undersuch a multi-stage risk model with multiplicative
projection effects. because of the nature of the change
in the risk function and the effects of competing
causes of death (which effectively terminate theobservational experience at age 85 or so). the mean
age and the age distribution of cases in exposed adults
will be similar to those in the population at large[M4]. For these reasons, the age patterns of risk for
those exposed to single doses are in agreement with amulti-stage model, and no special life-history or tissue
sensitivity characteristics are required. other than inthose cases. e.g., breast, bone and leukaemia. where
tissue life-history plays an obvious role in sensitivity.

2.

Exposures to nuclear tests and fallout

440. The estimated dose-response pattern and its
possible significance for those who have been exposed
to fallout from a single nuclear detonation (adults in
the United States and British military service. Japanesefishermen and Marshall Islanders) are discussed elsewhere in this document. In sum. the numbers of
exposed persons were too small and too heavily
weighted towards young adults to provide good dataon age effects. Adult Japanese fishermen. although
feu in number, and hlarshall Islanders [C6] seem not
to have exhibited an escess risk. Non-haeniatopoietic
tumours do not appear to have arisen in these groups
in dctectably higher frequencies.
441. For adults exposed to chronic doses of radiation either occupationally or through the ingestion ofradioisotopes for therapeutic purposes or as a result of
nuclear testing. the duration of exposure is too long
and, typically, the dose too low to provide useful
information about special effects of age at exposure.
C.

GENETIC CONSTITUTION

442. Given the genetic variability that exists between
individuals within a group and between groups. it isreasonable to presume that the risk of cancer mayvary among individuals of the same sex, age andapparent life-styles when exposed t o the same amountof ionizing radiation. A number of relatively rare,largely recessive disorders are known in which fibroblasts from trait-bearers are deficient in the repair ofsome radiation damage in vitro; i t is also known thatthese individuals are at increased risk of a variety ofmalignancies, especially malignant lymphoma andleukaemia [Kl I]. Cell lines from patients with one
such disorder. xeroderma pigmentosum, in which UV
light is a mutagen, did not disclose a cross-sensitivity
in regard to cell-killing with gamma radiation, butenhanced sensitivity to cell-killing has been reported
in vivo in irradiated children. Some cell lines frompatients with heritable diseases. including cancerprone ones, have shown cell-killing sensitivity after
such radiation [A7, G5, P10, P l l ] , but this is notalways found [WIO]. One study [F7] has reported thatcell cultures manifesting a variety of chromosomal
aberrations have shown similar low-dose response
estimates.

443. The carriers of one major disease, ataxia telangiectasia (AT). may have been subjected to irradiationin numbers sufficient, eventually, to show a n excess ofcancers, if it exists. The gene for A T is relatively
common in Israel, where i t is expected that at least
some children irradiated for tinea capitis would be
carriers of the gene. The latest report [R22] suggeststhat Moroccan children, who have a high frequency ofA T carrier status, are especially susceptible. among
the total Israeli tinea capitis study series. This study
did not report thyroid cases. However, in anotherreport from the Israeli series, the thyroid cancer
pattern may also reflect this fact, although genotyping
has not been done on the cohort and only some of thechildren were given ionizing radiation as opposed to
UV therapy.
The cells of these individuals carry two copiesof the "susceptibility" allele, one on each parental
chromosome, i.e.. they are homozygous for an abnormal
allele (form of the gene). However. in their families there
will be many heterozygous individuals whose cells
have only one copy of the abnormal gene. the otherbeing normal. Indeed, not only in these families but
also. by virtue of the frequency of the susceptibility
allele, in the larger population, there will be a
substantial number of individuals, perhaps several
per cent, who are heterozygous "carriers" of theabnormal allele. For them. affected relatives will be
unlikely and would arise only when a heterozygote
a n d another carrier marry. a relatively rare occurrence.
Substantial speculation has centred on the likely cancer
risks of individuals heterozygous for these genes.
Little direct information exists as yet since there is no
simple. easy test for heterozygotes. However, on thepresumption that the parents of affected individuals
must be carriers (except for very rare instances inwhich a mutation occurred in the child), some testingof the radiosensitivity of fibroblast cultures from theseparents has been carried out. This work. though stilltentative in nature, suggests that there is a n intermediate level of radiosensitivity, measured by cell
survival, between affected a n d normal homozygotes
443.

[PIO]. While it is unlikely that excluding very small
subsets of abnormally radiosensitive individuals would
alter population risks importantly. their existence will
require separate estimation.

445. The Li-Fraurneni syndrome is a dominantly
inherited genetic susceptibility to cancers of many organsites [L13]. Normal fibroblasts from Li-Fraumenifamily members are resistant to killing by radiation:
Chang et al. [C18] found that in non-irradiatedcultures of such cells, the c-myc oncogene has athreefold to 18-fold increased expression and thatc-raf- l expression was also elevated. Kasid et al. [K23]have found that elevated expression of the c-raf-1
oncogene is associated with a cell line of laryngeal
carcinoma which is radioresistant (in vivo a n d inculture). Why this oncogene should apparently be
associated with carcinoma risk and radioresistance is
not clear.
446. In retinoblastoma when the individual is a n
obligate heterozygote for a cancer-related region on
chromosome 13, the subsequent risk of radiogenic
tumour is a reflection of the susceptible genotype.
447. Less has been written, indeed less is known,
about the role of genetic predisposition to specificmalignancies a n d the relationship, if any. of thispredisposition to radiation-induced risk. Are. forexample, women who come from "breast-cancer
families" more prone to develop breast cancer after
irradiation of the breasts than women who d o notcome from such families'! One study in Japan may
begin to provide an answer [Y3]; there was anincreased risk of second tumours in women with afamily history of breast cancer relative to those
without such a history, and there was evidence
suggestive of an interaction with radiation in producing
this risk. A substantial fraction of colon cancer cases
is familial, although to date no study has looked fora n excess susceptibility in irradiated persons fromhigh-risk families. A variety of shared environmental
factors could lead to a familial appearance of cancer.
s o that a definitive answer to the question of carriersusceptibility must await the development of practicaltests for genetic susceptibility.

448. As reviewed in detail above. many second
tumours following radiotherapy occur in individuals
whose primary tumour was of a heritable kind. In
some of these families there is an excess of cancers ofother types in the relatives of the probands. Such
relatives d o not suffer the index disease, but they may be
carriers of some modifier allele at a different genetic
locus or, for some other reason. predisposed to develop
cancer. Retinobiastoma and childhood sarcomas haveboth been involved in such studies. If these probands
are from cancer-susceptible families, or if their cancer
reflects a cancer-proneness, dose-response estimates
for them may be of little value to the population as awhole, but the identification and characterization ofsusceptible genotypes may be extremely important intheir own right.
449. Data relevant to these issues are sparse. but
those that are available suggest there may be a small

but non-trivial fraction of the human population thatis prone to develop cancer and, as a consequence, may
be much more liable to develop radiation-related
cancers. This may mean that the average dose-response
pattern is a relatively poor indicator of individual risk.
I t may be too low for those individuals especiallypredisposed, and too high for those individuals who
are not at special risk. However. to improve theestimation of risk, one must be able to. identify thesusceptible individuals, which is not practicable atpresent.
450. In ankylosing spondylitis patients there is strong
association with specific genes at the histocompatibility
loci, in particular an allele known as B27. Individuals
with at least one copy of this allele are much more
susceptible to spondylitis than are those with otheralleles. It is thought that this may involve thedevelopment of auto-antibodies in such individuals
after exposure to some agent. possibly an unidentified
virus. At present there is no evidence that the HLA
type is related to cancer or to cancer induction, so thatfrom this point of view the ankylosing spondylitis
patients may be thought of as representative of thegeneral population.

D.

ETHNIC CHARACTERISTICS

451. Shore et al. [S16, S27] have suggested thatradiation-induced skin cancer is functionally related tothe degree of pigmentation of the exposed individual.
No increase in skin cancer with exposure has been
seen among the 2,226 blacks who made up 25% of
their tinea capitis population. but 41 cases occurred in
the white children who made up the remaining 75%.
Nor has an increase been seen among the Japanesesurvivors of the atomic bombings of Hiroshima andNagasaki [C4, 021. These results correspond to theprevailing skin cancer rates in blacks and in Japanese.
This suggests that partially transformed cells, exposedto the DNA damage of UV radiation in light-skinned
individuals, may become fully transformed. However,no UV-radiation cross reaction has been found in celllines carrying UV-sensitive genotypes (reviewed above).

E.

HORMONAL EFFECTS

452. A deficit in breast cancer has been observed in
the cohorts of women who had been treated for
gynaecologic disorders (malignant and non-malignant)[B12, L11, W6]. At the same time, ovarian cancer wasseen to be reduced i n women who had been treated for
gynaecologic cancer [B12]. These observations agreewith a cell-killing effect at the ovary. depriving thebreast of oestrogenic compounds that may contributeto carcinogenesis in partially transformed breast cells.
However, breast cancer was also reduced in women
treated for benign conditions, who did experienceelevated ovarian cancer [W6], the explanation istherefore not obvious at present, and non-representative subjects (i.e.. subjects who present an inappropriate expected risk) may be responsible.

453. A study specifically designed to detect interaction between various hormone-related variables andbreast cancer risk in women irradiated for postpartum
mastitis was conducted in 571 patients and 993
controls in Rochester. New York, United States [S3T].
This study found that women with benign cystic
breast disease were at excess risk following radiation,
but because the benign disease occurred after irradiation, a causal relationship could not be established.
Oral contraceptive use, family history of breast
cancer, late age of parity, menopausal hormone use
and ovarian-related factors (cysts. missed menstrual
cycles) were tested, but no interactive relationshipwith radiation was detected. Another United States
study reported similar results [B I].
454. In the Japanese data [T14], breast cancer risk
seems to be less if the radiation exposure occurred
after menopause. However, this may be a cohort
effect, attributable to different levels of hormonal
stimulation in the United States and Europe on the
one hand, and Japan on the other. Japanese-American
women are developing age-specific breast cancer
frequencies much like those of other Americans, andbreast cancer is becoming more frequent at older ages
in Japan. If this is a cohort effect, and if radiogenic
breast cancer is related to the hormonal stimulationthat appears to be responsible for these international
differences. post-menopausal radiogenic breast cancer
may increase in Japan [T14].
455. Tokunaga et al. found a slight but nonsignificant excess risk among women who had borne
their first child after age 30 [T14]. Nulliparous women
may also have elevated radiogenic risk [B I]. Similarly.
irradiation after the first childbirth seemed to lead toelevated risk; age at first childbirth is certainly related
to the occurrence of breast cancer. but how thisinteracts with radiation is not known. This and otherstudies seem to suggest an age effect on breast tissue
susceptibility.
F.

OTHER DISEASES

456. It has already been discussed whether individuals
irradiated for the treatment of cancer suitably represent
the general population in terms of their susceptibility
to radiation-induced cancers. In general. most studies
find similar patterns of radiation risk. An exception tothis is excess sensitivity among children who havegenetic predispositions, which suggests that children
exposed for cancer treatment should not be considered
for general risk estimates. Presumably some adults
also have greater genetic susceptibilities for cancers,
but these individuals cannot be identified in general
populations.
457. Although the non-random HLA genotypes inankylosing spondylitis patients (reviewed above) may
not affect their radiation susceptibility, they clearly
suffer from proportionally different causes of deaththan the general British population [S28]. Their
pattern of relative risk for a variety of causes is given
in Table 1 of [S28]. In addition to the colorectal
cancer which may be confounded by the higher risks

of colitis and its associated cancer risks in thesepatients. many other causes of mortality are different
from a general population. Even if this does not apply
to their general cancer susceptibility, it clearly affects
the interpretation of relative risks derived from theUnited Kingdom baseline cancer a n d general mortality
rates.

that are relevant t o three questions, namely: (a) whatroles d o smoking, diet, and the like play in cancer
risk? (b) are life-style attributes related in any way t o
the absolute o r relative risk differences in the irradiated?
(c) can an understanding of the interaction of risks
lead to an understanding of the action of radiation?
Regardless of the answers to these questions.
relative and absolute excesses of cancer attributable toradiation must at present be evaluated in the context
of local baseline patterns. For the cohorts of individuals who have been exposed to large doses ofradiation, the levels of environmental risk exposure
have been changing in the populations in which theylive. Without adequate cognizance of these changes, itwill be difficult to identify the effects of radiation, perse, o r to say whether the effects of radiation are thesame in populations with vastly different sociocultural environments.
462.

V.

ENVIRONMENTAL FACTORSTHAT MODIFY RISK

458. I t has been asserted. based on world-wide cancer
data, that 85-90% or even more of all cancers are
avoidable; that is, that they are due to exposures toenvironmental carcinogens, e.g., smoking, diet, personal habits and the like [D13]. This assertion is basedon the observation that age-standardized incidence rates
for virtually every type of cancer vary greatly among
the populations of the world. Doll a n d Peto, in theirreview of cancer patterns in the United States. haveestimated that 1-1.5% of all cases in that country areradiation-induced (non-occupational sources of radiation) [D13]; some of these cases will be due t o natural
background radiation, but the remainder will be due
to man-made sources of exposure.
459. The most systematic data on variation in sitespecific cancer incidence, by age and sex, is the seriesof volumes published by the International Agency for
Research on Cancer (IARC) [W17]. They provide thebest available baseline cancer risks and, while they
include the effects of radiation on a population basis
a n d cannot be used specifically to identify environmental causes, they can be used in computations ofrisk assessment. as discussed in chapter 11. Radiogenic
effects will be functions of the baseline risk. In
addition, as seen in chapter I11 in regard to second
cancers in patients irradiated to treat cancer, radiation
risk is highly dependent on the effects of other risk
factors.
460. The observed pattern of world-wide cancer
variation is not highly correlated with ethnicity in any
simple way that would suggest that this variation has
a genetic basis, so it is generally assumed thatenvironmental factors must be responsible. I t isusually also assumed that in any population a large
fraction of the baseline cancer rate, for any tumour
site, is determined by local exposures to various agents(including radiation). Smoking and diet, pollutants inthe environment, endogenous as well as exogenous
hormones, and many other agents are known to be
associated with variations in cancer risk.

461. Among the more elusive of the host factors andenvironmental factors that can influence the occurrenceof a radiogenic cancer are the health status and lifestyle of the exposed individual. Their roles have beendifficult to assess, for the variables themselves are
difficult to define and to measure adequately. Smoking
habits are more than just the sum of the cigarettes one
smokes daily, weekly, annually or in a lifetime ofsmoking: moreover, these habits change with age andperception of risk. Data are beginning to be available

In addition to changes in mean levels of
exposure within a population over time, there will beinter-individual differences in exposure that are relevant both to the analysis of specific cohorts and t o theestimation of future risk. Although the data arelimited, in many study cohorts it has been possible t omake observations, or plausible inferences. about therole of certain environmental co-variates. These will
now be reviewed.

463.

A.

SMOKING

Clearly. cigarette smoking is one of the mostdefinite, and easily assessed, risk variables: it applies
to cancer of the lung in smokers whose lungs are
exposed to radiation, as well as to certain othertumours. However, Kato and Schull [K7] found n oevidence that smoking increased the radiation-induced
lung cancer incidence in Hiroshima and Nagasaki
disproportionately. Prentice et al. [P7] and Kopecky etal. [K22], in a more elegant and broader analysis of
the same data. reached a similar conclusion. Persons
heavily exposed to both cigarette smoke and radiation
had significantly lower cancer mortality for all cancers
except leukaemia, stomach cancer and digestive cancer
other than stomach cancer than predicted with amultiplicative risk model. The lung cancer relative riskfunction could not be distinguished as either an~ultiplicativeo r an additive form, though there might
have been a slight preference for the latter.
464.

465. Women treated for gynaecological disorders
have experienced an increase in the incidence ofcancer at smoking-related sites, including lung, bladder,oropharynx, and oesophagus [B2. B12, W6]. This has
been observed in irradiated and non-irradiated patients.
Since smoking is a well-established risk factor forcancer of the cervix, which typically selects for womenof lower socio-economic status, some of the excess
risk of smoking-related cancers in these women may
be due to their smoking habits; alternatively. it may bethat they were susceptible to cervical carcinogenesis
for a variety of reasons; among them, smoking. They
may have been more susceptible to smoke than thepopulation from which their expected rates werecomputed [BIZ. W6]. In a case-control analysis of asubset of the cervical cancer series. Boice et al. [B38]were able to show an association between smoking
a n d smoking-related cancers, as well as for otherknown risk factors and their associated cancers (i.e.,nulliparity effects on breast cancer risk. and obesity
a n d menopausal oestrogen therapy for endometrial
cancer).
466. The relative risk of lung cancer in the international cervical cancer study of women under age 40
was more than 12, a much greater risk than can be
accounted for by the effects of smoking in the patients[B 121. For women who had not received irradiation.
the relative risk was the highest of any group in the
study, about 3, and a similar excess of bladder cancer
was found in the women treated for benign conditions[B 12, W6]. A different series, of 2,500 French women
treated for cervical cancer, observed 10 cases ofbronchial carcinoma, with only 28 months. on average.
intervening between the diagnoses [S36]. This latency
time is too short for radiation t o have induced cancer
in the lung. The possibility that the excess lung cancer,
a t least. reflects the misclassification of metastatic
cervical cancer has also been considered [B12. D9.
S36]. although these authors argue that the persistenceof excess risk in the large international study after
20 years suggests some of the excess may be real.
Given the lo\. dose of radiation received by the lung,a truly radiogenic effect would be difficult to detect[B 121.
467. One extensively studied potential interaction isthat between smoking and radiation in occupationally
exposed underground miners. The alpha radiation of
the radon daughters present in the air of undergroundmines provides long-term, generally low-level exposure
to the lungs, as does smoking. Some aspects of thesestudies have been mentioned earlier.
468. Most of the miner populations studied had ahigh percentage of smokers, so that the independence ofthe two effects has been difficult to evaluate accurately.
However, Navajo Amerindian men working in mines
in New Mexico. United States, also developed excess
lung cancer and relatively few of them were smokers[S20]. None the less. the data o n smoking andradiation with respect to miners are complex andinconsistent [C4]. One study of iron miners innorthern Sweden indicated that smoking had. roughly,a n additive effect in the exposed miners [R7], while
another [ D 121 purports to find an interactive effect. In
their recent study of six Czechoslovakian mining
groups, Sevc et al. [S51] found smoking t o have anadditive effect. Thomas et al. [T20] have found an
effect intermediate between additive and multiplicative.
However. in an analysis of data from uranium miners
in the Colorado plateau (an area including parts of thestates of Colorado, Utah, New Mexico and Arizona,
United States), Whittemore and McMillan [W12]found strong support for an interactive relationshipbetween smoking and radiation exposure. It should be
noted that the dose estimates were uncertain and may
have been higher than in other series. This could
explain some of the difference in results [C4]. Also,

while earlier analyses of these data had not revealed
an interactive effect [C4]. the more recent study used
proportional hazards analysis, a better method thancategorical analysis because it compares risk within
the exposed cohort and is not dependent on assumptions about control group risks. Whittemore andMcMillan also demonstrated that the models fit thedata better when cumulative exposure (to both smoking
and radiation) was used, instead of average annual
exposure. The best data on this topic show that theinteraction between smoking and radon daughter
exposure is intermediate between additive and multiplicative [S51]. This was also the conclusion of the
BEIR IV Committee [C20].
469. There is clearly a radiogenic risk of lung cancer
in the absence of smoking as a co-factor. In general,the difference between the absolute risk for miners
who smoke and that for those who do not has beensmall, but the difference in the relative risk between
the two groups is great [C4. R7]. As was true in somemining studies [C4. R7]. data from the Japaneseatomic bomb survivors fit additive and multiplicativemodels almost equally well [P7, K221.
470. The time from first exposure to lung cancer hascommonly been about the same for smokers and nonsmokers [C4. R7]. implying that radiation, and notsmoking, was responsible. Even in the Colorado
miners, where an interaction was inferred, there was
no evidence for an age of onset difference [ W 121. Thisfinding disagreed with earlier analyses of these data
[W13]. which seemed to show such a difference
perhaps due t o overestimation of the exposures [C4.
R7, W121. The latency period reported for Japanese
non-smokers is longer than that for smokers. Althoughsome of this difference could also be due t o errors in
the estimation of smoking and radiation exposures.
some of it may reflect the dissimilarity between
chronic mining exposures and the single exposures inJapan. There have been large differences in the
exposure levels of the various mining cohorts. anddissimilar doses can have disparate effects (interactions
not apparent in some situations may be detectable inothers).
B.

DIET

471. Stomach cancer is very common in Japan. a n dsome dietary factors have been implicated (e.g.. thehigh-temperature cooking of meat and fish a n dpreservation methods for fish). Thus. radiation exposures in Japanese can be expected to have effects thatare related to the high level of exposure to these otherrisk factors. In a multiple regression analysis of
stomach cancer in Hiroshima and Nagasaki. lkeda
et al. examined the relative importance of various risk
factors for stomach cancer [I8]. Their study. which
had a total residual (unexplained) variance of less than
I%, showed a statistically significant association
between stomach cancer risk and age, sex. consumption of milk and consumption of broiled (but notdried o r pickled) fish. Radiation dose had a muchsmaller. non-significant effect [IS].

472. Stomach cancer in irradiated persons in
Hiroshima and Nagasaki tends to occur more often inareas of intestinal metaplasia. and the frequency of thelatter appears linearly related to dose [M15]. As noted
earlier. intestinal metaplasia in the lower third of thestomach is a characteristic precursor of gastric carcinoma in Japan, suggesting that irradiation has interacted with predisposing dietary factors. Because gastriccancer rates are dropping in Japan as diet changes, it
is imaginable that Japanese exposed to radiation at afuture time would have fewer partially transformed
cells and, hence, a lower risk of radiogenic cancer.
Radiation may induce cancer by increasing the prevalence of the precursor state as well as by furthertransforming cells already in such a state.

The risk of a subsequent cancer among patients
receiving both kinds of therapy was greater than for
those receiving only one kind, both at 12 years and(especially) at 18 years after initial diagnosis. These
differences were significant at the 5% level. although
Draper noted that since the modes of radiotherapy
may have been different for those also given chemotherapy, there could not be too much emphasis on thespecific numbers. Thus, in genetically susceptible
individuals, combined therapy adds to the risk ofcancer: the excess risk is apparently experienced both
inside and outside the radiation field. The fact that theeffect of combined therapy seemed much greater after
18 than after 12 years suggests that an even greater
effect may be revealed as more follow-up time
accumulates.

C . INTERACTION BETWEEN THERAPEUTIC
MODALITIES

476. In the data on Wilms' tumour [L3], combined
chemo- and radiotherapy was given to four of thenine radiation-associated second tumour patients.
Combined therapy did not increase the risk of cancer
relative to radiation therapy alone, when all cancers
were considered. The relative risk of chemotherapy,
among irradiated patients, was 1.02. However, if only
tumours arising in the field of irradiation wereconsidered, the relative risk of chemotherapy was
1.50, significant at the 5% level. These patients
received orthovoltage therapy.

473. The findings in patients given combined radiation and chemotherapy for cancers, especially adultcancers, were described earlier. Generally, the strongest
effects were those of chemotherapy. and some studies
found no specific radiogenic effect on solid tumoursor on acute non-lymphocytic leukaemia (ANL), only achemotherapeutic effect. Some applications of radiation have probably led to intense local irradiation andcell sterilization, which may actually weaken the
combined effect of the two types of therapy. It is notknown if either the presence of disease or the methodof applying the therapies affects the nature of any
interaction. As reviewed above, in several adult cancer
series, the relative risk of persons who had notreceived radiotherapy was greater than 1.0. which shows
how important it is to have proper reference groups
when comparing the effects of different modalities oftherapy. Even if those treated with combined therapy
show greater cancer risks, if the patients do not
represent the population at large, the inferences about
the effects of therapy, including radiation, will not be
precisely applicable to a general population of exposed
individuals. In any case. chemotherapy is commonly
part of the treatment in which radiotherapy is used, sothat the potential effects of the latter alone cannot bereadily assessed; this is particularly so in view of theconstantly changing therapeutic schedules and agents.
474. Gne of the most interesting sets of subjects inwhich to examine the effects of combined radiationand chemotherapy is the set made up of patients who
were treated for retinoblastoma. Since, as noted
earlier, about 25% of patients with this childhood
tumour have a genetic susceptibility to it and to othercancers also, this cohort provides an opportunity to
examine the effects of the different therapies both
inside and outside a well-delimited radiation field. For
patients receiving no chemotherapy, there are goodbaseline data.
475. An analysis of British retinoblastoma patientshas been reported by Draper [Dl51 (Table 43). The
small sample sizes and the fact that most patients
given chemotherapy were genetic cases limited theanalysis to those with the genetic form of the disease.
472

D. STATISTICAL REFLECTION
OF HIGH POPULATION RISKS
477. In the parallel analysis of cancer data fromankylosing spondylitics and the Japanese series, Darbyet al. [Dl I] plotted both the relative risk and the excess
risk of various cancers against the expected risk in thetwo populations. These are shown in Figure XIII.
Most of the tumours cluster in a small area on such agraph (RR< 5: risk per lo5 and year< 25). The
points for stomach cancer. which is very prevalent inJapan, and for lung cancer, which is very prevalent in
the United Kingdom, are among the few outliers on
the respective graphs. Both exhibit very low relativerisk contrasted to their population risks. It appears
that the pattern observed by Darby et al. is, with the
exceptions of leukaemia and CNS tumours, a linear
one, with the relative risk roughly between 1.5 and 3
for all epithelial sites.
478, Central nervous system (spinal cord and nerve)
tumours were much elevated, relative to their normallyrare occurrence. This is probably because these tissues
are seldom exposed to environmental mutagens (bloodCNS barrier), with almost no mix of spontaneous andradiogenic tumours in the data sets. For leukaemias, therelative risks were different in the two groups (about 3 inspondylitics and 9 in the Japanese survivors), but the
population prevalences were similar. The relative risks
for both sites (CNS and leukaemia) were different
from the relative risks for most carcinomas. The
explanation for this is not clear, but the discrepancy
highlights the difference between haematopoietic andepithelial tissues and perhaps serves as indirect evidence for the importance of environmental risk factors
in the epidemiology of radiogenic carcinomas.

E.

GENERAL CONSIDERATIONS ABOUTINTERACTIONS

479. The many factors discussed in the previous
sections indicate that there are numerous ways inwhich radiation could have. or could appear to have,an effect on the irradiated individual. Clearly, it isvery important to ensure that the expected rates withwhich the risk in irradiated subjects are compared are
representative of their population. The 1980 BEIR Ill
Report [C4] attempted to derive summary risk coefficients of the excess cancers to be expected per
10' PYGY.
480. The BEIR 111 estimates [C4] were developed byconsidering all the data available. in an effon tosynthesize the information from a variety of heterogeneous data sets. There are, however, pitfalls in suchan approach. One reflection of the uncertainties
surrounding the use of these estimates shows up in a
conlparison contained in one of the reports by theinternational group studying the risk of second cancer
in cervical cancer patients [B12, D9]. This comparison
showed a poor correspondence between the number ofexcess cancers (based on the expected number of casesin the referent populations of the eight collaborating
tumour registries) and the number of excess cancers
that was predicted by applying the BEIR 111 risk
estimates [C1] to the doses and exposure times in thecervical cancer data. The comparison is given in
Table 44. It should be remembered that the expectedcases were based on risk coefficients per lo4 PYGy
derived largely from the Japanese T65 dose estimates,
and the comparison in Table 44 is based on thecervical cancer data in [B 121.
481. The biggest difference is in the leukaemias; theauthors attribute this difference to cell sterilization in
the pelvis and hence to an overestimate of the effective
dose [B12], and which their case-control study, taking
marrow-weighted doses and cell-sterilization inroaccount, showed to be an artefact of assuming uniform
dose to all marrow (i.e., when marrow-weighting isdone, the discrepancy largely disappears [B36]. Dosefractionation may also have reduced the apparent
relative risk per unit dose relative to that found inother studies [B36]. However, the difference is toolarge to be attributed solely to that factor. In addition.
more excesses of lung cancer have been observed thanwere predicted and fewer excesses of most othercancers, notably breast, kidney and bladder. These
have plausible explanations which were reviewed
earlier (paragraphs 269-284). In general. however, it
must be emphasized that (a) cancer patients are notrepresentative of the population at large in respect ofmany risk-factor exposures; (b) risk-factor exposures
may be relevant to more than one type of cancer; and(c) radiation itself may have direct or indirect effects
on the risk of cancer in other organs. Thus, tounderstand the true risk associated with radiation may
be difficult, since good background cancer risks are
not usually available for the special subset of individuals exposed to ionizing radiation.
482. These facts stress the importance of taking
other environmental and host factors into account.

They also show that whole-population exposures may
in many ways be more informative than exposures of
selected population subsets, and that internal controls,
rather than the whole population, may be the mostappropriate comparison group. In the instance of thecervical cancer data, the appropriate comparisongroup is probably the benign gynaecologic diseasegroup (to the extent that they in fact did not receive
radiation therapy themselves). The data from Hiroshima
and Nagasaki are as close to the ideal in this regard as
any available.

VI.

SUMMARIES OF RISK ESTIMATESIN MAJOR COHORTSA.

STUDIES PROVIDING SUMMARY RISKESTIMATES

483. This chapter provides overall summaries ofradiogenic cancer effects from the most comprehensive
data sources currently available. Details from studiesof tissue-specific exposures or susceptibilities werereviewed in chapter 111. Here, results relevant to risk
estimation and projection are given.
484. There are only three sets of data from whichradiation effects can be estimated for a large variety ofsites: those for the Japanese atomic bomb survivors.
the ankylosing spondylitis patients and the cervicalcancer patients. In all three, the sample was large. theindividuals were followed for long time periods and an
essentially similar kind of exposure was received bymany parts of the body. Each set of data has its own
characteristics. The Japanese data included internal
controls, as did the cervical cancer data (i.e.. patientstreated without radiation). All the data are for shortterm. low-LET exposures. In the spondylitics and thecervical cancer patients, groups of tissues receiving
approximately the same level of dose were analysedjointly; the whole-body exposures experienced inJapan could not, of course, be included in thisanalysis. Only from Japan do we have effective
comparisons of the exposure effects in males andfemales. The Japanese cohorts also provide the mostcomprehensive data from which to estimate doseresponse patterns.
485. The most commonly used measure of the effectof exposure on a given site is the number of excess
cancer cases per 10,000 persons exposed to I Gy after
one year (10' PYGy), although some estimates countexperience only after a five-year or 10-year latency
period. The methods by which this number has been
computed were discussed in chapter 11.
486. Summary estimates of sire-specific risk coefficients are available for the Life Span Study in Japan[K7], the Nagasaki tumour registry [WS], the ankylosing
spondylitis patients [S31], the BEIR 111 Report [C4]and an older report from the ICRP [I9]. Land [ L l l ]has collated some additional data. These risk estimates
can now be revised in the light of newer dose estimatesand longer follow-up times. In this chapter. the latest
reports available are summarized.

8. PROJECTION OF RELATIVE RISKIN THE MAJOR STUDIES
1.

Results from exposure to treat cervical cancer

487. For most sites, the international study ofcervical cancer patients [B12, D9] found that the
number of excess cancer cases was smaller, except for
the lung. than would have been predicted based on:(a) the number of person-years at risk; (b) the
expected number of cases in the appropriate registry
populations; and (c) the BEIR Committee estimates[C4] of the excess number per lo4 PYGy for the samesites. This difference has already been set forth inTable 44, at which point the question was raised of
how well the irradiated subjects typified their larger
populations.

Pooled heavily irradiared sites. To summarize
the general effects of heavy irradiation such as was

488.

received to treat cervical cancer. the authors haveanalysed the joint manifestation of second primarycancers occurring in heavily irradiated sites; that is,sites close to the irradiation and likely to havereceived more than 1 Gy (stomach, small and large
intestine, liver, gallbladder, pancreas, uterine corpus.
ovary, other genital organs, kidney, bladder. bone andconnective tissue). These will be referred to as heavily
irradiated sites. In general, the pattern observed agrees
with what has been found in Japan and in theankylosing spondylitics [Dll]. The details of theseparate registries and site-by-site analysis may befound in [D9]; the results are summarized in [B12],
from which the following is taken.
The minimum latency period for the heavily
irradiated sites after cervical cancer was about 10 years:
the excess risk thereafter did not diminish for at least
30 years. Figure XV compares these exposed patients

489.

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to tlme of dlagnosls of cervlcai cancer, for patients treated wlth and wlthout radlatlon. The number of cancers areglven above the 80% confidence bars.

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40-49

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10 years of observation, for women treated with radlatlon. The number of cancers are given
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[B121

with non-exposed cervical cancer patients, who manifested no increased risk when all the heavily irradiatedsites were aggregated. Many of these women were
followed for the rest of their lives (some lived into
their nineties) and i t was seen that risk apparently
continues to remain elevated during all post-irradiation
life [B 121.
490. In terms of relative risk, women are moresensitive if irradiated under the age of 30, butthereafter age at irradiation appears to have little
effect for these pooled sites. Since the background riskof cancer at these heavily irradiated sites increases
with age, the absolute risk rises with age at exposure.
This is shown in Figure XVI. The Japanese data havetypically showed high sensitivity among those who
were young at the time of the bombings.
49 1. Individual heavily irradiared sires. These samedata have been analysed separately for each site [B 12.
D9]. Some of these findings are important enough towarrant review here. The patterns of relative risk
following exposure at some of these sites are given in
Figure XVII. Table 26 gives the most recent relativerisk values for these projection effects, pooling dataon all ages at exposure, based on a subset of thecervical cancer patients and a control group forcomparison.
492. Figure XVII shows that bladder cancer increased
gradually with time, with a relative risk of about 3.0.
The projection effect appears to be radiogenic. As
noted earlier, however, bladder cancer was among thesmoking-related sites with similar patterns in the nonirradiated; but in the non-irradiated i t decreased withtime. While it is curious that rectal, but not colon,
cancer was elevated, the projection pattern of rectal
cancer is clearly the kind of pattern to be expected forradiation-related malignancies, and i t obtained only
among irradiated patients [B 121. Endometrial cancer(corpus uteri) had a relative risk of less than 1.0; thismay be due, at least in part, to a high prevalence ofhysterectomy. The increase in the relative risk 10 years
after irradiation, with a levelling off afterwards,
suggests a radiation effect. The marked and significant
increase in "other genital cancers" refers mainly to anincrease at the vulva, vagina, and unspecified sites;
these sites probably share risk factors (e.g., HPV
susceptibility) and may not reflect a radiogenic effect;
they were at elevated risk in all groups in the study.
493. The bladder cancer projection is typical of aradiogenic epithelial cancer, except that it appeared in
the first 10 years after irradiation. Boice et al. [B12]
attributed this to mis-classified cervical metastases.
After a 15-year latent period, there was no association
between risk and age at exposure. The high level ofrisk and the increase over time suggest that more thanthe confounding effects of smoking are involved[B 121.
494. In terms of sites remote from the source of
exposure, an increase in smoking-related cancers wasfound. most dramatically in the lung. The incidence
pattern (relative risk highest five to 10 years after
irradiation and no excess cases after 20 years) is not

typical of radiogenic lung cancer. The deficit of breast
cancer is attributed to ovarian ablation by theradiation, which indirectly has a protective effect.
495. Haemaropoieric tissue. Figure XVII shows theoverall pattern of relative risk of leukaemias following
irradiation. Pelvic marrow in these women received
3-15 Gy. While there was a marked deficit in leukaemias.
relative to the BEIR 111 estimates (see Table 44). thepattern of excess leukaemias matches the pattern, withregard to projection effects, that is expected forradiogenic leukaemias (an excess beginning two to five
years after exposure and diminishing after about
20 years). The relative deficit in excess cases is attributed
to local cell killing [B36]: the dose received by the
peripheral marrow is estimated to have been < 1 Gy,
a dose which is leukaemogenic. The figure also shows
the small excess of multiple myeloma and its persistentincrease.
2.

Results from exposure to treat ankylosing
spondylitis

496, Results have recently become available thatsummarize some of the effects seen in the patients
exposed to treat ankylosing spondylitis. The analysis
presented here pertains only to the effects of single
courses of x-ray treatment [D21. S28. S311. The
expected numbers were derived from British nationalmortality statistics. Table 45 presents the relative risks
for major groups of sites as a function of time since
irradiation [D21]. In these data the relative risk forleukaemia can be seen to rise rapidly and to persist
beyond 25 years after exposure. The relative risks forthe other sites remained approximately constant for
the first 25 years after exposure, with values between
1.5 and 2.5, but then tended to disappear. Little effect,
overall, was seen in lightly irradiated sites.
497. The site-specific projection effects are given in
more detail in Table 46, also from [DZI]. The authors
found that for several sites the relative risk waselevated as early as up to two years after exposure aswell as from three to nine years after exposure. They
attributed this unexpectedly early appearance of excess
relative risk to the possibility that tumours that had
existed had been mistaken for ankylosing spondylitis.
and they suggested that the relative risk at six to eight
years' post-exposure was only slightly different from
1.0 [S31]. In their view, these data are consistent with
the Japanese and other results for solid adult tumoursin terms of the first appearance of excess risk, though
not in terms of the disappearance of excess risk after
25 years.
498. Table 47 gives the relative risk values for thesame series of patients as a function of their age at
exposure, for leukaemia and for the heavily irradiatedsites. The relative risk for leukaemia appeared to beslightly lower among those exposed at under age 25
and roughly constant afterwards. but none of thedifferences were significant. Also, the differences were
not significant for all heavily irradiated sites combined.
499. A recent study has improved the dose estimates
for the spondylitis patients [L 161. Earlier estimates, inparticular the BEIR I11 estimates, were very different
from these new values, so that summary tables of the
new values are included here for reference (Tables 48
and 49). This study was based on a sample of 934
patients (1/15 of the total series), for 903 of whomorgan dose estimates are reported in the tables.
Estimates were based on an Oak Ridge Laboratory
program [W19] that models the process based on amathematically defined human phantom. I t is clear
from the tables that there was great inter-individual
variation in dose; thus, dose-response patterns fromthe entire series of over 14.000 patients are not basedon precise individual exposure estimates. The newdose estimates are about 19% higher than priorestimates and very different from BEIR 111 [C4],although they are close to recent estimates by Drexler
and Williams [D22].

3. Joint analysis of Japanese (T65D)andankylosing spondylitis data
500. The detailed analyses of the risk effects from
Hiroshima and Nagasaki, based on the revised (DS86)
dose estimates, constitute the most important single
data set on risk effects in existence. However, toaugment the information from this and the large seriesof ankylosing spondylitis patients, Darby et al. [Dl I]
analysed the Japanese and spondylitis data jointly. A
summary of their results and of some of the basic data
are presented. However. it should be noted that (a) thedata from Japan apply to the old dosimetry (T65DR):(b) the spondylitis doses have been revised [L16]; and(c) the spondylitis risks have been revised [D21] since
this joint analysis was prepared. Therefore, the joint
analysis must be considered only rough and qualita-

AriKYLOSING 'SPONOYL,lTIS

SERIES

rive in nature, and it is to be read carefully in regard
to carcinoma risks more than 25 years after exposure.
501. With these cautions in mind. Table 40 gives
joint. summary relative and absolute risk values for
the Life Span Study [WS] and the spondylitis patients[S28]. This paper [ D l l ] provided some summary
statistics on projection effects, with regard t o a seriesof selected sites for which results between the two data
sets could be meaningfully compared.
502. In the spondylitics. absolute risk standardized
for time since exposure increased rapidly with age at
exposure: in the Life Span Study, there was lessevidence of such a trend. The result was similar for
absolute risk by time since exposure standardized forage at exposure: a trend in the spondylitics but not in
the Japanese. For the studies t o be compared more
directly, the observed Japanese risks were standardized
to the same exposure-time distributions seen in the
spondylitics, aid this produced clear trends in thedata from Japan for age at exposure and time since
exposure. The joint estimate was an absolute risk of
3 1.7 per 10' PY (SE = 8.5) for every 10-year increasein age at exposure, and the studies did not differ
significantly. In Japan, but not in the spondylitics.
there was a statistically significant (p < 0.05) trend intime since exposure. The combined analysis showedno significant difference ( p > 0.10). and the joint
estimate was an average increase in absolute risk withtime since exposure of 34.0 per 1@ PY (SE = 15.7) for
each ~ i x - ~ e timea r period. This was significant at the
5% level.
503. Relative risk results are summarized in Figure
XVIII, which shows that in the ankylosing spondylitis

L I F E SPAN STUDY SAMPLE(above 1 Gy / 0-0.09 G y )1 'Figure XVIII.

1

I

<25

$5-

I

I

35- 45- 55+

AGE AT EXPOSURE

AGE AT EXPOSUREYEARS SItdCE EXPOSUREYEARS SINCE EXPOSURE

Relatlve risk of cancer In selected sites combined In relation to ageat exposure and timesince exposure lor theankyloslng
spondylltls serles and for the Life Span Study sample (T65DR doses).
[Dl11

patients there were no trends in relative risk for age at
exposure, and only before 10 and after 22 years did
relative risk fall below its generally flat projection
pattern: there was no evidence that these two factors
interacted [Dl]]. The data from Hiroshima andNagasaki showed significant linear and quadratic
trends in relative risk with age a t exposure (declining
with increasing age), and a log-linear trend in relativerisk could be fitted to the data. The trend in relativerisk with time since exposure was roughly level, both
before and after incorporating a log-linear trend in
relative risk with age at exposure. In analysing thesejointly. Darby et al. found no trend in the relative risk
in time since exposure; for five to 30 years after
exposure, the relative risk remained about constant.
Jointly there was a significant log-linear trend in
relative risk for age at exposure, with the joint
estimate of the trend in log ( R R ) with exposure age of-0.5 (SE = 0.13).
4.

Recent results from studies of the Japanese
exposed to the atomic bombings

504. The Atomic Bomb Casualty Commission andits successor, the Radiation Effects Research Foundation. have at various times used a variety of measuresof individual exposures t o the atomic bombings ofHiroshima and Nagasaki. These included distancefrom the hypocentre [M38]; the presence o r absence ofthe symptoms associated with acute radiation illness[NlO]; and, now, no fewer than three separate physicaldosimetries, namely, the T57 [R 19, A171, (for an
application of these doses, see [IIO]), the T65 [M24],
and the new Dosimetry System 1986, or DS86 [M39.
NI1, R20]. Each successive method of expressing
doses has necessitated a re-estimation of the risk
coefficients associated with the various known effectsof ionizing radiation and a re-examination of thedose-response relationships. With these changes there
has emerged a better ability to estimate the risk
coefficients in terms of organ absorbed doses o r organdose equivalents rather than in terms of kerma.
whether free-in-air or in-house (shielded).
505. The newest system of dosimetry is an outgrowthof a series of events. In 1975, Preeg of the Los .4lamos
National Laboratory (United States) re-examined the
gamma-ray and neutron spectra from the Hiroshimaa n d Nagasaki atomic bombs using a one-dimensionalmodel and discovered that they differed considerabl!
from the spectra used in calculating the T65 doses.
Simple calculations based o n these spectra suggested
that the T65 neutron dose was markedly overestimatedfor Hiroshima. Subsequently, Loewe and hiendelsohn
at the Lawrence Livermore National Laboratory(United States) and Kerr and Pace at Oak Ridge
National Laboratory (United States) independently
calculated the air doses at Hiroshima and Nagasaki
a n d reported that both the neutron and the gamma
doses differed substantially from the T65 estimates.
These findings prompted a complete re-evaluation of
the atomic bomb radiation dosimetry (for a fuller
account of the events that preceded this reassessment,see [R20]). The reassessment, begun jointly by theGovernments of Japan and the United States, culmi-

nated in March 1986 in a consensus system known
as the Dosimetry System 1986 (DS86). The principal
differences between this system and the T65 dosimetry.
the heretofore most commonly used system (seeTable 50), are as follows [R20]:(a) the yield of the Hiroshima weapon is now
presumed to have been approximately 20% greaterthan had earlier been thought; that is, I5 rather
than 12.5 kilotons:(b) although the free-in-air (FIA) gamma doses are
somewhat greater at distances of 1.4 km o r more
in Hiroshima, neutron exposures are less in bothcities. and substantially so in Hiroshima, about
10% of their previously estimated value (30% in
Nagasaki). Since delayed radiation from thefireball makes a relatively greater contribution to
the total DS86 dose. the loss or gain of shielding
as a result of the blast effect, particularly in thefirst several seconds following the detonation of abomb, could substantially influence kerma inshielded areas and, ultimately, organ absorbed
dose. Time-dose dependencies have not. however,been taken into account either in this new system of
dosimetry or the old;(c) attenuation of the FIA gamma kerma by wooden
Japanese structures, houses and tenements isapproximately twice as great under the DS86 thanunder the T65 dosimetry (the average transmission
factors under the two systems are 0.90 (T65)
versus 0.46 (DS86) in Hiroshima and 0.80 versus
0.48 in Nagasaki). However, attenuation of theneutron kerma by such structures differs muchless strikingly (the average transmission factors
are 0.36 (T65) versus 0.31 (DS86) in Hiroshima
and 0.41 versus 0.35 in Nagasaki);(d) transmission of gamma rays through tissue issignificantly higher, at least for the deeply situatedorgans. than had previously been estimated [K 141.
I t must be borne in mind, however, that in the
T65 system each specific organ transmission
factor is a constant averaged over all postures.
orientations and ages; tvhereas in the DS86system,
fixed values are not used for the proximally o r"heavily" exposed (defined as those survivors
within 1.600 m in Hiroshima and 2,000 m in
Nagasaki), where detailed exposure histories are
generally available, Their organ doses reflect
the circumstances of their individual exposures.
including posture, orientation and age at the timeof the bombing. The increased tissue transmission
for most organs tends t o offset, wholly o r largely,
the changes in the shielding transnlission factors;(e) finally, for some 18% or so of the exposed
niembers of the Life Span Study cohort (largely
individuals suryiving in concrete buildings o r
factories), doses cannot as yet be computed, a n d
the new dosimetry improves but does not clarify
all of the implausibly high exposures seen with
the T65 system. There remain a number ofsurvivors whose estimated whole-body shieldedkerma exposures exceed 4 Gy or, in some cases,
6 Gy. These are doses at o r above the recently
estimated LD95 in these cities [F13]; given thevirtual obliteration of the immune system atdoses in excess of 7 or 8 Gy, survival under thecircumstances that obtained in these cities would
be most unlikely. Better means are neededto address these incongruities than the simple
truncation of dose, since their inclusion in analyses
can affect the shape of the dose-response relationship as well as estimates of its parameters [G13,G 18, 561.
506. As previously seen with the T65 doses, astatistically significant increase in the frequency ofdeaths with increasing dose is observed for leukaemia,
cancers of the oesophagus. stomach. colon, lung, breast,
ovary and urinary bladder and multiple myeloma. No
significant increase is as yet observed for cancers of
the gallbladder, pancreas, uterus and prostate o r for
malignant lymphoma. The most recent report was
extended to include other sites of cancer. such as
bone, pharynx, nose and larynx, and skin except
melanoma. but none of these sites showed a significant
dose-response relationship [S49]; however. mortality
from tumours of the central nervous system other thanthe brain tends to increase with dose (0.10 > p > 0.05)(mortality from brain tumours alone does not).
507. While the excess in leukaemia mortality has
declined with time, it none the less remained significantly elevated as late as 1981-1985, showing that theperiod of risk is at least 40 years rather than thecommonly supposed 25. For cancers other than
leukaemia, excess deaths continue to increase withtime in proportion to the natural cancer rate for theattained age. and the relative risk remains unchanged
over time for all specific age cohorts except the
youngest, i.e., 0-9 years at the time of the bombings.
For the latter cohort, unlike the older ones, the timefrom exposure to death is shortened with increasing
dose for all cancers except leukaemia, and the relativerisk decreases with time (Tables 5 1 and 52).
508. Tables 51 and 52 show the time course of excess
risk in the DS86 subcohort data as a function of age
at and time since exposure, for relative and absolute
excess risk, in 10-year groups. The relative risk at
1 Gy changes significantly with time after exposure.
The magnitude of this change is known only over alimited time period (about 40 years) since exposure.
509. Tables 53 and 54 give three summar) measuresof risk, namely, the excess relative risk at 1 Gy, excess
deaths per lo4 PYGy and the attributable risk. for all
malignant neoplasms, leukaemia, all cancers except
leukaemia, and eight specific sites of solld tumours
based on the T65 and DS86 systems. These risks were
derived by fitting a linear dose-response model to thedata from both cities, both sexes and all ages at
exposure within that subset of individuals in the Life
Span Study sample for whom both T65 and DS86
doses are presently available (some 82% of all exposed
individuals in the sample). Nore that in so far as
shielded kerma is concerned (Table 53), under the
DS86 system. the excess relative risks are increased
from 35% (stomach cancer) to as much as 53%(cancer of the ovary and other uterine adnexa). For
excess deaths, the corresponding figures are 31%(multiple myeloma) and 61% (cancer of the ovary andother uterine adnexa). However, for no site o r groupof sites does the attributable risk change as much as

10%. For organ absorbed dose (Table 54). with the
exceptions of cancer of the female breast or the ovaryand other uterine adnexa, the risks are invariably
lower with the DS86 doses and as much as 30% lower
in the case of cancers of the stomach (excess relativerisk).
5 10. Over the range of doses from 0 to 6 Gy, there is noclearly significant evidence of non-linearity (althoughother forms of response fit the data), so from a purely
statistical point of view linear risk estimates are areasonable summary of the dose-response. Moreover,when linear. quadratic. and linear-quadratic models(with o r without provision for cell-killing) are fitted tothe data on all cancers except leukaemia and on those
five sites where a clear dose-response curve had
previously been obtained (i.e., leukaemia, and cancersof the stomach. colon, lung and female breast). a
simple linear model fits the data on leukaemia,
cancers of the stomach, lung and female breast, a n d
all cancers except leukaemia better than the quadraticmodel and as well as the linear-quadratic model. as
judged by the deviance (that is, twice the difference inthe log likelihoods under the full model, which exactly
fits the data, and under the model based o n theparameters that have been estimated). Inclusion ofcell-killing does not significantly improve the fit,
except in one instance where leukaemia mortality
under either the linear or linear-quadratic model fits
somewhat better with a cell-killing term. These findings
hold true both for organ absorbed doses and shieldedkerma.
511. Under the DS86 system. the neutron doses.
although not wholly negligible, are so small thatmeaningful estimation of the neutron RBE is difficult,if not impossible. Reasonable RBE estimates cannot
be derived directly through maximum likelihood
estimation: however, some insight is possible if it isassumed that the small inter-city differences that stillobtain reflect differences in neutron exposures. With
the DS86 organ doses. assuming an equality of excess
relative risk between Hiroshima and Nagasaki, theneutron RBE for ieukaemia is 20-30; for all cancers
except leukaemia, 30 or more; and for cancers of thestomach, lung and female breast, less than 1. Based o n
an equality of excess deaths between the cities. theneutron RBE for leukaemia or all cancers except
leukaemia is 30 or more; for lung cancer. 10-20; andfor cancers of the stomach and female breast, less than
1. The disparity between these estimates attests further
to the difficulty of deriving meaningful estimates of
the RBE with the new dose estimates for the survivors.
512. The differences between the cities are smaller
under the new system than under the old for all sites ofcancer, including leukaemia. and are no longer statistically significant. However, at face value, mortality in
Hiroshima remains higher at most doses than in
Nagasaki, for leukaemia as well as all cancers except
leukaemia. This fact. when coupled with a similar
consistent tendency for other indices of radiation
damage (such as the frequency of chromosomal
aberrations, lens opacities. and epilation), suggeststhat some explanation for the small inter-city difference
in dose response is still necessary.

C.

UNCERTAINTIES ASSOCIATED
WITH RISK ESTIMATES

513. Even after many decades of study. the uncertainties that surround estimates of the carcinogenic
effects of radiation are many and fundamental.
Indeed, there is still no model of the underlying
process that is clearly the correct one. The importanceof a good theoretical model is greatest where the data
are weakest, at low doses of low-LET radiation, sothat our ability to estimate these risks is severely
limited.
514. Because the majority of all cancers appear tohave an environmental origin in the sense thatavoidable exposure to environmental risk factors is
involved [D13], much of this Annex has dealt with the
problems in risk evaluation caused by the existence ofmultiple risk factors. In addition to environmental
risk factors, there are also many host factors, such as
genes. age, hormonal status, sex and the like. that
affect risk.
5 15. It is probable that in any population exposed toionizing radiation there is variation in the exposure toother risk factors. At low levels of radiation. thisvariation may be greater, perhaps much greater, than
the risk produced by the radiation itself. It is not
surprising that it is difficult to estimate risk at low
doses or that different results are often obtained. The
methods used to estimate confidence intervals tacitly
assume that all exposed individuals in a given category(e.g., age. sex or dose) have equal risk. which seems
unlikely to be true.
516. The most important documented other risk
factor is smoking. Another source of bias is the"healthy worker effect": in occupational cohorts,
workers are often healthier than the general population so that their baseline cancer rates may differ fromthe rates of the larger population, complicating the
problem of determining the expected number of casesin these cohorts unless control groups from within thecohort are used.
517. The twentieth century has been a period of
rapid change in levels of exposure to cancer-causing
agents in all populations in which radiation exposure
data are available. This is reflected in changing cancer
rates within populations over time. All of the major
cohorts used in radiation biology to estimate cancer
risks have experienced changing exposure levels, though
it has not been possible to account for this well in any
study. Estimates of risk derived from cohorts thathave been followed for the past half-century to thepresent will have inexact application to cohorts
exposed now or in the future, and the degree of theinexactness is not known.
5 18. There is substantial variation in general mortality
rates in different countries. Exposed individuals may
be expected to experience somewhat different lifetime
risks in a developing country as compared with anindustrialized one. However, much of this differencein overall mortality occurs during childhood andwould have little effect. Also, cancer rates for mostsites are lower in developing countries, so that theabsolute excess, and perhaps even the relative risks forthe same dose, may be different. Most large population exposures studied to date have occurred inindustrialized nations; there are few data and perhaps
less exposure in the developing countries.
519. In addition to changing baseline cancer risks
and the effects of other exposures, there is uncertainty
over the dose-response pattern. Most current studies
use a linear model for breast and thyroid cancer and alinear-quadratic model for other sites; these are thebest-available models only, for the data do not reallypermit the validation of a specific model with confidence. It is unfortunately true that most estimates of
low-LET. low-dose effects are based on extrapolations
from high-dose data.

D.

UNCERTAINTIES ASSOCIATED
WITH RISK PROJECTIONS

520. The many uncertainties involved in the estimation of risk from observations on exposed cohorts
have been reviewed in this Annex. The main limitations may be stated as follows: (a) no single large
cohort has as yet been followed throughout its entire
lifetime, so that the lifetime effects of exposure cannot
be empirically determined; (b) the data that areavailable are most incomplete for those who wereyoung at exposure: these individuals have not reachedan advanced enough age for the bulk of their risk to
be expressed, yet their lifetime risks may be thegreatest; and (c) there are not now, and for theforeseeable future will not be, sufficient data on low
doses to allow useful risk estimation.
521. In the face of these limitations. there areformidable problems in determining what modcl(s) to
use in projecting risk forward into the unobserved
future lifetimes of potential cohorts. Once the current
cohorts have been completely observed. risk projection will have a sounder empirical basis.
522. The work of Muirhead and Darby [M36, M371,
cited earlier, as well as models applied by the Radiation Effects Research Foundation (RERF) [S49], shows
clearly that, depending on what covariates are considered and on how their effects are modelled, one canobtain strikingly comparable degrees of fit even to thebest available data on the major exposed cohorts. In
the Muirhead and Darby models, the parameter y
expressed, at values of 0 and 1, the 'pure' multiplicative and additive projection effects; however, themost likely value of this parameter was sometimes
statistically indistinguishable from either of thesemodels under certain combinations of covariates.
With an intermediate value of y, the intuitive biological meaning of the model becomes unclear, andthe model is probably best thought of as an empiricalone only. Given this, it is clear, as noted in Muirhead
and Darby [M37] that a variety of models could beconstructed with approximately equivalent goodnessof-fit.

523. Although the goodness-of-fit of several projection models to the empirical data may be comparable,their projected lifetime risks may not be as close.
Being, therefore. currently unable to make lifetime
projections with much confidence. alternative models
have to be presented, which, hopefully, bracket thetrue risks. Even so, there is no way of specifying
quantitati\,ely the degree of uncertainty in thesealternatives.
524. Until very recently. it had appeared fromexperimental animal data and empirical data on
humans that the relative risk projection model was themore appropriate of the two models for most solid
carcinomas. However. if the excess risk of thesetumours eventually declines with advancing time since
exposure. as some data now suggest, then neither
simple additive nor simple multiplicative projection
effects will pertain, and none of the models, evenhybrid models such as those of Muirhead and Darby.
which describe the effects of time since exposure in amonotonic way, will be applicable.
525. These are fundamental problems, for i t does not
currently appear possible to discriminate among thevarious projection models based on their fit toempirical data. The only practicable solution to thisproblem may be to wait until the experience of theJapanese, the spondylitics and the other cohorts ismore fully expressed than at present and t o derive
empirical projection models. Even so. changes inbaseline risks, as well as confounding cancer risk
factors. may make such projections inaccurate for
future cohort experiences.

VII.
A.

RISK PROJECTIONSGENERAL CONSIDERATIONS

526. In chapter I1 of this Annex. the various
concepts related to risk projection, the kinds of datarequired, and past efforts to estimate lifetime risk
from exposure to ionizing radiation were discussed. In
this chapter. the most appropriate existing data will be
used to compute estimates of lifetime risk for thosecancer sites for which sufficient information exists tomake meaningful projections. The purpose is t o derive
approximate estimates of the risk of exposure t o lowLET radiation, taking into account sex, age at
exposure and time since exposure for the lifetime of an
entire exposed population.
527. Radiation-induced mortality in a population
may be represented in a number of ways, mostcommonly as either the expected lifetime number ofexcess cancer deaths in the exposed population o r thenumber of person-years of life lost because of cancer
deaths, both per unit collective dose. Estimation ofthese expressions of risk remains formidable. as does ameaningful synthesis of the estimates that are alreadyavailable. The task is complicated by one o r more of thefollowing main difficulties: (a) the unique nature ofsome of the samples from which risk coefficients havebeen derived; (b) the differences between studies insample sizes and in the periods of follow-up; (c) the
methods ofcase ascertainment that have been employed;(d) the poor knowledge of the doses received and theirdistribution over sites; and (e) the nature of thecomparison groups used.
1.

Whole-body risk coefficients

528. Some of the numerous studies described elsewhere in this Annex, although important in their own
right. are of limited value for projection purposes;
they provide the relative frequency of occurrence ofcancer in an exposed group. as contrasted with a nonexposed referent one. but often at only one of themany sites of interest. a n d the dosimetric uncertainties
make estimates of the risk of cancer per unit dose
difficult. Commonly. doses in these particular cohorts
have been concentrated in one part of the informative
range for estimating dose-response patterns, making it
difficult to estimate effects at low or intermediate
doses. Three studies, namely, those of the ankylosing
spondylitis patients [Dl 1, D211, the women treatedwith radiotherapy for cervical cancers [B12] and thesurvivors of the atomic bombings of Hiroshima andNagasaki [S48. S49J. have been the bases for estimating
the frequency of occurrence of cancer. per unit dose,at multiple sites of malignancy. But. even here,
however. derivation of a combined risk coefficient isdifficult and has not been attempted.
529. While these three studies agree generally in
identifying the sites at which the frequency of cancer iselevated following exposure to ionizing radiation. thestudy-specific estimates of the excess relative risk forspecific malignancies per unit dose, based on theinformation currently published vary. particularly
in so far as the cervical cancer series is concerned.
There are numerous reasons why this should be so.
but especially pertinent are the conditions of exposure,the nature of the dose data presently a\failable,
differences in the age or sex distribution of the
exposed individuals in the study sanlples, the dissimilar
periods of follow-up, and the background rates used
to compute the expected number of cases. Table 55
summarizes the main characteristics of these threestudies and illustrates the differences between them in
the respects just enumerated. These points werereviewed in chapters I11 and IV.
530. Exposure of the patients with cer\,ical disorders
or ankylosing spondylitis occurred because of illness;this was not the case among the Japanese survivors.
The reasons why these patients may not be representative of the general population were discussed inchapter IV. In the two patient series, exposure was toeither x rays or gamma rays. whereas the atomic
bomb sur\~ivorsreceived a mixed dose of gamma rays
and neutrons. albeit primarily the former. The Japanesesample alonc includes a full representation of sexes
and ages; the other tulo studies are restricted either
wholly or largely to one sex. and they d o not include asufficient number of individuals beloit the age of 25 at
the time of exposure, when the excess relative risk
appears to be larger, to provide an estimate applicable
to a general population. Individual estimates of doseare not available for all (or even the majority) of thepatients with cervical disorders or ankylosing spondyl-

itis. Risk coefficients have been derived from themean dose among a 7% random sample of thespondylitis patients, and dose-response estimates. basedon the individual doses received by the cervical cancer
patients in that series, encompass only a subset of thepatients. However. mean doses are often poor descriptors of the dose distribution, notably among cancer
patients, because of the highly skewed nature of theindividual doses and their wide range. As t o theperiods of follow-up, the maximum length of followu p of the first sample members is similar in the threestudies, but since enrolment proceeded over a longer
period of time in the two patient series, the mean
years of surveillance for them is substantially shorter
than for the atomic bomb survivors. In terms ofsample size. the atomic bomb survivors and thecervical cancer series are approximately equivalent.
but the number of the person-years at risk in the study
on the atomic bomb survivors is much larger. In thecervical cancer and spondylitis series, unlike theatomic bomb survivors, the variation in doses among
exposed organs is very different, because the treatment
was concentrated on one part of the body. This makes
whole-body equivalent dose estimation difficult. There
have also been marked changes in the nature of x-ray
equipment and in therapeutic methods. Finally, there
are differences in the nature of the referent groups in
the three studies: these were thoroughly discussed
earlier in this ,Annex (see chapters I and Ill). A
summary of the excess relative risks per gray obtainedin these three studies is provided in Table 56.
531. A special feature of the atomic bomb survivors
is that they received esposure from low-LET radiationand from neutrons simultaneously. I t is important
therefore to consider how the projections to follow
would be affected by the assignment of either a fixedo r a dose-variable RBE for neutrons, relative togamma rays. Figure XIX provides. in graphical form,
the change in the estimated number of excess deaths

A 1 1 except leuhaenla
Organ dose
Shielded kerma
Leukaemi aOrgan dose0 Shielded kerma

RELATIVE BIOLOGICAL EFFECTIVENESS (RBE)

Figure XIX. Changes in rlsk coetllcients lor varying values of
the RBE of neutrons, reiatlve to gamma rays, based onJapanese DS86 data.
[S481

with fixed values of RBE varying from I to 20. I t will
be noted that the risk coefficients for both leukaemia
and all cancers other than leukaemia become smaller
as the assigned RBE increases. Over the range of 1 to
20. the risk estimates based on shielded kerma
diminish by about 54-72%; however, the estimates
based on organ dose equivalent diminish by only
15-20%, reflecting the higher transmission values
associated with gamma- and neutron-radiation under
the DS86 system of dosimetry. Elsewhere, Shimizu etal. [S48] have shown that the use of a variable RBE,
one changing as a multiple of the inverse of the squareroot of the neutron dose, would have an approximately
equivalent effect on the projections. Thus, for example,
the estimate of the excess deaths from leukaemia,
using an RBE equal to 1 / 1 D,., where D, is theneutron dose in gray, is 2.93; whereas that based onan RBE equal to 2 0 / 1 6 is 2.47. Similar changes
occur for excess deaths attributable to cancers otherthan leukaemia: the risk coefficient changes from10.08 to 8.86 excess deaths per lo4 PYGy. or slightly
less than 20%.
2.

Site-specific risk coefficients

532. In addition to the three studies that involved(albeit under different conditions of exposure) thesimultaneous irradiation of many tissues in the bodyand from which risk estimates could be extracted a n dtheir relationships analysed, there are a large numberof other studies in tvhich single tissues were exposed t oradiation for a variety o f purposes and from whichrisk estimates 10 individual tissues have been derived.
as reviewed in detail in chapter 111. The risk coefficients resulting from these studies are summarized inthis section.
533. Since the UNSCEAR 1977 Report [U?],in whichradiation carcinogenesis in humans was last reviewed.
several organizations have estimated summary risk
coefficients (absolute or relative) for a variety ofmajor organ sites. These include studies by BEIR 111[C4] in 1980 and by the United States Nuclear
Regulatory Commission in 1985 [GI I]. and theUnited States National Institutes of Health. also in
1985, in the radioepidemiological tables [U3]. Theirreports attempted t o combine the literature available
at the time. The BEIR 111 Report synthesized individual
studies along with the most recent Japanese data thenavailable: Gilbert [G 1 1 1 and the radioepidemiologicaltables relied heavily on BEIR 111, modifying theirestimates according to a few other reports but mainly
basing them on the then-latest data from the patientstreated for ankylosing spondylitis and the atomic
bomb survivors. Each of these studies, to which thereader is referred, discussed the reasoning behind its
respective site-specific coefficients. For comparison
purposes only (because the information on which they
are based is now out of date), the summary risk
coefficients for each study are given in Tables 4 and 8[C4, G I I].
534. Because these studies appeared in the period
1980-1985, they could not include the results of thelatest data and dose revisions in Japan [R20, S49] a n d

in the spondylitis series [D21, L161, nor could they
include the recently published risk coefficients fromthe cervical cancer series [B36, B38]. Site-specific risk
information from the most recent studies is given here
in Tables 26, 46, 51, 52, 53 and 54. These tables
provide the current estimates of risk from the threelargest studies based on age a t exposure, time since
exposure and sex. The scientific details of these studies
were discussed earlier, along with the limitations andspecific characteristics of each study population.
535. Chapter 111 of this Annex reviewed many otherstudies in which site-specific risk coefficients were
estimated. While they vary greatly in their particulars,e.g.. sample size and the like, it is worth summarizing
the risk coefficients from these studies. For each site.
reference will be made to the tables and figures,
discussed in chapter 111, that provided the best datao n risks. Also. the principal bibliographic references
for each site will be given. as will be the general rangeof risk estimates from other studies not alreadyincluded. Note that the estimates in the following
summary that are derived from the Japanese or
spondylitics are based on the old dosimetry and do
not include the most recent data reports (these values
are given in Table 561.
536. Leukaetnia. While many studies of different
types of exposure have found an excess of leukaemia.
the best risk coefficients come from the spondylitis
patients [D21. L16, S311. the Japanese data [S48,S491, and, very recently, from the marrow-weighted
study of cervical cancer patients [B36]. These individuals received exposures to external IOU-LETradiation.
The risk coefficients are included in Table 56. Someother dose-response data, from gynaecologic patients,
were summarized in Table 31. The BEIR I I1 Conlnlittee
estimated the absolute risk coefficient for briefexposurein childhood to be about 0.01-2.2 excess cases per
IOJ PYGy [C3; see Tables V- 17 and Cr- 181. and Ron
and Modan [Rl] estimated absolute risk to be 0.60 maleand 0.87 female cases for the same unit of exposure.
although this difference was not statisticall! significant.
537. ,Mulriple tt~j.eloma.Risk coefficients for multiple
myeloma are summarized in Table 32. The mostimportant reference for these data is [CIO]. A recent
estimate from Japan gives 0.48 incident cases per
1 0 V Y G y bone marrow dose [Hj. 121; however. thelatter estimate is based on the T65 dosimetry.
538. Bone. Table 33 provides a s u m m a 9 of risk
coefficients for bone cancer based on an analysis by
BEIR 111 [C4]. Figure VIII presents dose-response
data. Other estimates for gamma-emitting radionuclides are 2.4 excess cases per lo4 PYpCi for long-halflife isotopes (absolute): 1.8 (children) and I (adults)
for short-half-life isotopes: and for alpha-emitting
radionuclides (absolute) 200 per IO' P1'Gy [TI I].
There are many cases of bone cancer in exposedchildren, but dose-response estimates are unreliable
relative to a general population since most of thechildren, exposed during treatment of retinoblastoma,
are genetically susceptible to osteosarcoma even in theabsence of irradiation (see section 1II.B).

539. Breasr. There are no data on breast cancer inmales. Tables 36, 37 and 38 summarize the details ofrisk coefficients from a variety of studies. For adultexposures, the range of absolute risk coefficients is3-10 per loS PYGy, and that of relative risk coefficientsis 2-5. For juvenile exposures the data are less reliable,
but absolute risk coefficients are 3-8 per lo4 PYGy
[B6. T6] and the excess relative risk a t 1 Gy, based ondeath certificates, is about 0.69 in the most recent
T65D data from Japan [P15].
540. Thj~roid.Thyroid cancer risks (incidence) aresummarized in Tables 20. 21, 22 and 39 and in Figure
I. Other estimates are 1-4 per lo4 PYGy [C4. 231 foradults and 1.5-9.5 for children [S13, S381. as judged bya variety of studies, including those of exposure to
fallout. A major recent report discusses thyroid cancer
induction in detail [NS]. There is about a 3:1 sex ratioof cases, with females predominating. and it has been
estimated that only about 10% of all cases become
fatal: many benign tumours also arise. The latency
period for fatal cancers appears, however, to be very
long (even up to 40 years or more). so that the current
data may still be incomplete.
541. Skin. Satisfactory summary risk estimates forskin cancer incidence do not exist. The BEIR 111
estimates (see [C4], Table A-32) of between 0.44 and1.02 cases per lo4 PYGy, based on scalp and thymus
irradiation. are not consistent with the chest fluoroscopy
data. In uranium miners, Sevc [S5 I] has estimated one
excess case of basal cell carcinoma of the skin per
IOS PYSv. Information is not yet available from.lapan.
542. Lut1.q. Other than the Japanese and spondylitis
patients, the best data on lung cancer are derived fromindividuals who inhale alpha-emitting radionuclides.
Alost data come from males, except in Japan. and theoccurrence of this cancer is seriously affected bysmoking interactions; there is as yet no consensus onwhether the effects of smoking are more additive innature o r more multiplicative. Thomas and McNeill's[TI 1. T20] summary of these risks is provided inTable 10. These absolute risk coefficients are in unitsof million person-years per working level month(WLM); as discussed earlier, an approximate factor
for converting from cases per lo6 PY WLM to cases
per 104 PYGy is 1.67 (with 1 WLM corresponding to
6 mGy absorbed dose in the bronchial tree). The
absolute estimates range between 5 and 50 cases per
10' PYGy. As noted in chapter 111. even when they arebased on the same data, the estimates do not always
agree. and they must be treated as uncertain. Mostestimates of relative risk from brief external exposures
to doses of less than 10 Gy are 1.2-2.0. Full treatmentsof risks to the lung will be found in [C20. 11 I].
543. Digestive system. The estimates presented fromJapan and the spondylitis patients (see Table 56)
constitute the best information available on mostdigestive system cancers. As previously discussed, thedata from the spondylitis patients are not reliable inregard to colo-rectal cancer because of their highspontaneous rates of colo-rectal disease, and theresults from studies of pelvic irradiation to treat
gynaecological disorders are inconsistent and appear

to be affected by cell sterilization and other biologicalor environmental effects. Most liver cancer data comefrom internal emitters, particularly the Thorotrast
patients. The Japanese and the spondylitis patientsshow uncertain results. and neither the studies bythemselves nor their joint analysis has found an excess
sufficient to derive useful risk coefficients (the BEIR 111
best estimate is given in Table 4). The liver is a site of
frequent metastasis, and risk estimates may confoundprimary and secondary hepatic cancers.
544. Salivary glands. Detailed risk coefficients forsalivary gland cancers, based on results of manystudies. are given in Table 42. These were derived byLand [Ll I] in a summary analysis of this site. Landestimated the best overall absolute risk coefficient forthis site to be 0.26 10.06 cases per lo4 PYGy. A recent
estinlate from Japan, based on T65 dosimetry, is0.056 f 0.036 per lo4 PYGy 104. TlS].
545. As has been noted, the inter-srudy spread ofvalues observed for single tissues is large, sometimes
very large, presumably owing to the differences
mentioned in paragraph 527. There is no fully
satisfactory way to make suitable allowance for thesedifferences in generating a combined estimate. Thus.
there are only two options: either to combine the data
without regard to the important differences enumerated
above, a step that does not appear defensible; or to selectthe best possible set of estiniates from among the various
studies. Therefore, the Committee compares in thesection to follow the data from the atomic bomb
survivors, the ankylosing spondylitis series and theseries of patients irradiated for cervical cancer.

547. In addition to excess cases per 1.000 persons
exposed to 1 Gy, estimates will be provided of lost life
expectancy in person-years per 1,000 persons.

1.

The basic projection model

548. The lifetin~erisk coefficients estimated in thischap~er have been computed using an interactive.
parametric demographic projection model developedby the Centre d'Etude sur I'Evaluation de la Protection dans le Domaine NuclCaire (CEPN, France) in1985. I t eniploys classical double-decrement life-table
techniques and is not dependent on the data norass~~mptions
used in the present calculations. The
model is sufficiently general to permit a wide rangc of
choice of demographic, epidemiological and biological
data or assumptions. Several kinds of computations
can be made. including: ( a ) the effect of a single
exposure on a cohort of a given age and sex. and(b) the effect of a single exposure to a given populationof mixed ages and sexes.
2.

Analytical expression of the model

549. The analytical formulation for calculating lifetime risk is the following: at age a and for a dose D,
the absolute excess mortality rate V(a,D) is considered.
If an exposure at age a, is assumed, the corresponding
lifetime risk U(a,,D) is
1 on
U(a,,D) = V(a.D)[N(a.D)/N(%)ldaa,

B.

SUMMARY O F RlSK PROJECTIONMETHODS AND RlSK ESTIMATES

546. The projections by the Committee will consider
the induction of leukacmia and other cancers separately.
drawing from the atomic bomb survivors and theankylosing spondylitis and cervical cancer patients.
Estimates are computed at 1 Gy of high dose rate
exposure based on a linear dose-response model in thecase of solid cancer. Data on leukaemia in the
spondylitis and cervical cancer series take account ofcell killing. The Committee has adjusted for this fact
in the estimate it used to project the lifetime risk
among the spondylitis patients, but could not d o so inthe case of the cervical cancer series. Separate estimates
are computed from an additive projection model anda mul~iplicativeprojection model. using the life-table
methods and minimum latency periods described
below. These methods are similar in concept to thoseused by the BEIR 111 Committee [C4] and by the
Nuclear Regulatory Commission of the United States[GI I]. although the details differ, largely to accommodate new data. I t has generally been presumed thatthe additive and multiplicative models encompass therange of reasonable projections; however, Muirhead
and Darby [M36, M37] have questioned whether thisis true. As was seen in chapter 11, they contend that i t
is difficult, given current data, statistical methods andbiological theory, to choose between the additive andmultiplicative models, or to determine some intermediate ones.

where N(a,D)/N(a,) is the probability of survival toage a for an individual alive at age a,. taking into
account the risk of mortality both from radiationinduced cancer, and from all other causes.
550. To compute this lifetime risk. the studies onirradiated populations provide the following risk
coefficients: (a) the absolute excess mortality rate.
I(D), and (b) the excess relative risk per Gy, that isK(D).
551. The following two expressions for V(a,D) areassociated with the additive (absolute) and multiplicative (relative) projection models, respectively:

where C(a) is the baseline cancer mortality rate in the
population for the sites under consideration.
552. Thus. the lifetime risk estimates can be expressed
as follows:
Additive risk projecrion trlodela,+ I.+ P

U,(a,.D) = I(D)

/ EN(a,D)/N(a,)lda

4.4 L

Mulriplicative risk projecrion model
a,,+ L+ P

U,,,(a,,D) = K(D)

( C(a)[N(a.D)/N(%)lda++I-where L is the minimum latency time and P theplateau period (i.e., the period of time following
exposure during which manifestation occurs, and overwhich the risk is presumed to be constant). It should
be noted that this method of estimating lifetime risks
is essentially the same as that employed in the BEIR 111
Report [C4] and in the NUREG Report [GI]. Analternative approach would be t o calculate separately
the total number of cancers occurring in a lifetime ina n exposed and a non-exposed population, and to
take as the excess number of cancers the difference
between these totals. The latter method would resultin a smaller number of excess cases, for it excludes
from the excess that fraction of cases which would
have developed cancer for non-radiation related reasons
at a later date.
3.

Calculation of the loss of life expectancy

553. Using the same notation as in paragraph 549,
the life expectancy at age a, (i.e.. the average survival
time for individuals alive at age a,)) is given by
IW

If this is computed both assuming no radiation
exposure and assuming exposure at dose D, the difference between the two quantities is the loss of life
expectancy due to exposure.

4.

Demographic and background epidemiological datarequired554. The characteristics that must be known for the
population under study are the following: age and sex
structure, overall mortality rate and cancer mortality
rate by site. Since the model uses a year as the timescale of interest, annual values are obtained by linear
interpolation from the published information (whichis generally presented in age intervals of 5 o r 10 years).
The survival rates are computed from current mortality
rates and the projections assume that these will notchange in the future.

5. The computational process
5 5 5 . The principle of the model is to compute, by adiscrete time analog of the basic demographic equation, for every year, i, the numbers of alternative
outcomes possible for survivors through the previous
year. i - 1. (that is, the numbers of fatal cancers at
each site under observation, of deaths related to allother causes and of survivors to the next year). The
first value is calculated and serves to increment the
cumulated number of cancer cases already computedfor the previous years and then to modify the baseline
life-table. This calculation is limited to the assumed
period of expression of excess cancer risk after the
exposure. This period depends on the site o r tissue
under consideration: the minimum latency period has
been taken to be 2 years for leukaemia and 10 years
for all solid cancers. The plateau durations are

assumed to be 40 years and lifetime for all cancers
except leukaemia and 40 years for leukaemia. The
number of survivors a t age i + 1, N(i + I), is equal to
the number of survivors at age i. N(i), minus thenumber of those who die from baseline mortality,
minus the number of those who die from radiation
exposure.
6.

Reference population

556. The reference populations considered here as
the bases for the lifetime projections are the current
general Japanese population for the atomic bomb
survivors, the current adult male population of theUnited Kingdom for the spondylitis patients and thecurrent adult female population in the United Kingdom
for the cervical cancer series. The first two populations
were selected since the studies were carried out inthese two countries, The adult female popula~ionof
the United Kingdom has been assumed to be representative of the other populations among which thecervical cancer study was conducted. The validity of
extrapolation t o other populations will be consideredlater.
7.

Risk coefficients

557. The excess risk coefficients for the atomic bomb
survivors are those based on the DS86 subcohort, asgiven in Table 54. These coefficients were derived by
the authors [S48, S49] on a linear relative risk model,using organ absorbed doses from the explosions, andare restricted to mortality. The RBE of neutrons was
assumed t o be 1 in their estimation procedure. The
coefficients represent mean values for both cities. both
sexes (except for the breast and ovary), and all ages at
the time of the bombings combined. The sites ofcancer that have been selected for risk projection are[hose for which a statistically significantly increased
mortality with increasing dose has been shown;namely. the bladder, breast, colon, leukaemia, multiple
myeloma. oesophagus, ovary and stomach. Thyroid,
lung and bone will be discussed later. For the
spondylitis and cervical cancer series. the risk coefficients are given in Table 56. It is important to note,
first, that in all three instances the risk coefficientsthat are used have been obtained from publishedreports and d o not take into account the underreporlingof cancer deaths on death certificates. BEIR 111 [C4],in its projections, increased these coefficients by 23%
to take account of underreporting. A comparable
action here would increase the Committee's projections of excess lifetime mortality by 20-25%. Second,and specifically with respect to the risk coefficients
derived from the atomic bomb survivors, there is alevelling off, or a plateauing of the risk at shieldedkerma of approximately 4 Gy and higher, and thus a
linear relative risk model fitted to the full array ofobserved doses may underestimate the risk at doses
below 4 Gy (approximately 3 Gy in organ absorbed
dose). When the risk is estimated based on shieldedkerma of less than 4 Gy, the excess deaths perloJ PYGy are approximately 5% higher for leukaemia,

and 15% higher for all cancers except leukaemia

C.

RESULTS OF PROJECTIONS[S48].

558. Two kinds of coefficients are used as input, as
in Table 54; these vary with the type of model chosen
for the lifetime projection: the excess relative risk
per Gy is used for the multiplicative projection model(constant relative risk) and the excess mortality per
10' PYGy is used for the additive projection model(constant absolute risk). In all cases, both the multiplicative and the additive projection models have been
used, for comparative purposes (even though, as
discussed earlier, for some sites one model appears to
be more realistic than the other). Use of the twomodels in this context is not meant to imply any
description of causative biological processes; thc
models are simply used to derive lifetime risk projections.
8.

Indexes of harm

559. The indexes of harm have been restricted todifferent espressions of the effects of excess mortality
associated with radiation-induced cancers in a lifetime
after esposure. Two indeses are presented. The first is
the lifetime excess number of fatal cancers, and thesecond is the loss of life expectancy in a population of
1,000 persons esposed at various ages to a single doseof 1 Gy of low-LET radiation at a high dose rate toeach tissue.
560. Although the values of the indexes are calculatedby the Committee at 1 Gy, values may be computed atother doses, provided the shape of the basic dose-risk
relationship (linear, linear-quadratic, etc.) is known.

9. Treatment of uncertainty

561. The risk coefficients given in Tables 54 and 56
are accompanied by their 90% confidence intervals,
when available. The upper and lower 9 0 9 statisticalconfidence intervals of these coefficients have beenused to calculate the uncertainty inherent in theindexes of harm. It must be emphasized that this does
not encompass the total uncertainty associated withthe projections but only the statistical one attributable
to the risk coefficients used as inputs. Uncertainties ondose and on demographic variables are not considered
explicitly.
10.

Fractionated and low-dose-rate exposure562. The risk coefficients derived from the Life Span
Study and given in Table 54 relate to instantaneous
exposures to moderate to high doses and in principle
represent only such exposure conditions. As shown in
Table 55, irradiation of the cervical cancer patientswas protracted over a few days or weeks, and that of
the spondylitis patients was fractionated over a few
weeks. For low-dose rates, an appropriate correction
factor should be used if the indexes of harm are toreflect the experience coming from such epidemiological and experimental conditions.

563. The projections that follow should be prefacedby some statements about the approximations inherent
in the model adopted. First, the Committee's lifetime
projections are based on a simple modelling procedure,and deliberately so. More complex models could havebeen used and more effort to adjust for the known
shortcomings in the data could have been made, butwith each such ad hoc adjustment the results would
have become progressively more particular and lessand less applicable to the broad community ofcountries to which the Committee's deliberations are
directed. As an illustration, the risk coefficients theCommittee has employed are based on deaths reported
to be due to the presence of a malignant?. Deathcertificates, however, are known to underreport thedeaths that actually are attributable to cancer. An
adjustment could have been made to account for thisunderreporting, but the Committee has not done so,for the degree of underreporting sill undoubtedly
vary from country to countrj.
564. The Committee has used other simplifications.
.4mong these are age-constant risk coefficients (absoluteor relative) that do not change with time following
esposure (after the minimal latency period) or withage at exposure, as well as stable age-specific rates ofmortality ascribable to cancer and other causes. The
Committee has also ignored possible differences inmean survival time after the diagnosis of a malignancy
as a consequence of different medical standards in
different countries and their evolution with time.
Again, while the model used could accommodate otherassumptions, the data are still too sparse or contradictory to provide alternatives confidently. For example,
the observations on the patients with ankylosing
spondylitis suggest that the relative risk coefficient for
all cancers other than leukaemia declines with timeafter exposure [D21], but this has not been seen. atleast as yet, among the atomic bomb survivors ofHiroshima and Nagasaki [S49], except for those
exposed as children. If the relative risk does in fact
decline, then the Committee's projections will overestimate the lifetime risk. Similarly. if mean survival
time of cancer cascs increased, the loss of life
expectancy would decline. although the total numberof cancers tvould not change much (some diminution
would be expected, however, as a result of theincreased mortality from competing causes).
565. The coefficients assumed for the computations
have been derived by linear regression analysis in thecase of the atomic bomb survivors, the ankylosing
spondylitis patients, and the cemical cancer series withcell-killing correction for leukaemia in the latter case.
The n~odelused by the Committee to project lifetime
risks of cancer mortality or life span shortening at
1 Gy of low-LET irradiation administered at a highdose rate does not require selection of any givenfunction of the dose-response relationship and therefore the Committee has not imposed any pre-selectedfunction on the original data in order to derive its two
projections.
566. For reasons of convenience, the Committee willconsider separately the projections for the adultpopulation (males and females over 25 years of age),where comparisons among the three studies cited inparagraph 528 are possible: and the young population(below 25 years of age), for which the only reliablerisk estimates are those that come from the atomic
bomb survivors.
1. The adult population

567. The Committee's projections were carried out
according to the assumptions given in Table 57. TO
allow a comparison of the results of the three studies
cited in paragraph 528. the basic assumptions need tobe adapted somewhat. First. the atomic bomb sunivors
study comprises individuals of both sexes and all ages,
which the other two studies do not (see Table 551.
Consequently, for a meaningful comparison. it has
been necessary to examine only the adult populationin the Japanese series. This means that the basic risk
coefficients shown in Table 56 had to be modified totake into account the subtraction of the young
cohorts. It is these modified figures for the absolute
excess death per lo4 PYGy, shown in Table 58, thathave been used in the computations that will follow.
Of necessity, since the requisite risk coefficients havenot been published for the adult population only (norfor the working population, defined as aged 25-64),
the Committee has been obliged to use excess risk
coefficients based on atreraging the sex-specific risks
within the age groups 20-29. 30-39 and above 40. andweighting these averages by the proportion of the
population within each of the age groups. T o estimate
lifetime risks in the working population, the Committee has used the risk coefficients derived from a11
ages and both sexes. Figures of the ankylosing
spondylitis and cervical cancer series, tvhich were notcorrected, are also shown in Table 58. Second, thecervical cancer series refers only to females. so afemale population (that of the United Kingdom) has
been taken as the reference; similarly, the spondylitis
cohorts are mostly males and therefore the malepopulation of the United Kingdom has been adopted
as a referent. Thus, the results of the extrapolations
from the Japanese and cervical cancer series should becompared only in the female population, and theresults from Japan and the spondylitis series should bc
compared only in the male population. Third, forcancers other than leukaemia, a comparison is only
possible among two of the series. because no appropriate risk coefficient can be derived from the cervicalcancer series. The spread of doses between the heavily
irradiated pelvic organs (where cell sterilization could
be important) and the organs in the upper part of the
body (which received very low doses) is so large thatrisk coefficients based on atqeraged absorbed doses
would have no meaning. These reservations also
apply, though to a lesser extent, to the spondylitis
series: however, since the authors [L16] provided anaverage whole-body dose (in addition to excess relativerisk [D21]). the computations were made using thesesummary figures.

-(a) E.~cessI!ferinle morralirj.: leukaemia
568. Table 59 shows the results of the Committee's
projections, based on the model and assumptions

described. in respect to excess lifetime mortality forleukaemia using the risk coefficients for each of thethree major series (Table 58). Under the multiplicativerisk projection model. the risk estimates range from
2.8 to 8.1 for females and 9.0 to 14 for males, andunder the additive risk projection model from 1.4 to
7.0 for females and 4.4 to 13 for males (escess cases
per 1.000 persons at 1 Gy of high dose rate low-LET
exposure). Even considering the problems with therisk coefficients in these series. discussed earlier. thesevalues are all well within an order of magnitude ofeach other.
(b) E.1-cess I~ferinlemortalir!.:
all cancers orher rhan leukaeniiu
569. Only two of the three general series the Committee has cited give usable estimates of the excess riskof cancers other than leukaemia, namely, the atomic
bomb sur\rivors and the patients with ankylosing
spondylitis. For the assumption of a lifetime plateau(lower half of Table 59), the estimates of these twoseries are within a factor of about 2 to 4, the figures
being lower for the series on the ankylosing spondylitis
patients as compared to the Japanese atomic bomb
survivors. I t is tempting to speculate that this differencein risk relates to the modality of irradiation being
instantaneous for the aromic bomb sunritors andfractionated over a few weeks for the ankylosing
spondylitis patients. Although this phenomenon issuggested by the data and by no means demonstrated,
it is in the same direction that would be in agreementwith a large body of radiobiological literature, reviewed
most recently in the UNSCEAR 1986 Report and inreference [N I]. This shows that dilution in time of thedose yields generally lower effects than for the same
dose delivered at high dose rate and/or without
fractionation.
570. When the mortality from leukaemia is combinedwith that from all other cancers, assuming a plateauof 40 years for leukaemia and a lifetime plateau forall other malignancies (after the minimum latency),
between 46 and 56 additional cancers would be
expected in a population of 1,000 adults (500 males
and 500 females), based on the Japanese risk coefficients, under the additive and multiplicative projection
models. respectively.
(c) Loss of lifr e.rpec/anc.pf:leukaemia
Table 60 shows the results of the projections inregard to loss of life expectancy attributable to theadditional cases of leukaemia. The results are quite
similar to those for excess lifetime mortality; namely,
all three series provide estimates in generally good
agreement. The spondylitis patients and the Japanesebased estimates under the multiplicative model arein fact very similar. Even the greatest discrepancies,
between the cervical cancer and the other series, areafithin a factor of about 5.
571.

(dl Loss of life expectancy
all cancers other rhan leukaemia
572. Taking the figures in the lower half of Table 60
as the most conservative ones, the projections derived
from atomic bomb survivors are two to about fourtimes as great as those based on the ankylosing
spondylitis patients. Life lost calculated by the additive
risk projection model is higher than that calculated by
the multiplicatii*e risk projection model. but not bymuch.
573. As Table 60 shows, the expected number of
person-years of life lost from all cancers would be
about 840 for the additive model and about 620 for
the multiplicative model for irradiation of 1.000 adults(500 males and 500 females), based on the Japaneserisk coefficients, under the conditions described inTable 57.
574. I t warrants reiteration that the absolute values
given so far for irradiation of an adult (over 25 years)
population apply to 1,000 persons of both sexes whena constant risk coefficient is used.
2.

The population of children as a part of the population

575. The epidemiological evidence accumulated todate strongly suggests that the initial relative risk ofsubsequent malignancy following exposure to ionizing
radiation is appreciably higher when exposure occurs
early in life (within the first two decades after birth).
From what is so far known about the biologicalaspects of cancer induction. this finding is not
unexpected. However, apart from the data on theyoungest age at the time of the bombings cohorts in
the Japanese Life Span Study, there are few data fromwhich specific risk coefficients can be derived, andeven among the Japanese survivors the coefficientsavailable are based on small case numbers and haverelatively large sampling errors. These cohorts, furthermore, are those with the largest expected numbers ofyears still to live, and i t is far from clear whether thehigh excess relative risks presently seen will persist. It
is true that the Japanese data suggest a declining risk,both for leukaemia and all cancers except leukaemia,
notably among survivors exposed before the age of 10(the trends seen in Tables 51 and 52 for the 0-9 age
group are statistically significant). These cohorts have
only recently entered those years of life when the
background rates for virtually all solid tumours, aswell as for, the chronic forms of leukaemia. increase
markedly. Thus, it will be several decades before theircancer experience as middle- and older-aged individuals is clear. This poses a dilemma for the projectionof lifetime risks. On the one hand. i t would be unwise
to assume that the risks will decline, for if they did
not, the indices of harm could be grossly underestimated. On the other hand. to assume that theseexcess relative risks will persist throughout life, if infact they do not, will project a harm that is much toohigh for these cohorts. It is largely for these reasonsthat the Committee has elected to examine thechildhood population separately.
576. There are two separate aspects of the irradiationof young cohorts: first. their apparently greater
susceptibility to the carcinogenic effect of radiation(this aspect can be studied by a discussion of thedeclining risk coefficient as a function of age) andsecond, their longer life expectancies relative to adults

and the correspondingly longer time during which theconsequences of exposure may be expressed.
577. The first aspect has already been considered inTables 51 and 52. These Tables present excess relative
risks and excess deaths for the atomic bomb survivors(which is the only series for which such estimates,
although preliminary. are so far available) as afunction of age at exposure and age at time of death.
separately for leukaemia and all other cancers. The
limited experience does not tvarrant analysing thisphenomenon site-specifically.
578. The second aspect. as i t applies to the population of Japan, is illustrated in Table 61. Since the risk
coefficient has been presumed to remain constant over
all ages, the impact of the demographic component
introduced by the younger cohorts may be perceived
from this Table.
579. The main difficulties in assessing the impact of
exposure on the young arise when one attempts toevaluate the interaction between these two aspects forthe purpose of calculating an overa!l measure of risk
for the whole population. considering each age classseparately. In fact. each age class will be characterized
by its own coefficient of risk and its own demographic
future. Since it appears from Tables 51 and 52 that theexcess relative risk does not systematically change forages above 20. and certainly not for ages above 30 (atleast for solid cancer), the Committee has not attempted
to calculate the whole extent of these changes. It
should be pointed out that the observed values at the
younger ages, based as they are on a relatively small
number of cases, have large and unequal sampling
errors. Previous attempts to take age-related coefficients into account have relied solely upon a statisticalsmoothing of the observed values. The Committee
believes, however, that the observed changes insusceptibility as a function of age are not related totime alone, but also to the biological stages indevelopn~entthat are unique to certain ages, such as
puberty and its associated hormonal changes.

580. Under these circumstances the Committee
decided to make two separate sets of projections.
using the multiplicative and the additive projection
models: (a) the lifetime excess mortality and loss oflife expectancy as it applies to a population for which
the same risk coefficient is taken for all ages and (b)the lifetime excess mortality and loss of life expectancy
as it applies to a population at ages 0-9 and 10-19.
with coefficients specific for these age groups. Theselatter coefficients are as follows:
Age at irradiation
0-9
10-19
Leukaemia
Excess relative risk
19.1
4.5
3.42
1.52
Excess deaths
O ~ h e malignatlciesr
Excess relative risk
Excess death

These values have been taken from [S49] (Appendix
Tables 5a and 5b), averaging over the two sexes.

581. For the multiplicative model and for excess
lifetime mortality, the difference in the final effectintroduced by using a measure of risk related to thespecific age at exposure rather than a constant risk,that is a risk averaged over all ages and exposure. canbe substantial. The computations show that one
obtains three to four times more deaths due toleukaemia and all other cancers for the ages 0-9 at thetime of exposure by using the age-specific risk. For theages 10-19 at the time of exposure this difference inrisk tends to reduce to 1-2. In both cases thisdifference will be expected to decline further as theaverage age in the cohorts increases and the coefficientof risk adopted approaches the coefficient for thewhole population. This phenomenon is repeated in the
projections for loss of life expectancy.
582. For the additive, rather than the multiplicative,model, the difference between the excess mortalities
calculated using the constant coefficient and the agerelated coefficient is very small for leukaemia. and it
even tends to reverse for the age cohort 10-19. Thisaccords with the fact that the risk coefficient for thisparticular age group happens to be lower than the
average value adopted for computations on the whole
population. As is true for the multiplicative model,
these effects are almost repeated in the projections forioss of life expectancy.

and lower 90% bounds of the risk estimate are used(see Table 54). It shows that. under the conditions
specified above. one would expect to observe a total of
about 71 extra fatal cases under the assumption of amultiplicative projection. compared with about 45 cases
for an additive projection model.
586. The first method (Table 62) may overestimate
the lifetime excess mortality under the multiplicativemodel as the excess relative risk in the younger age-atexposure groups has been falling with increasing timesince exposure (see Table 51). On the other hand. thismethod may well underestimate the lifetime excess
mortality using the additive model, as the excess risks
have been increasing with time since exposure in theyounger age-at-exposure groups (see Table 52). Conversely, under the second method (Table 63) the
multiplicative model may underestimate the lifetime
harm for the younger age-at-exposure groups. but theharm for these groups under the additive model may
be overestimated. With the multiplicative risk projection model there is about a 30% decrease in estimatedlifetime mortality from all malignancies using thesecond method compared with the first, while with theadditive model the second method leads to about a
50% increase.
3.

583. T o provide estimates of risk to be applied t o thewhole population. computations have been madeusing the various age-at-exposure classes, attributing
to each of them the coefficient that applies t o thatparticular class. projecting the risk of that class over
the appropriate period of time (40 years o r lifetime)and summing up the overall effects over all age-atexposure classes. This was done for both the multiplicative and the additive projection models and forexcess lifetime mortality and loss of life expectancy,
separately. The final results of these summations are
given in Table 62.
584. Considering the number of fatalities from leukaemia and other malignancies together (upper part ofTable 62). it is seen that between about 42 and about
107 deaths would be predicted by the additive and themultiplicative model. respectively. The lower half of
the Table shows that between about 950 and 1.370
person-years can be expected t o be lost if the whole
population is exposed to 1 Gy under the conditions
specified.
585. There is a different way of arriving at similar
projections; namely. to use a single risk coefficientwhich does not take age at exposure into accountexplicitly. It should be noted that this method of
projection has its own shortcomings, for a risk
coefficient so estimated is essentially a weighted
average of the age-specific relative risks with weights
proportional to the numbers of cancer deaths in thespecific age groups. Thus most of the weight will begiven to the older age groups whose actual relative
risks are smaller. Nevertheless, t o provide a comparison, this has been done in Table 63 in respect to the
population of Japan. The values in parentheses
provide the corresponding numbers when the upper

Extrapolation to other populations

587. Risk coefficients are always estimated, a n dlifetime risks projected. in the context of a particular
population. Each exposed population from which risk
coefficients are estimated has its own backgroundmortality rates from all causes of death, and its own
age- and sex-specific cancer rates. Indeed. not allindividuals within any given population are at thesame risk. Considering this. it is fair to ask what use
can be made of risk coefficients obtained from one
population for predicting lifetime risks in any otherpopulation. The projections given in this chapter havebeen derived by applying the closest possible expected
rates of death (from cancer and from all other causes);
namely, thosc from the same country as the esposed.
Even so, baseline risks in the Japanese exposed to theatomic bombs, a wartime and post-war environment.
were not the same as those of current Japanese. noreven precisely of those of Hiroshima and Nagasaki
today. It is known that there are changes occurring inJapan in regard to baseline mortality rates and that
there are also regional differences in Japan. as in every
other country. Similarly. the all-United Kingdom
mortality patterns are certainly not exactly those of
the ankylosing spondylitis o r the cervical cancer
patients.
588. Because baseline mortality is always changing
in every population, and this includes major changes
in a variety of cancer risk factors, it is difficult t oknow how accurate lifetime risk projections might be.
One way to place outer limits o n this error would be
to compare the lifetime risk estimates based o n thesame risk coefficients and different baseline mortality
patterns. For this Annex three populations have beenchosen to compare projected risks. T o d o this, theabsolute and excess relative risk coefficients derived

from the experiences of the atomic bomb survivors
have been applied to (a) the Japanese population
using the Japanese 1980 national mortality patterns,
representing the nearest available representative rates
for those coefficients; (b) the United Kingdom, representing a rather typical older industrialized nation;and (c) Puerto Rico, representing (as best as worldwide data will permit) a population with high infant
and infectious disease mortality, and low cancer rates.
589. The populations are compared in Table 64, andthe results of this comparison for leukaemia, othercancers and all malignancies are given in Tables 65 and66. The latter Tables show that across these three
populations there is virtually no difference in risks
projected by the additive model. Even for the multiplicative model, the maximum difference, using Japan as thebasis of comparison. is a factor of 71/58 = 1.2. This
clearly shows that the lifetime risk projections are very
insensitive to differences in overall. and cancer-specificmortality differences within the range of contemporary
large national populations, and for leukaemia or all
cancers pooled. Thus, the risk projections derived here
would seem to have rather broad generality andapplicability. Much larger proportional differences
may apply to site-specific cancer with large international variation in risk, such as female breast,
stomach. large bou,el and lung.
590. I t should be pointed out. however. that thisconclusion applies to only one of the uncertainties inthe extrapolation of risk projections to other populations. I r is no1 yet known how much the risk
coefficients themselves might vary bctween different
ethnic groups or populations with differing exposures
to other carcinogens which could act synergistically;
the range of today's knowledge is limited essentially todata from Japan and from a variety of industrialized
populations. Within this context. and given thestatistical problems in estimation. the range of risk
coefficients is rather small, well below a full order ofmagnitude.
4.

Comparisons with previous studies

591. The Committee made its last previous estimatesof lifetime risk in the UNSCEAR 1977 Report [U2].
This Report gave values for all cancers of 1.0 lo-' Gy-'
(range 0.75-1.75, Annex G , paragraph 318) for low
dose low-LET radiation and 2.5
Gy-I (Annex G.
paragraph 317) for high dose low-LET radiation.
Leukaemia was about one fifth of the total. The
projection was carried out by assessing the leukaemia
risk and projecting a ratio of 5-7 for all cancers toleukaemia ultimately, thus obtaining the total cancer
risk.
592. Additional epidemiological and other information has accumulated since 1977. This includes extensions and changes in the data for the Japanese atomic
bomb survivors, in the ankylosing spondylitis series in
the United Kingdom and in various other specifictumour sites such as lung (radon), thyroid and breast.
A new study of patients surviving treatment for
carcinoma of the cervix has provided additional

information on second cancers at selected sites. Mostof these studies make some contribution to quantitative risk estimates.
593. The atomic bomb survivors are especially important and provide the largest single data set over arange of doses. In this population the data have now
accumulated over three additional time periods sincethe 1977 Report was written. viz. 1975-1978. 1979-1982
and 1983-1985. These are important time periods forthe expression of solid tumours, 30-40 years after
exposure to the bombs. Not only has the total amountof data on excess cancers increased by approximately
threefold, but the extension of the data in time and theincreasing information for all age cohorts, especiallythe young, provide further tests of models and thus
aid in methods of projection and in knowledge of age
dependence. Furthermore. the dosimetry of the survivors has been evaluated (and measured in thesurvivor range by thermoluminescent methods) andtends to increase risk by factors, when expressed interms of shielded kerma, between 1 and 2 dependingon the cancer site. Some improvements have also been
made in statistical methods.
594. The atomic bomb survivors have been used inthis report as the main source of risk estimates, while
the Committee notes that other sources of data suchas the ankylosing spondyliris patients are in generalterms consistent with these estimates. especially whenthe mode of delivery of the exposure is taken into
account. The Committee has not itself made primaryestimates of risk in the Japanese atomic bomb
survivors, but has relied on risk estimates developed inrecent publications for the appropriate period of
observation. These risk estimates have then been
projected to a lifetime separately by the additive andmultiplicative models and for both an age-structured
population and for risks averaged over one intermediate age range. Lifetime risks have been estimatedseparately for an adult population alone and an entire
population of all ages.
595. In this Annex the risk estimates for a population of all ages for riiortality from all cancers at 1 Gyof high dose ratc low-LET radiation range from 4 to1 1 10-zGy-' (Table 62). whereas for an adult population
alone the range is from 5 to 6 10-2Gy-l (Table 59) (theranges reflecting the additive and multiplicative models
of projection, respectively). Leukaemia accounts for
one quarter to one tenth of the total. The Committee
has also provided estimates of the years of life lost as
determined by the two projection methods. I t may
also be noted that while the age dependence has
become more evident than in the UNSCEAR 1977
Report, sex differences have become smaller.
596. General appraisals of risk estimates have been
made by various other groups since the UNSCEAR
1977 Report. The BEIR I11 Committee of the National
Academy of Sciences in the United States produced acomprehensive report in 1980 [C4] which provided a
range of from 0.1 to 5 lo-' Gy-I for all cancers using
additive and multiplicative models for projection andquadratic, linear-quadratic and linear models for dose
response. The preferred values of risk at the time thereport was issued were based on the linear-quadraticmodel and on additive projection and were quite
similar to the values in the UNSCEAR 1977 Report(see [C4]. Table V-25).
597. Later. for a repon of the Nuclear Regulatory
Commission in the United States, Gilbert [GI I]
developed risk estimates based on a linear-quadratic
dose-response model (together with upper and lower
bounds. roughly a factor of 3 above and below) andboth additive and multiplicative projection models
and years of life lost (Tables 8 and 9). The lifetime risk
estimates ranged from about 0.3 to 6 lo-' Gy-' with acentral value of about 2 lO-'Gy-' for low doses of
low-LET radiation.
598. A group constituted by the National Institutesof Health in the United States assembled risk information for the purpose of developing tables of probabilityof causation (i.e., risk estimates for specific cancer
sites at nominal ages as a function of time after
exposure [U3]). The input used risk inforrnation
updated from the BEIR 111 report similar to that ofGilbert. Lifetime risk estimates can be derived fromthe basic input using an additive projection model andagain values of about 2 lo-' Gy-I for low doses would
be found.
599. These ttvo recent groups had access to datafrom the Japanese atomic bomb survivors up to 1978
but were too early to obtain the full benefit of recent
risk estimates from Japan utilizing the additional time
periods and revised dosimetry now available to thisCommittee and included in this analysis.
D.

RISKS AT LOW DOSES .4ND
LOW DOSE RATES

600. .41doses and dose rates defined by the Committee
as low (less than 0.2 Gy and less than 0.05 mGy/min
for low-LET radiation) radiation-related carcinogenic
effects in an exposed population will almost always bemasked by the larger carcinogenic effects of otherfactors. Moreo\*er, in an exposed study population
there will always be some level of dose below which
no statistically significant excess of cancer occurs
compared with the control population. In the dose
range below this point, the excess cancer risk cannot
be observed and cannot therefore be directly determined. In this dose range the Committee has to use amodel to interpolate between the certainly zero excess
risk at zero dose and the observed excess risk at dosesof the order of 1 Gy. This may require the use of acorrection factor if the projections based on highdoses and high dose rates are to be applicable toexposures to low doses and low dose rates.
601. In the risk estimates derived above, no correction was made for the possible reduction of effects
under conditions of low dose or low dose rate. The
experimental literature contains a wealth of data
showing that there are such effects. This has been
recently reviewed by UNSCEAR [Ul] and earlier by
the National Council on Radiation Protection [NI].
The former report concludes that for low-LET radia-

tion most dose-response curves for tumours induced
in animals are concave upward and may be fitted bylinear-quadratic or quadratic models. although insome cases linearity may apply. Moreover, dose ratestudies with low-LET radiation almost invariably
show a decreased incidence of tumours with decreasing dose rate in animal populations.
602. The human data on this subject are sparse, but
are reviewed in the UNSCEAR 1986 Report [Ul]which concludes that extrapolation linearly down tozero dose would overestimate the risk by a factor up
to 5 in typical situations. The study by Howe [H6] andthe very recent study by Holm [H28] are notconsidered in the UNSCEAR 1986 Report but are
discussed earlier in the present Annex.
603. Since 1986 new data on human populations
relevant to the effects of low doses have emerged fromthe revision of the experience in atomic bomb survivors [S49]. Table 67 shows the excess relative risk
per I Gy of organ absorbed dose for doses above andbelow 0.5 Gy. using the entire 0-6 Gy dose range. andfor progressively lower dose ranges below I Gy [S49].
Considering first leukaemia. a significant difference inthe excess relative risk exists among survivors exposed
to 0.5 Gy or more, as opposed to those exposed tolower doses (5.53 versus 2.44, respectively). Thissuggests persistence of a curvilinear dose-effect relationship for haematopoietic malignancies. In so far as all
cancers except leukaemia are concerned, the excess
relative risk associated with the higher doses does notdiffer significantly from that at the lower doses (0.41
versus 0.37, respectively). At doses below 0.20 Gy, theJapanese data have not revealed a significant excess ofmalignant tumours. and the nature of the doseresponse relationship at these doses is uncertain. The
expected numbers of additional cancer deaths at theselower doses are still small. relative to the backgroundrate. even under the linear dose-response model, andthe scatter of the data points is such that they can be
fitted almost equally well by a quadratic, linearquadratic or linear dose-response relationship [S48].
604. Epidemiologic studies of continuous internal
irradiation of the thyroid gland by 13'1 represent one
source of inforrnation on the effect of low dose rates
in human populations. A preliminary study of 10.000
patients who received doses to the thyroid gland in therange of 0.5 to 1.5 Gy found no excess of thyroid
cancer after a mean follow-up of 17 years although 16
excess cases would have been expected based on
external low-LET irradiation of the thyroid [H27]. An
analysis of this study by the National Council on
Radiation Protection of the United States concluded
that "'I should be considered no more than one-thirdas effective as external irradiation at high dose rates
probably due to factors related to dose rate and dose
distribution. An expanded study of 35.000 patients
receiving diagnostic examinations has been published[H28]. These studies are discussed in paragraph 398.
Both conclude that doses received from internal "'I
irradiation are less carcinogenic than similar doses
from external acute irradiation. A factor of at least 3
has been proposed [NS]. and possibly even 4 [H28].
Although the reduction of dose rate is held by some tobe a major contributor to the evident reduction in
effectiveness, others contend that non-uniformity ofdose distribution in the gland from "'I may occur andcontribute too [NS].
605. Epidemiologic s~udies of highly fractionatedexposures to external low-LET radiation represent a
second source of information on a low dose or low
dose rate factor. As discussed in paragraph 367, there
appears to be a non-linear dose response in the
Canadian study of breast cancer following multiple
fluoroscopic examinations [H6]. This appears to berelated to the much smaller dose per examination
received by the breasts of women who were irradiatedposteriorly rather than anteriorly. A fractionation
effect was not demonstrated in the similar but muchsmaller Massachusetts study [B3]. However, in thisstudy it was not possible to distinguish a low dose
cohort irradiated posteriorly. There appears to be alow dose or low dose rate factor of at least 3 in the
Canadian study [H6].
606. Previous attempts to estimate lifetime risk forhumans, such as BEIR 111 [C4], the Nuclear Regulatory
Commission [GI I]. and the National Institutes of
Health [U3] have handled the problem posed by low
doses and low dose rates differently. BEIR I11 used alinear-quadratic dose-response function as one of theirtested models. but the BEIR I11 Committee felt unable
to recommend a specific general reduction for low
dose rates. The other reports [G 11, U3] both relied on
the NCRP summary of the experimental literalure[Nl]. This was done by using a quadratic term in thedose-response function only for modelling exposure at
low-dose rates. In the celitral estimates by Gilbert[ G I 11. for which the results are given in Table 8, thelinear coefficient was reduced by a factor of 3.3, andin the lower bound estimates by a factor of 10, for allorgans except breast and thyroid.
607. From examination of' both experimental andhuman data the Committee concludes that the carcinogenic effects of low-LET radiation are generally smaller
at lour doses and at low dose rates compared withthose at high doses and dose rates. The reduction
factors will vary with dose and dose rate and withorgan system but will generally fall within the range 2
to 10.
E.

LIFETIME RISK ESTIMATESFOR SPECIAL TISSUES
1.

Lung

608. The computations provided in this Annex,
based on DS86 risk coefficients, include low-LET.
high-dose-rate exposure to the lung, based on theatomic bomb survivor experience. However. it isimportant to also estimate risk coefficients and lifetime risks for the alpha-irradiation experienced inconnection with radon daughter exposure in the home
and work-place. Thomas et al. [T20], ICRP [I 111, and
BEIR IV [CZO] have reviewed the literature on radon(and related) exposures and have estimated lifetime
risk. The Committee has reviewed these findings,
along with other recent reports. in chapters 111 and IV.

609. Life-table methods essentially identical to thoseused in this Annex have been used by ICRP [I1 11 to
derive lifetime risk estimates for continuous exposure
to radon progeny, the high-LET exposure. Since theCommittee believes that those estimates are reasonable in the light of [he available data. it sin~pl)presents them i n Table 68.
610. Thomas et al. [T20] have provided risk estimates
for two types of exposure: (a) occupational exposure at
4 WLM up to a maximum of 200 WLM and (b) lifetime exposure of 0.02 WL 17 hours per day. 7 days
per week as an upper tolerable limit for exposure thatmight be experienced in homes. The risk figures were
adjusted for active breathing (occupational exposure)and quiescent breathing (home exposure), but they
were not adjusted for age to account -for varying
susceptibility. The authors suggest, however, thatsince recent dosimetric studies indicate that breathing
rate corrections may be inappropriate, their lifetime
natural risk estimates might be doubled. Thomas et al.
[T20] used eight risk models: namely, all combinationsof additive and multiplicative projections: constantand age-varying risk coefficients; exposure times overwhich exposure is effective in incrementing risk. The
projections were based on the Canadian life-table andlung cancer risks. Table 10 provides their risk coefticients and the lifetime excess risks.
61 1. The ICRP used similar assumptions and essentially the same demographic method of projection[I1 11. Their publication reviews the entire literature,
biological and physical. on radon daughter exposure,including the available studies on mining, in-home
exposures and the relationship of risk to smoking, age,sex, and latency period. Their results are given in
Table 68. For details and the methods of deriving therisk coefficients see the ICRP study [I 1 I]. The ICRP
concludes that the multiplicative risk projection model
gives a better "best" fit for the data and provides amore realistic way of extrapolating from the higher
mining doses to lower in-home doses than the additivemodel. I t cites several published estimates. ranging
from 0.10% to 1.0% excess cases at a constant annual
exposure of 0.19 WLM.
612. Risk estimates for adult male uranium miners
have been reviewed in [C20, 1 1 1, 112. U2]. Morerecent publications and papers prepared for publication have been noted by the Secretariat. Some of thesedata suggest that the minimum latency period toinitial appearance of excess lung cancers after first
exposure to high concentrations of radon progeny isfive years, rather than the 10 years previously assumed[K28, M40, S511. The interaction between cigarettesmoking and exposure to radon progeny was closer toadditive than to multiplicative for the Czech miners[S5 I]. These data have not yet been analysed in depth
by the Committee. The preliminary analysis available
does not suggest any reason for a major change in theprevious risk estimates [I 12, U2] of 1.5-4.5 10-Vatallung cancers per WLM. More detailed consideration of
epidemiological data relating to lifetime risk estimatesfor cancer induction by inhalation of radon and radon
progeny is anticipated in future UNSCEAR Reports.

613. The Committee is unable to provide reasonable
lifetime risk estimates for exposure to low- o r highL E T irradiation for bone cancer. The data from Japand o not provide statistically meaningful risk coefficients, a n d there are problems with using the available
literature o n adults (e.g., the radium dial painters andpatients injected with radium isotopes) to assess
lifetime risk with demographic projection methods.
The literature is summarized in chapter 111.
614. While exposed children are probably sensitive
to bone cancer induction, the genetically atypicalnature of the available cohorts, relative t o whole-body
exposure, precludes a useful estimation of risk fromtheir data. other than as discussed in chapter 111.
3. Thyroid

615. The best estirnates of thyroid cancer are available from [Nj].and were given in Table 39. This was
based on the most recent data yet available. There areno published data from Japan from which to makeprojections beyond those already given in this Table.
Recent data from Holm [H28] have been noted
earlier.

F.

RISK ASSESSMENT BY CANCER TYPE

616. In section VI1.C. the Committee calculates the
projected risk of induction of malignancies for two
broad classes of malignancy: leukaemia and othersolid cancers. The reason for considering only thesetwo classes is that in the patient series reported therea r e not enough observations to allow, separate computations for all cancer sites and all ages in order toobtain an overall estimate. The only series in which
there appears to be enough information for at least an
exploratory site-specific analysis is that on the atomic
b o m b survivors from Hiroshima and Nagasaki. Therefore. simply to show what type of data the model used
could generate-given
the appropriate backgroundinformation-the Committee has refined its analysisof the Japanese series to compute the risk of radiationinduced cancers by anatomical site. o n the basis ofmultiplicati\-e and additive risk projection models andfor the two indices or radiation harm described earlier.
These computations were performed using the risk
coefficients and the assun~ptionsspecified in Tables 56
a n d 57; the results arc given in Tables 69 and 70.
617. It should be borne in mind that the final resultsof the computations are no better than the original
data from which they were derived. Although theatomic bomb survivor study is the only study thatallows these projections. the number of cancers
observed for each site and each age class is often
small. Consequently, the projected values carry large
uncertainties. It should also be pointed out that thesecomputations apply strictly to the Japanese population a n d could not be transferred easily to otherpopulations having different demographic a n d epidemiological characteristics.

618. The Tables are computed on the assumption ofa n age-constant risk coefficient, since there was notenough information for most sites (panicularly inyoung cohorts) to allow meaningful analysis of theradiosusceptibility of young cohorts exposed below
20 years of age separately for each site. Taking thisfactor into account u~ould.of course, increase the risk
attributable to younger ages and, since these ages
dominate the overall risk projection, they would
increase the expected risk substantially. The Committee
considers that taking an average risk coefficient
overestimates to some extent the risk of the age classes
that are old at the time of exposure and underestimates
the risk of the younger cohorts. The data available atpresent d o not allow quantification of this statement
on a site-by-site basis.
619. Table 69 presents the expected additional cancer
cases at nine specific sites, including the marrow. a n d
for all other sites collectively, designated as theremainder, under the two risk projection models. It
should be noted that the number of escess cancers atsites not specifically identified, i.e.. the remainder, hasbeen computed. first. through subtraction of theexcess cancers at the identified sites from the total
projected excess number at all sites and. second,through the actual computation of the risk coefficientassociated with this collection of sites, and projecting
the excess number from the estimated risk coefficient.
The difference between these two methods ofestimating
the expected number is small. Table 70 summarizes
the loss of life expectancy per person after exposure to
1 Gy, under the same assumptions as in Table 69.
G.

SUMMARY AND CONCLUSIONS

620. The Committee had available to ir certain
additional data that made it desirable t o reconsider
the assessment of the risk of radiation-induced cancer.
These additional data were the result of: ( a ) a reevaluation of the doses of the Japanese atomic bomb
survivors; ( b ) an extension of the observation periods
for several cohorts during which radiarion-induced
cancers continued t o occur: (c) the availability of datafrom several new cohorts; and (d) the introduction
into the analysis of both the additive a n d themultiplicative risk projection models for lifetime
cancers and loss of life expectancy, taking into
account competing causes of mortality.
621. In its projections. sumnlarized in Table 71.
some of the risk coefficients used by the Committee
were derived by the authors of the reports from which
they were taken using a linear dose-response relationship. However, there is no direct epidemiologicalevidence that substantiates this at low doses and/or low
dose rates, a n d there is in addition some epidemiologicalevidence of non-linearity. Based primarily on theexperience of the atomic bomb survivors who received
uniform whole-body irradiation at high doses anddose rates a n d low-LET. the Committee derived excess
absolute and relative risk coefficients. Using these risk
coefficients, the Committee estimated lifetime risks ofmortality in the range of 4 to I 1 lo-? Gy-'. The
Committee considered that these risk estimates apply
to a dose range of 0.5-6 G y and noted that they arestrongly influenced by the finding that children are
considerably more sensitive to radiation effects thanadults.
622. The above estimates are qualified by the facts
that (a) the estimates have been derived using Japanesedata and the extent to which they apply to otherpopulations is not clear; (b) although the multiplicative model leads to higher estimates of projectedmortality than the additive model, the projected
estimates of the expected years of life lost are similar
under the two models. This is because under themultiplicative model a large proportion of the projected deaths occur in very old people when the yearsof life lost are few; and (c) there are two other major
cohorts, those of patients irradiated for ankylosing
spondylitis and cervical cancer, which give rise to
somewhat lower estimates of lifetime risk.

623. The Committee agreed that there was a need fora correction factor to modify the risks given above forlow doses and low dose rates. The Committee
considered that such a factor certainly varies widelywith individual tumour type and with dose rate.
However, the appropriate value to be applied to total
risk for low dose and low dose rate should lie between
2 and 10. The Committee intends to study this matterin detail in the future.
624. The Committee has not presented risk estimatesfor high-LET radiation in general in this Annex except
for the exposure t o radon of uranium miners. For low
doses of external high-LET radiation it would benecessary t o multiply the risks for low-LET radiation
by an appropriate quality factor. No dose or dose rate
reduction factor is considered necessary for high-LET
radiation at low doses.

T a b l e

1Populatlon qroups exposed t o lonlzlnq radlatlon
used In rlsk evaluatlon studles

Study
population
slze
Atomlc bomblngs
Resldents of Hlroshlma and Nagasakl
91.000
Nuclear w e a p o n s testlng
Mllltary test observers
10,000Populatlons near test sites
500,000
Marshall Islanders
250
Uedlcal therapeutic exposure:14.000Ankyloslng spondylltls patients
Cervlcal cancer patlents
1 80,000
P a t l e n t s recelvlng chest Irradiation
10,000
2.000
Patlents recelvlng Thorotrast lnjectlons
Patients recelvlng head and thymus lrradlatlon
20.00010.000Hodgkln's d l s e a s e patlents
Patlents Irradiated for lmnunosuppresslon
H e m n g l o m patlents
10,000Chlldhood cancer patlents b/
Fetus recelvlng pre-natal examlnatlon
1.000
Occupatlonal exposure
Nuclear shlpyard workers
24.000R e a c t o r a n d processing plant personnel
30.000Underground mlners
22,000R a d l u m dldl palnters
4.000
10,000
Radlologlsts
Natural background
Persons w l t h elevated exposure due t o geography
Persons llvlng ln houses hlth hlgh radon levels
Nuclear accidents
Indlvlduals In publlc. workers, emergency c r e w s~ p l d e m i o l o q l c a l studles used t o assess radlatlon carclnoqenesIs In man

Cohort studjes
P r o s p e c t i v e follow-up
S u r v t v o r s of atomlc bomblnqs
Marshall Islanders
Retrospectlve/prospectlve follow-up
Indlvlduals ldentlfled from medlcal records
Patlents lrradlated therdpeutlcally
Radlologlcal workers and radlologlsts
Indlvlduals ldentlfted through employment records
Occupatlonally exposed lndlvlduals
Mllltary test observers
Indlvlduals identified through geoqraphlc d a t aPopulatlons In high natural background a r e a s
Indlvlduals llvtng ln local fallout areas
Case-control studles
Retrospective ascertainment
Pre-natal exposures
Opportunlstlc or ad hoc studles
Nuclear accldent vlctlms

T a b l e

3

M o r t a l l t y t o Incldence r a t l o s f o r transtormlnq r i s k estimates[C41

E x p e c t a t l o n o f cancer ( p e r c e n t )S l t e ofcancerMales

Mortallty

Mortality/
lncldence
ratlo

femaleslncldence

Hortallty

Incldence

Males

Females

Oesophagus
StomachIntestine
Pancreas
Lung
Urlnary
Lymphoma
BreastThyrold
Llver

T a b l e

4

Excess c a n c e r i n c i d e n c e ( e r c l u d l n g l e m m l a and bone c a n c e r )p e r 1 0 4 p e r s o n y e a r s and GY, 11-30 y e a r s a f t e r exposure,e s t i m a t e d I n t h e BEIR 1980 R e p o r t[C41

Age a t exposure ( y e a r s )
Sit e
0-9

10-19

20-34

35-40

>50

Agewelghted
average$1

Males
Thyroid
Lung
Oesophagus
StomachIntestine
Llver
Pancreas
Urlnary
LymphomaOther
A l l sltes
Females
Thyrold
BreastLung
Oesophagus
StomachIntestine
Llver
Pancreas
Urinary
Lymphoma
Other
All sltes

a/ Average o f

t h e a g e - s p e c l f l c c o e f f t c l e n t s . w e l g h t e d according t o
t h e age d l s t r l b u t l o n o f t h e p o p u l a t l o n o f t h e U n i t e d S t a t e s .

T a b l e

5

Excess mortalltv from all cancers Der lo4 pee z o s e d to low-LET radlatlon ertlmated In the 8EIR 1 9 8 0 Report[C41

Excess deaths
Dose-responsemodel applled

Absolute
rlsk
projection

model

Relativerlsk
projection
model

Slngle exposure to 0.1 Gy q/
Llnear-quadratlc
LlnearOuadratic

7.66
16.71
0.95

22.55
50.14
2.76

Contlnuour exposure to 0.01 Gy per year b/

a_/ Normal

expectatlon of deaths from cancer
In follow-up perlod: 1638.
b/ Normal expectatlon of deaths from cancer
in follow-up perlod: 1673.

T a b l eb

Llfetlme rlsk of cancer mortal&f r o m low-LEI radlatlon estimated In the RElR 1 9 8 0 R e ~ o r t[C4

Excess deaths per 10'
Dose- responsemodel applled

Absolute
rlsk
prajectlon
model

per GyRelatlve
rlsk
projectionmdel

Slngle exposure to 0.1 Gy
Llnear-quadratlc
LlnearQuadratic

71

167
10

226
501
28

Continuous exposure to 0.01 Gy per year
Llnear-quadratlc
Llnear

61
158

169
403

T a b l e

7

Ratlos of excess deaths from radtatlon-lnduced cancers
other than leukaemla and bone cancer
to excess deaths from radlatton-Induced leukaemla and bone cancer[C4

Duratlon of
exposureand dose rate

I
Absolute
rlsk
projection
model

Relativerlsk
projectionmodel

Llnear-puadratlc
Llnear

2.4
2.6

7.5
8.1

Between ages 20-65(0.01 Gy/year)
Llnear-quadratic
Llnear

3.0
3.3

5.7
6.2

Llfetlme(0.01 Gy/year)

Dose-response modelT a b l e8Models and-assumptions for cancer rlsk estlmatesused In the Unlted States Nuclear Requlatory Comnlsslon study[Gll I

Mortality rlsk coefficient

EffectLeukaemlaBone cancer
Breast cancer
Lung cancer
GI cancer b/
Thyrold cancer

Other cancers

c/Type of model

Latency

Plateau(Years)(Years)Absolute,
linear-quadratic2

25

Absolute,
llnear-quadratic

2

25

Relatlve, linear.
non-age-speclflc

10

Absolute
per 104
per GyRelatlve
percent
per GyRelatlve,
linear-quadratic

10

Relatlve.
1 lnear-quadrat lc

10

Absolute. Ilnear.
age- and sex-spec I f lc
age < 1 8

5

Relatlve.
ltnear-quadratlc
Absolute. llnear

10
0

10

a/ Flrst coefflclent ls for exposure under, second for exposure over age 20.
b/ lncludlng cancers o f the oesophagus, stomach, colon, rectum, pancreas, andother unspeclfled gastolntestinal cancers.
c/ lncludlng all cancers except leukaemla.

T a b l e

9Llfetlme rlsks of cancer mortality
from low-LLT radlatlon at lov dose rates (<0.05 GY Der d a y 1
estimated In the Unlted States huclear Requlatory Comnlsslon study[Gll I

Number of deaths(per 104 per Gy)

Years of llfe lost(per 1 0 4 per ty)

Lower
bound

Centralestlnate

Upper
bound

Lower
bound

LeukaemlaBoneareas tLung
Gastro\ntestlnal
Thyroid
Other

5
0.2
4
5
9
7
5

14
1
60
20
51
I
29

48
2
87
138
189
7
96

168
7
97
100
222
20
124

505
22
955
288
661
203
378

1682
75
1452
1971
2202
203
1260

Leukaemla a/
Other a/

1.2
1.2

1 .2
l .2

3
3

80
80

80
80

200
200

Central Upper
estlmate boundp/ Due to In utero exposure.

T a b l e

10

Estimated rlsks of lunq cancer In uranlum and non-uranlum mlners[Tll I

Lung cancer deaths
Locat \onof mlneType ofmlne

CanadaOntarlo

Mean
dose
(wLM)

Observed

Uranlum

Ontarlo
Ontar lo
Newfoundland

Uranlum
Gold
Fluorspar

Czechorlovakla

Uranlum

SwedenKlrunaIron

Zlnkgruven

Lead.zinc

Malmberget

lron

Ndtlonal survey
Unlted Klngdom

Iron

Unlted States

Metal

Coloradoplateau

Uranluma/ Values ln parentheses are standard errors.

Expected

Excesscases
per 1 0 6
PY WLM

Relative
rlsk

a/

a/

ger

1 0 wLMRef

T a b l e

11Goodness of flt of dlfterent llfetlme projection models
for all cancers other than leukaemia in t h e population of Enqland and Uales[M371(Single exposure to 0.1 Gy hlth gamna and neutron components
ln the same proportlon as at Hlroshlma;
The models that flt the data well a r e undcrllned.)

Covarlateof rlsk

Mlnlmum
deviancea/Yb/

Devlance a/a t y = O(Multlpllcatlve
rlsk model)

Devlance a/
aty.1(Addltlve
rlsk model)

None (constant
rlsk)
Sex
Age
Tlme slnce
exposureSex, a g eSex, time since
exposure
Age, tlme slnce
exposureSex, age. tlme
slnce exposurea/ for ease of presentatlon, a value of 400 has been subtracted
f r o m these deviances.
in comparing the difference In devlance
resultlng from the lncluslon of a n extra varlable In t h e model.
a reductlon In devlance of 3.84 1s slgnlflcant at t h e 5% level
and a reductlon of 6.63 Is slgnlflcant at the 1% level.
b/ y denotes the value of the parameter that mlnlmlzes t h edevlance.

T a b l e

12Appllcatlon of a qenerallzed rlsk model t o data on mortallty
from all cancers other than leukaemla
In t h e Hlroshlma atomlc bomb survlvors
r~371( A 10-year mlnlmal latent perlod Is assumed.)

Covarlateso f rlsk

Rlsk modelSex. age

Wultlpllcatlve
Addltlve a/

TIme slnce exposurey = 0.57

Sex, age, tlme
slnce exposure
Sex, age, log (tlmeslnce exposure)b/

Number o f
deaths per lo4

Years of llfe
lost per 104

225
28
1460

Multlpllcattve
Addlvlve983
81 6Multlpllcatlve
Addltlve

104
87

a/ Thls model does not flt the Hlroshlma data well.

0/ y denotes t h e value o f the parameter that mlnlmlzes t h edevlance.

T a b l e

13

Staqe In carclnoqenesls posslbly affected by radiation ln various orsans
as deduced f r o m theoretlcal multl-staqe models

Stage affected and tumour slte

f xposure type

Population studled

Ref.

Early stage posslbly affected
All cancers except leukaemla
All cancers except leukaemla
All heavily lrradlated sites
BreastBreastBreastBreastThyrold
Lung

SlngleAtomlc bomb survlvors
Ankyloslng spondylltls Brlet chronlc
lrradlatlon
patlents
Brlef chronlc
Hetropathlc
Irradiation
hemorrhaglca patlents
SlngleAtornlc bomb survlvors
Atomlc bomb survlvors
SingleBrlef chronlc
Chest fluoroscopy
lrradlatlon
pat lents
Post-partum mastltis
Brlef chronlc
lrradlation
patlents
Brief chronlc
lntant patlents
lrradlatlon
Long chronlc
Underground mlners
exposuret o radon

Late stage posslbly affectedLeukaemia
Leukaemla

Ankyloslng spondylitls
patlents
Radlologlsts

Brlef chronlc
lrradlatlon
Long chronlc
exposuret o x rays

LC21

Radlunl dlal palnters

Long chronic
exposuret o radlum-226[H3]

Atomlc bomb survivors

Slngle1841[S4]All stages posslbly affected
Osteosarcoma

Uncertaln stages affectedLeukaemla

T a b l e

14

Relatlve rlsk of leukaemla in pre-natally exposed chlldren

Study locatlon

UNSCEAR (uelghted mean)
Unlted States
Unlted States
Whlte
Black
Unlted Klngdom
Flnland
Hiroshima-Nagasakl
Engltsh twlns
Unlted Stater tulns

Years oflncldence

Relative
rlsk

Ref.

2.88
0.00 b/1.48 a_/1.90
2.15
2.20 a_/1.60 c/

1031
(031
[S5]
1511
[I1 1
[Hl]
[Hll]

g/ Slgnlficant at 0.05 level or better. UNSCEAR value Is
sample-slze uelghted
value of studles done before
1964. lncludlng nlne sets of data ulth a total of
1.626 cases contrasted ulth 2.706 controls. Relatlve
rlsk from Japan was calculated from t h e dose-speclflc
rlsk rate data ln [ I l l nnd Is not slgnlflcant ( s e etext).
Host cases and excess rlsk reported here
occurred before the age o f 10.
b/ No cases observed.
c/ In this serles, relatlve rlsk of solld tumours uas
3.2. not slgnlflcant; other serles have found values
less than t h e RR for leukaemla.

T a b l e

15

Second p r l m a r y cancer I n c h l l d r e n t r e a t e d f o r a p r l m a r y cancer
In281

Number o f recond cancers
Type ofsecondcancerTotal

Bone
Soft-tlssue
sarcomas
Haematopoletlc
Sk l nBraln
Thyrold
BreastA l l others

Radlotherapy
group

Chemotherapy
group

Other
non-radlotherapy

67
59
59
30
28
26
13
24

T a b l e

16

D e v e l o ~ m e n to f recond p r i m a r y cancers I n c h l l d r e n[ T4 IP r l m a r y cancer

Wllms' tumour
Hodgkln's dlsease
Retlnoblastoma
Neuroblasto~
E u l n g ' s sarcoma
Rhabdomyosarcoma
B r a l n (excluding
medulloblartoma)
nedullobtastoma
Sof t - t l s s u e sarcoma
Non-Hodgkln's lymphoma
Acute l y m p h o c y t l c leukaemta
Osteosarcoma

a/ I nb/

Number o fchildrenPercentage
u l t h second
cancer

1248
1036
319
790
213
385
764
285
550
423
1530
271

o t h e r s t u d l e s . occurrence o f second cancers I n
Wllms' tumour p a t l e n t s I s about 2.5% [L3. 5101.
I n v o l v e d about 5 years o f f o l l o w - u p ; l n a n o t h e r s t u d y[ S l l ] o f 10 years o f f o l l o u - u p l t has been e r t l m a t e d
t o be 35%.

T a b l e

17

Cancer rlsk In chlldren lrradlated to treat tumours
havlnq a substantlal heritable fractlon

Increased
second cancer
rlsk ( X )DiseaseSltelrradlated

Dose
range

10
(Gy)

years

30
years
9-14

Retlnoblastoma

Head>I00 a/35-50 b/2-3

Ewlng's sarcoma

Bones54-65 b/35

Ullms' tumour

Abdomen25-30 a/

1-2

a/
b/

15

Second cancer typeRef

80% osteosarcomas
20% other sarcomas
8 0 X osteosarcomas[A3,A8,015.f2.
S2b.Vl)[Sll ]

Varlous carcinomas[L3]

Orthovoltage therapy.
Megavoltage therapy.

T a b ! e18

Occurrence o f second non-ocular tumours In ~ a t l e n t swlth retlnoblastomas[A31

Prlmary tumours
andtype of treatment

Bilateral

Number ofcases

Number ofsecondtumours

Number tn
treatment
f leldNumber outslde
treatment
f leld
31
3

693
18

89
5 a/

5R

Unllateral
Radlatlon
No radlatlon

688
23

89
5

b2
1

a_/

7

Includes three patients wlthout famlly hlstory of retlnoblastoma.
one case wlth cobalt plaque who developed t u m u r In thehumerus.

b/ Includes

T a b l e

19

Cumulatlve lncldence of second prtmarv cancers
In ~ a t l e n t swlth qenetlc retlnoblastoma

Slte of second cancer

Number ofpatlents

All sltes

384

In radlatlon fleld

314

Outslde radlatlon field

384

Type ofsecond cancer

A11 cancers
Osteosarcoms
All cancers
Osteosarcoms
All cancers
Osteosarcomas

Numberofsecondcancers
26
17
14
8
12
9

Cumulatlve lncldence(per cent) at
1 2 years

18 years

4.3
3.6
3.4
2.4
1.6
1 .b

8.4
6.0
6. b
3.7
3.0
3.0

T a b l e

20

Rlsk of thyrold and other cancer In chlldren
recelvlnq head and neck lrradlatlon

Slte orcause of
irradiation

Numberln
study

Tlnea capltls

10842

ThymusTonslls
MarshallIslanders
Atomlc bomb
survlvors
Local fallout
(USA)

Dose
(Gy)

Tumour type

Increasedrlsk at
30 years

2226
2651

0.09
3.8
3-6
1-10
7.8

0.15
0.13
C1 . O
1 .O
to. 5
8.0

3.5
1 .O
3.6

[S13, H1

2578

Thyrold
Leukaemla
Basal cell
Thyrold
Leukaemla
Thyrold250

7-20

Thyrold

7.3

1.8[Cb,ClO,L9]

0-6

Thyrold

7.1[U2]

0.3-2.4

Thyrold

2945

Excessrisk perlo4 PYGy

Reference[Rl. 5271[L9]?

T a b l e

[C41

21

Oose-response relatlonshlps
for thyrold cancer In chlldren Irradlated for enlarged thymus[ 538 I

Dose range (Gy)Control

Person-years

118157

Mean dose0

Cancers
5
Rate (/I0 PY)
Expected cases a/
Relative rlsk
~ x c e s s / l 0 PYGy
~

0.7
1.43
0.7

a/

1

0.01-0.49

0.50-1.99

2.00-3.99

4.00-5.99

>b.OO

33449

6020

11456

6382

1727

0.17
4

1.2

2.5

4.5

7.5

1

6

11

5

12.3
0.31
12.9
6.9

18.8
0.07
13.6
1.5

51 .O
0.13
45
2.0

128
0.08
130
2.8

154
0.03
196
2.0

Expected based on age and sex-speclflc thyrold cancer rates for New Yorkstate 1969-1971.

T a b l e

22

Oose fractIonatlon and rlsk ln thymus-lrradlated chlldren
[slei

Mean
dose
(GY)

Personyears

Cancers

Expectedcancers

Excessper 104
PYGy

Dose per fractlon
0.01-0.49 Gy
0.50-1.99 Gy
>2 Gy

0.18
2.2
3.1

33268
8622
14340

4
6
12

1 .O
6.8
14.2

6.1
2.2
2.3

Number of fractions
1
2
3

0.74
1.5
2.5

29414
22417
5445

7
6
9

5.1
9.7
7.3

2.9
1.S
3.8

T a b l e

23

Rlsk o f b r e a s t cancer I n atomlc bomb survivors under 10 y e a r s o f ape
a t t h e t l m e of t h e bomblnqs[T71-

Dose range (Gy) (T650R)
00.01 -0.09

0.10-0.49

0.50-0.99>1 .OD

Mean dose (Gy)
0

0.026

0.17

0.55

1.9

Observed
Expected

6
13.2

5
5.45

5
3.56

5
0.85

3
0.93

Relatlve r l s k

0.45

0.92

1.40

5.88

3.23

T a b l e

24

R l s k s o f leukaemta and o t h e r c a n c e r s
I n p a t l e n t s t r e a t e d f o r Hodqkln's d l s e a s e

R e l a t l v e r l s k a/Treatment

A l l cancers[fill]

[Bll]

[G4]

1.6
Chemotherapy o n l y 4.0
14.5
Combt ned

15.0
9.3
20.0

2.60
4.27

X rays o n l y-

R l s k r a t e s b/

Leukaemla

A1 1 c a n c e r s

1641

[Bll]

[C7]

[fill][C7]

1.0
0.0034
1.0 c/ 0.0075
261.0 0.0093

0.015
0.029
0.030

0.00100.00400.0070

0.000
0.062
0.064

147
118

[fig]

r/

Leukaemlaa/ R e l a t l v e r i s k s a r e observed/expected.
a r e cases/persor-year e x c e p t f o r t h e l a s t , whIch Is a
Rlsk r a t e d a t acumulattve (actuarial) r l s k a f t e r 7 years p o s t - e x p o s u r e .
C/ NO second cancers were observed I n t h e s e g r o u p s , so b a s e l l n e v a l u e( r e l a t l v e r l s k ) may be s e t t o 1.0.

T a b l e

25

Relatlve rlsk ot second cancer followlnq radiotherapt
for benlqn qynaecoloqic dlsorders and tor cervlcal cancer
[Ha.

BIZ]

[Cancer patlents followed for at least 10 years; other patlents
followed for a variable length of tltne. but generally m o r e than 10 years.
Rlsks slgnlflcant at the 0.05 or better level a r e underllned.)

Relatlve rlsk
Organ dose leveland slte
of second cancer

Radlotherapy treatment

Hlgh doses a/Colon
Rec t urn
Uterlne corpus
Ovary
Bladder
Other genltal
Intermediate doses b/
StomachPanc rear
KldneyOesophagus
Small bowel
GallbladderL o w doses (remote sites) c/
Lung
BreastThyrold
Oral cavlty
Sallvary gland
Braln
General systemlc cancerof unknown orlglnal slte
Leukaemla
Multlple myeloma
Lymphoma
Hodgkln's dlsease

Cancerpatients

Non-cancer
patlents

1.1

1.1
1 .2

1 .O
0.9
3.5
3.2

2.8

1.0
1.2
0.8
1.1
2.4
0.8

0.8
0.5
2.1

2.3

0.7

0.9
0.9

1.4
1.7
1.7

1.9

1.8

2.1

1.3
1.4
0.1

0.5
1.2
2.8
0.6
0.9
2.1
0.0
5.0
1.5

1.3
0.9

2.2
0.9
0.6
1.7
0.0
2.0

0.b

2.3

0.9
1.4
1.3
1 .C

No
radlotherapy
treatment

2.3

0.6
0.0
0.3
1.1

a/ For cancer patlents around 10 Gy; for non-cancer patlents 1-10 Gy.

b/ for cancer patlents 1-10 Gy: for non-cancer patlents comparatlvely
smaller.
c_/ Forcancer patlents
cornparatlvely smaller.

around

0.1

Gy:

for

non-cancer

patlents

T a b l e

26

R e l a t l v e r l s k and excess cases o f c a n c e r
f o l l o w l n ~l r r a d l a t l o n t o t r e a t c e r v l c a l cancer
1838 I(90% c o n f i d e n c e I n t e r v a l s I n p a r e n t h e s e s . )Second cancers
Colon
Cec umRectumA l l female g e n l t a l
Ovary
Vag lna
Other g e n l t a l
BladderConnectlve t l s s u e
StomachPancreas
KldneyBreastThyrold
Leukaemla
CLL
AL and CWLa/Relatlve r i s k
a t 1 Gy a/l x c e s s casesp e r 104 PYGy

1.00 (0.00-1.02)
1.02 (0.99-1.09)
1.02 (1.00-1.04)
1.01 (1.00-1.02)
1 . 0 (0.98-1.14)
1.03 (1.00-1.08)
0.98 (0.95-1.07)
1.07 (1.02-1.17)
0.95 (0.89-1.13)
1.69 (1.01-3.25)
1.00 (0.72-1.62)
1.71 (1.03-3.24)
1.03 (0.13-2.29)
13.30 (0.00-71.0)

0.01 ( - 0 . 0 3 -0.18)

0.06 ( 0.000.05 (-0.010.05 ( - 0 . 0 3 -

0.16)
0.17)
0.60)

-0.01
0.12
-0.01
3.16
0.00
1.10
0.54
6.87

1.00 (0.90-1.43)
1.14 ( 1 . 0 0 - 1 4 5 )0.00 ( 0.000.10 ( 0.00-(-0.07-

0.03)
0.30)
( - 0 . 0 3 - 0.03)( 0.05-10.40)( - 0 . 6 5 - 1.43)( 0.06- 3.50)(-14.6-21.1)(-2.04-39.2 )( 0.01-

0.17)
0.31)

See o r l g l n a l p u b l l c a t l o n f o r d e t a l l s o f t h e calculations.

T a b l e

27

R e l a t l v e r l s k o f second cancers I n p a t l e n t s t r e a t e d f o r o v a r l a n cancer[Rll I( R l s k s s l g n l f l c a n t a t t h e 0.05 o r b e t t e r l e v e l a r e underlined.)

Relatlve r l s k
S l t e ofsecond c a n c e r

Non-lrradlated patients

Irradiatedpatlents

N = 6713 a/

N = 6596 a/

N5455 b/All sltes
Bladder
BreastColon
Connectlve t l s s u e
Lndometrlum
Leukaemla
Lung
Lymphoma
Myeloma
Rectum
Stomachp/ Study group f r o m U n l t e d States N a t t o n a l Cancer Institute
End R e s u l t s Program.
o f a s u r v e y o f 70 U n l t e d S t a t e s m e d l c a l c e n t e r s
u s l n g chemotherapy.
Less t h a n 2 p a t l e n t s observed.

b/ Studyc/T a b l e

28

R e l a t l v e r i s k o f second c a n c e r s I n p a t l e n t s t r e a t e d f o r b r e a s t cancer[HZ01

Relatlve r l s k
S l t e o f second c a n c e r

Irradiatedpatlents

KldneyOesophagus
N o n - H o d g k l n ' s lymphoma
C h r o n i c l y m p h o c y t t c leukaemla
Acute non- l y m p h o c y t l c leukaemta
Lung. 1 0 - 1 9 y e a r s a f t e r l r r a d l a t l o nLung. 20-29 y e a r s a f t e r l r r a d l a t l o n

Non-lrradlated
patlents

1.9
1.7
1.7
1 .2
2.5
2.3
4.8

R e l a t l v e r i s k o f leukaemla t o l l o u l n q t r e a t m e n to f o t h e r p r l m d r y cancers I n a d u l t s( S l t e s n o t l l s t e d p r o d u c e d no cases o f subsequent l e u k a e m l a and t h e r e t o r e
t h e r e l a t i v e r l s k I s n o t e s t l m a h l e ( o r 1s 0 . 0 ) .
R l s k s s l g n l f l c a n t a t t h e 0.05 o r b e t t e r l e v e l a r e u n d e r l l n e d . )Slte ofprlmary
cancerOral/buccal
Oesophagus
StomachCo 1on
Rec t um
LarynxLung/bronchus
Connectlve
Helanoma
Breasttndometrlum
Ovary
Prostate
TestlsBladder
Kldney/renal
Thyrold
n u l t l p l e myeloma
A l l otherAll sltes

Surgery only

Radlatlon only

NumberNumberRlsk

Rlsk

Chemotherapy o n l y
NumberRlsk

T a b l e

30

Relatlve rlsk of leukaemta in ankvloslns s ~ o n d y l l t t spatlents
and In atomlc bomb survlvors

I
Populatton

Relatlve rlsk

Ankyloslng spondylltls
pattents
Atom\c bomb survlvors

4.19 (3.4- 6.6)
9.38 (1.0-12.6) &/p/

Excess cases per

lo4 PY

1.96 (1.24-2.88)
3.95 (3.04-4.86)

indlvlduals exposed to >1 Gy compared to those exposed tot0.l Gy (Tb50R).

T a b l e

31

Relatlve rlsk o f leukaemla ( l n c l d e n c e l
In women treated for qvnaecoloqical dlsorders

Dose ( G y )Cases

Condltlon treatedMean marrow d o s e a_/0.4-1.3
Benlgn and malignant dlsorders
1 .O-3.0
Benlgn and mallgnant dlsorders
Benlgn and malignant dlsorders
3.0-15
Total
Mean pelvlc
marrow dose
1 .b-3.2
Benlgn disorders
1 .6-5.0
Benlgn dlsorders
Uetropathla haemorrhaglca
2.2-5.2
3.0-9.0
Benlgn dlsorders
Uterlne mallgnancles
9 .O-45
a_/

b/

9
3

Relatlve
rlsk

21

3.5
1.2
1.1
1.5

I0 b/
9
6 b/
3
9

2.8
3.5
4.6
I .2
1.1

9

Includes cases treated for benlgn as well a s mallgnant dlsorders.
Based on leukaemla deaths.

T a b l e

32

Relatlve rlsk of multlple myeloma iollowlng varlous radlatlon exvosures[ClOI(Rlsks slgniflcant at the 0.01 or better level are underlined.
t h e others a r e slgnlflcant at the 0.05 level.
9 0 X confldence Intervals In parentheses.)Group and exposure type

Uterlne cancer
All cohorts receiving
appreciable alpha-radlatlor
All other cohorts recelvlng
gamna- or x-ray therapy
or dlagnosttc exposure
All cohorts recelvlng only x rays
All cohorts except uterlne cancer
All cohorts

Numberof cases

Relatlve rlsk

3

0.28 (0.1-0.7)

14

4.32 (2.6-6.8)

13
11
50
53

2.05 (1.2-3.3)
2.02 (1.1-3.3)
2.25 (1.7-2.8)
1.61 (1.3-2.0)

T a b l e

33

R l s k c o e f f i c i e n t s f o r r a d l a t l o n - I n d u c e d bone sarcomase s t i m a t e d I n t h e BEIR 1980 R e p o r t[c41

Type o f r a d l a t l o n and model

Cumulative
rlsk
coefflclentp e r l o 4 PGy

Alpha particles ( h l g h - L E T )Llnear
Dose-squared

Rlsk
rate
coefflclentp e r l o 4 PYGy

27
3.7 a_/

B e t a , garnna. and x r a y s (low-LET)
Llnear
1.4
Dose-squared
9200 a/1
980 b/

0.05
24000 b/a_/ Per l o 4 P G ~ ? .
b/ Per 104 P Y G Y ~ .
P r o v l s l o n a l c o e f f l c l e n t s f o r e n d o s t e a l doses up t o a few G y .
The r l s k - r a t e c o e f f l c l e n t 1s d e t e r m l n e d b y d l v l d l n g t h e
c u m u l a t l v e r l s k b y 27 y e a r s , t h e t o t a l r l s k p e r i o d ,foralpha p a r t I c l e exposure.

T a b l e

34

R e l a t i v e r l s k o f s k l n c a n c e r I n p a t l e n t s who r e c e i v e d s c a l p I r r a d l a t l o n
t o t r e a t tlnea c a p l t l s[C41

Age o r t l m e ( y e a r s )Numberof s k l ncancers

Age a t e x p o s u r e
1-19
20-24
25-29
30-34
35-39
40-44
>4 5

0
0
4
8
12
5
0

Tlme s l n c e exposure
1- 9
10-1 4
15-19
20-24
25-29
30-34

0
0
1
7
14
9

Relativerisk

T a b l e

35

R e l a t l v e r l s k o f b r e a s t cancer bv dose and aqe a t exposure,H l r o s h l m a and Naqasakl incidence data, 1950-1980[TI41

Kerm (Gy)
Age
at
the
t \me
of
bomblng

0.0

0.01-0.09

0.10-0.49

0.50-0.99a/1.00-1.99

2.00-2.99

Average t l s s u e dose ( G y )T o t a l b/ 1.0

1.0

1.3

1.4

2.7

3.00-3.99

a/

4.5

a/ Based on Tb50R.
b/ T o t a l s o b t a l n e d f r o m [Tb).

T a b l e

36

R e l a t l v e r l s k o f b r e a s t cancer l n f o u r d l f f e r e n t s t u d l e r( M o d l f l e d f r o m [Hb]. based on data t r o m 183. Hb. 16. 51. 7141)

Age a texposure

Atomic bomb
survivors(Tb50R)New Yort
mastltls

Massachusetts
fluoroscopy

Canadianfluoroscopy

Rates compare d l s e a s e I n women exposed t o more t h a n 1 Gy u l t hcases e x p e c t e d I n unexposed wcmen.
a/ I n s u f f l c l e n t d a t a .

>4.00

T a b l e

37

B r e a s t cancer l n c l d e n c e l n womenR e l a t l v e r l s k a t age
StudysertesAge a texposure

Number o fbreastcancers

20-29

30-39

40-49

50-59

60-69

4.1
1.1

3.1
1.7

3.1
1.2

2.1

4.9
2.0

3.1
1.9
0.3
2.2

3.4
2.4
0.8
0

1.2
1.0
1.8

Rochestermasiltls
patlents

20-29
30-39

18
13

Hassachusetts
fluoroscopy
patlents

10-19
20-39

15
24

9.0

40 a/
31
19
12
11

8.8

10-19
LSS patients.
1950-1974
20-29(T65DR doses) 30-39
40-49
>SO

a/

Exposure o f 0.1 Gy o r more.

T a b l e

30

B r e a s t cancer l n c l d e n c e l n I r r a d i a t e d r e l a t l v e t o unexposed women[H6]. based on [B3. Hb. L b . 511)

BreastAtomlc bomb
tlssuesurvlvorsa/dose (Gy)New York
mastltlr

Massachusetts
fluoroscopy

Canadlanfluoroscopy

Data g l v e n a r e r e l a t l v e r a t e s of b r e a s t cancer e x c l u d l n g t h e
f l r s t f l v e years o f post-operatlon observatton l n a l l except
t h e Canadlan s e r l e s , t o exclude non-radiogenic cases.
a / Based on T65DR.
-

>70

0.7
1.6

T a b l e

39

Estlmate of excess thyrold cancer cases (lnctdencel
per lor lndlvlduals exposed to 0.06-15 Gy[H51

Source oflrradlatlon

Exposed under age 18

Annual excess
Internal &/External b/
Llfetlme excess
Internal a/External b/

Exposed over age 18

Male

FemaleMale

Female

0.28
0.84

0.56
1.68

0.56
1.68

1.12
3.36

2.74
8.22

6.80
20.40

4.83
14.50

10.50
31.50

&/

Internal doses Include exposure to lodlne lsotopes 125. 131.
External doses Include exposure to x or g a n m radlatlon
or to lodlne lsotopes 132. 133. 135.
Mortality can be assumed to be 1/10 the lncldence values qlven ln
the Table. Assumes excess rlsk = 2.5 cases per lo4 PYGy. based ondata derlved from North Amertcan children. both sexes pooled.
b/

T a b l e

40

Relatlve rlsk of cancer In heavily lrradtated sltes
for comblned data ofankyloslng spondylltIs patlents and the Japanese Llfe Span Study[Dl1 I(Rlsks slgnlflcant at the 0.05 or better level are underltned.
90% confldence Intervals In parentheses.)Stte ofsecond cancer
Pharynx
Oesophagus
St~machPancreas
LarynxLung
Ovartes
SkIn
Bones (excluding
jaw and nose)
Multlple myeloma
Other lynphonras
CNS tumours (spInal
cord and nerves)
OthersA l l heavlly
Irradiated sltes
Selected sltes

Relatlve risk

1.76 (0.73-4.22)

1.82 (1.29-2.57)
1.24 (1.09-1.41)

1.24 (0.87-1.76)
1.35 (0.70-2.59)
1.54 (1.36-1.76)
2.39 (1.54-3.72)
0.61 (0.19-1.98)-

2.40 (1.08-5.34)
2.16 (1.11-4.20)
1.58 (1.07-2.33)-

9.31 (4.72-18.4)

1.62 (1.28-2.03)
1.46 (1.35-1.57)
1.11 (1.30-1.53)

Excess cases
per 104 PY

T a b l e

41

Sex differences ln cancer mortallty rlsks
In atomlc bomb survivors IT65DR doses1[PI51

Excess r\sk
per 104 PYGy

Male

Femalea/

MaleFemalea/

Backgroundmortality
sex
ratio
(F/M)

Relatlve r\sk
at 1 Gy exposureP

P

Leukaemla
All cancers
except leukaemla

3.84

4.08

0.96

1.95

1.20

0.03

0.54

1.11

1.25

0.007

3.29

4.42

0.3

0.57

Bladder, kidney
Colon
Oesophagus
Llver b/Lung c/Multiple myeloma
Stomach

1.41
1.18
1.09
1.31
1.19
1.64
1.07

1.77
1.60
2.23
1.46
1.67
1.43
1.19

0.5
0.8
0.03
0.8
0.03
0.8
0.15

0.27
0.19
0.14
0.11
0.78
0.07
0.90

0.23
0.37
0.22
0.06
0.92
0.06
1.07

0.8
0.5
0.8
0.6
0.95
0.7
0.8

0.47
0.55
0.12
0.33
0.32
1.27
0.46

a/ Slgnlflcance Is two-slded test of sex dlfference.

b/c/Includes lntra-hepatlc blle ducts.
Includes trachea and bronchial tree.

T a b l e

42

Rlsk of sallvary qland cancer lncldence ln medtcally lrradlated populatlons
ILll I

Mean
NumberUean
age at irradla- follow-up
exposure
ted(years)a/ After a five-year latency.

b/

Benign cases.

Uean
dose
(Gy)

Numberofcancers

Excess cases
per 104 PYGy

a/

Ref.

T a b l e

43

E f f e c t o f t ~ D eo f t r e a t m e n t on c u m u l a t l v e l n c l d e n c eo f second D r l m a r y cancers I n D a t l e n t s w l t h q e n e t l c r e t l n o b l a m[Dl51

Type o ftreatment

S l t e ofsecond cancer

Number o fpatients

NumberofsecondcancersA l l sltes
I n radlatlon fleld
Outslde r a d l a t l o n f l e l d

140
140
188

Radlotherapy
wl t hchemotherapy

All sltes
In r a d l a t l o n f i e l d
Outslde r a d l a t l o n f l e l d

62
62
65

8

Chemotherapy

A l l sites

3

1

Radiotherapy

Curnulatlve l n c l d e n c e(per cent) a t
12 years

18 years

4.2
2.9
1 .O

4.2
2.9
1 .O

6.6
4.2
4.6

14.2
9.9
1.5

4
3

1

4

5

100

100

No radiotherapy.
no chemotherapy A l l s l t e s

T a b l e

44

Comparison o f p r e d l c t e d and observed excess second cancers

I n women l r r a d l a t e d t o t r e a t c e r v l c a l cancer[El21

Secondprlmary
cancers

StomachColon
Llver
Pancreas
Lung
BreastKldneyBladder
Thyrold
Lymphom
Acute and NL
leukaemla

Rlsk
coef f l c l e n t(cases p e r
104 PYGY)[ c4 I

Organ dose (Gy)

Predicted
excesscancers

Observed
excesscancers

a/

1.68

1.12
0.70
0.99
3.94
5.82
0.88
0.88
5.80
0.27
2.70

I n wornen. e x c e p t t h o s e u l t h leukaemla. l l v l n g rnore t h a n 10 years;
women 4 t h leukaemla. v a l u e s are f o r 1-20 y e a r s a f t e r l r r a d l a t l o n .
b/ Averaged o v e r e n t l r e bone marrow.
c/ E x c l u d l n g p e l v l s c o n t r l b u t l o n .
E x c l u d l n g p e l v l s , lumbar s p l n e , and upper femur c o n t r l b u t l o n s .
a_/

a/

for

T a b l e

45

R e l a t l v e r i s k of cancer m o r t a l t t y
l n a n k ~ l o s l n q~ ~ o n d y l l t pl sa t l e n t s
021 I

r

Tlme s l n c e f l r s t t r e a t m e n t ( y e a r s )Total

A l l neoplasms
LeukaemlaColon cancer
A l l o t h e r a/

a/

1.77
5.45
2.40
1.57

1.53
12.51
0.54
1.28

1.48
4.67
2.41
1.30

1.61
2.41
1.38
1.60

1.51
2.19
1.87
1.47

1 . 1
1.46
0.46
1.19

1.08
1.94
1.02
1.07

A l l neoplasms o t h e r t h a n leukaemla and cancer o f t h e c o l o n .

T a b l e

46

R e l a t l v e r l s k o f cancer m o r t a l l t v a t s p e c l f l c s l t e s
l n ankyloslng spondylltls pattents[021 I( R l s k s s l g n l f l c a n t a t t h e 0.05 or b e t t e r l e v e l a r e u n d e r l l n e d .
R e l a t l v e r l s k computed as observed/expected r a t i o . )Tlme s l n c e f l r s t t r e a t m e n t
Total
>5
(5

5-25

>25

Mouth
Pharynx
Oesophagus
StomachRectumLlver
Pancreas
LarynxLung
BreastUterus
Ovary
Prostate
KldneyBladder
Sk ln
Splnal cord
Other CNS
Bone
Hodgkln's diseaseO t h e r lymphoma
M u l t l p l e myeloma
Other
Total

a/

A t l e a s t f l v e years have elapsed s l n c e t r e a t m e n t .

a/

1.33
3.17
1.30
1.28

T a b l e

47

Relatlve rlsk of cancer irortal!tv In aqe QrouDs ofankyloslna ~ ~ 0 n d v l l t~la ~t l e n t s
r 021 I

Tlme slnce flrst treatments (years)
Age at flrst
treatment

A11 but colon and leukaemla

5-25

>25

Total
>5

Leukaemla

5-25

>25

p/

&/

Total
&/

1.38

1.07

1.26

Total
>1

5.01

1.87

3.03

At least ftve years elapsed slnce treatment.

b/ At least one year elapsed slnce treatment.

Organ dose estimates (Gy) for ankvloslna spondvlltts patlents
calculated uslnq the Monte Carlo technlaue
[LlbI

Organ

Adrenals
Bladder
Braln
Gastrolntestlnal tract
StomachUpper large lntestlne
L o w r large lntestlne
Small lntestlne
Oesophagus
Genltalla
TestesOvarles
Other than above
Heart
Kldneys
Llver
Nasal reglon
Pancreas
Pulmonary reglon
Lungs
Maln bronchl
Trachea
Skeleton
Pelvls
Rlbs
Splne
Other than above a/
Skln
Trunk sktn
Skln excludlng trunk a/
SpleenThyrold
UterusTotals
Trunk
Legs
Head
Total body&/Indlrect calculatlon.

Mean ofestlmated
doses

Medlan ofestlmated
dosesStandard
devlatlon

Range

10-90%
range

T a b l e

49

Red bone marrow dose e s t t m a t e s (GY) f o r a n k y l o s l n q s p o n d y l l t l s p a t i e n t s
c a l c u l a t e d u s l n q t h e Monte C a r l o t e c h n l a u e[LlbI

Marrow s l t e

Proport lonof t o t a l redbone marrow
mass
(XI

Mean o f
estimated
dosesMedian o festlmated
dosesStandard
devlatlon

Range

10-90%
range

Arms
Legs
Cranlum
Mandlble
Clavtcles
Scapulae
Rlbs
PelvlsUpper s p l n e
Mid s p l n e
Louer s p l n e
Total marrow

T a b l e

50

Compdrlson o f t h e mean s h l e l d e d terma and orqan absorbed dose (mGylt n atomlc bomb s u r v i v o r s exposed t o 0.01 Gy and over under t h e T65DR and 0586 d o s l m e t r l e s[s481

Both c l t l e s
Organ dose

Hlroshlma

NagasakiDosesystem

Shleldedkerma

0586
T65DR

Bone marrow

0586
T6 5DR

Large i n t e s t i n e

OS86
T6 SORLung
Stomach

DS86
TbSDR

Female b r e a s t

0586
TbSOR

Bladder

DS86
T650R

Ovary

DS86
Tb5DR

Number

Total

Gamna

NeutronNumber

Total

Garma

NeutronNumber

Total

Gamna

Neutron

41719
41316

295
414

287
350

8
64

31044
26146

304
442

295
344

10
99

10675
15170

267
366

265
362

3
4

T a b l e

51

R e l a t l v e r l s k a t 1 Gy b y aae a t t h e t l m e o f t h e bomblnqs (AT8)and age a t d e a t h based on OS86 s h l e l d e d kerma[s491( R l s k b e f o r e t h e assumed mlnlmurn l a t e n c y p e r l o d of 1 0 years
l n d l c a t e d \n parentheses.)Age a t t l m e o f d e a t h

Leukaemla
0-10
10-19
20- 29
30-39
40-49
>50
Total
A l l cancers
except leukaemla
0-10
10-19
20-29
30-39
40-49
>50
Total
Stomach c a n c e r
0-10
10-19
20-29
30-39
40-49
>50
Total
Lung cancer
0-10
10-19
20-29
30-39
40-49
>50
Total
Breast cancer
0-10
10-19
20-29
30-39
40-49
>50
Total

44.16

3.41

8.64

0.95

(70.07)(40.90)5.89(0.82)

1.96
1.66(1.38)(0.84)

1.86
1.59
2.09
(1.12)(1.25)

2.22

1.60

1.58

7.22
(0.82)

1.30
1.26(0.82)(76.88)

1.54
1.21
2.66
(1.00)
(160)

1.30

1.26

1.70

0.84
(0
)

0.82
0.81
)
(0
(0
)

0.83
5.56
0.83
(0.81)
(0
)

0.82

2.32

0.92
10.48
(2.10)(0.83)

3.04
2.16
0.81
(0.80)
)
(0

3.72

1.63

75.32
( 0
( 0

)
)

0
( 0

)

( 0

)

0
( 0
( 0

0

0.84
)

)

0
(0

0

)

1.68
1.74
1.11
(1.12)(2.58)
1.39

1.37
1.23
1.13
(0.95)
1.13

1.48
1-33
1.15
1.29

2.88
1.93
0.97
(1.17
(3.30)
1.40

1.77
1.18
1.05
(0.92)
1.06

1.48
1.24
1.12
1.22

1.50
1.75
1.49
(1.58)(0.85)
1.57

1.03
1.50
1.34
(2.29)
1.44

1.26
1.40
1.44
1.39

4.21
2.05
2.86
(0.82)(8.16)
2.57

5.78
2.28
1.13
(0.82)
1 .

1.03
0.82
1.37
1-01

T a b l e

52

Excess d e a t h s p e r l o 4 PYGv by age a t t h e t i m e o f t h e bombings (ATB)
and aae a t d e a t h based on DS86 s h l e l d e d kerma[S(91( R l s k b e f o r e t h e assumed mlnlmum l a t e n c y p e r l o d o f 1 0 y e a r s
I n d i c a t e d I n parentheses.)Age a t d e a t h
0-20
Leukaemla
0-10
10-19
20-29
30 - 39
40-49
>50
Total
A l l cancers
except leukaemla
0-1 010-1 9
20-29
30-39
40-49
>50
Total
Stomach c a n c e r
0-10
10-19
20-29
30-39
40-49

>so

Total
Lung c a n c e r
0-1 0
10-1 9
20-29
30-39
40-49
>50
Total
Breast cancer
0-10
10-19
20-29
30-39
40-49

>so

Total

20-29

30-39

40-49

50-59

60-69

>70

T a b l e-

53Comparison o f 0'586 and T650R r l s k c o e f t t c t e n t s t o r m o r t a l l t ybased on s h l e l d e d kerma I n t h e Jaoanese OS8b subcohort( B o t h c l t t e s , b o t h sexes and a l l ages AT8 comblned.
90% c o n f l d e n c e t n t e r v a l s I n p a r e n t h e s e s . )S t t e o f cancer

Oosesystema/

Excess r e l a t t v e
r l s k per Gy

Ratlo
OS86/
T65OR

Excess deathsp e r 104 PYGy

Rat10
OS86/
TbSOR

A1 1 ma1 tgnant
neo~lasms
Leukaemta

A l l except
leukaemla
Oesophagus

StomachLarge l n t e s t l n e
except r e c t u mTrachea.
bronchus
and l u n g
Female b r e a s t

Ovary and o t h e r
u t e r l n e adnexa
Bladder. o t h e r
unspeclfled
urlnary
H u l t l p l e myeloma-a/ TbSORf= TbSOR-full, meantng t h a t r l s k c o e f f l c l e n t s
u s l n g TR65OR dose on t h e f u l l T650R c o h o r t .

were c a l c u l a t e d by

T a b l e

54

Com~arlsonof 0586 and T65DR rlsk coeff\clents for mortality
based on absorbed dose In the Ja~anese 0586 subcohort[ s48 I
(80th cltles. both sexes and all ages AT8 comblned.
90% confidence Intervals In parentheses.)

Dose
systemExcess relatlve
rlsk per Gy

Ratlo
DS86/
Tb50R

Excess deaths
per 104 PYGy

Rat10
OS86/
T650R

Leukaemla

OS86
T650R

5.21 (3.83-7.12)
5.76 (4.24-7.86)

0.90

2.94 (2.43-3.49)
3.11 (2.56-3.71)

0.95

All except
leukaemla

DS86
T650R

0.41 (0.32-0.51)
0.58 (0.46-0.77)

0.71

10.13 (7.96-12.44) 0.73
13.97 (11.11-17.04)

Oesophagus

OS86
T65DR

0.58 (0.13-1.24)
0.67 10.12-1.47)

0.87

0.45 (0.10-0.88)
0.49 (0.09-1.00)

0.92

Large lntestlne
except rectum

OS86
T65OR

0.85 (0.39-1.45)
1.04 (0.43-1.85)

0.82

0.81 (0.40-1.30)
0.98 (0.42-1.63)

0.83

female breast

DS86
T650R

1.19 (0.56-2.09)
0.91 (0.43-1.57)

1.31

1.20 (0.61-1.91)
0.90 (0.46-1.42)

1.33

Ovary

OS86
T650R

1.33 (0.37-2.86)
1.21 (0.11-3.06)

1.10

0.71 (0.22-1.32)
0.64 (0.06-1.43)

1.11

Bladder

OS86
T650R

1.27 (0.53-2.37)
1.59 (0.63-3.03)

0.80

0.66 (0.31-1.12)
0.81 (0.34-1.38)

0.81

Multlple myeloma

0586
T650R

2.29 (0.67-5.31)
2.39 (0.75-5.56)

0.96

0.26 (0.09-0.47)
0.29 (0.11-0.53)

0.90

Slte of cancerLung

T a b l e

55

Com~arlson of the maln characterlstlcs of the atomlc bomb,
ankyloslnq spondylltls and cervlcal cancer serles

Nature of study

Atomlc bomb
survlvors

Spondylltls
serles

Prospec tlve

Retrospectlveprospectlve

Sample slze

76000

Sex composltlon

f = 59%Age at lrradlatlon (years)
Average follow-up (years)

0->90
28.8

Cervlcal cancer
serlesRetrospectlveprospectlve

14000
F

:

17%

>15
13.0

Type of control

internal

Natlonal rates

Natlonal rates
and Internal

Type of doslmetry

Indlvldual(OS86)

Indlvldual forleukaemla. 1/15
random sample
elsewhere

Mean doseof a sample

Type of lrradlatlon

Instantaneous. Fractlonated.
whole-body
non-unlform,
partlal-body

Chronlc.
fractionated,partlal-body

0.24(0.01-6.0)

Extremely uneven

Oose dlstributlon
Mean dose
Range of doses

(GY)
(Gy)

Person-years at rlsk

21 85000

T a b l e

56

Sumnary o f t h e estlrnated r l s k o f cancerp e r 1 GY o f orqan absorbed dose o b t a l n e d From t h e a t o m l c bomb.
a n k y l o s l n q s p o n d y l l t l s and c e r v l c a l c a n c e r s e r l e s
EXCESS RELATIVE RISK

Organ o r t l s s u eAtomlc bomb
survivors( T a b l e 54)
1~491
5.21 (3.83-1.12)

Spondylltls
ser lesC e r v l c a l cancer
serles[S31] and [ 0 2 1 ]

(8381

a/

Leukaemla
A l l cancers
except leukaemla

0.41 (0.32-0.51)

Bladder
BreastKldneyLarge l n t e s t l n e
LarynxLung
M u l t l p l e myeloma
Oesophagus
Ovary
Rectum
Stomach1.21 (0.53-2.31)
1.19 (0.56-2.09)
0.58 (-0.09-1.94)
g/0.85 (0.39-1.45)
0.51 (-0.05-1 -68) g/
0.63 (0.35-0.97)
2.29 (0.67-5.31)
0.58 (0.13-1.24)
1.33 (0.31-2.86)
0.00 g/0.21 (0.14-0.43)

3.5

b/

0.88

0.14

c/

d_/

ABSOLUTE RISK
(excess deaths p e r l o 4 PYGy)

Organ o r t l s s u e

Leukaemla
A l l cancers
except leukaemla

Atornlc bomb
survivors( T a b l e 54)~ 4 I9Spondylltls
serlesC e r v l c a l cancer
serles[S31] and [ O Z l ][B381

2.94 (2.43- 3.49)

2.02

0.61

10.13 (1.96-12.44)

4.61

d_/

a/ Values I n parentheses a r e 90% confldence I n t e r v a l s .

They a r e those g l v e n
by t h e a u t h o r s .
b/ Thls f l g u r e was d e r l v e d by t h e Comnlttee f r o m [S31] u s l n g d a t a f r o m
l n d l v l d u a l s r e c e l v l n g a mean m a r r o r dose of 3 Gy o r l e s s .
c/ A l l cancers except leukaemla and c o l o n cancer.
d/ An e s t l m a t e o f t h e r l s k o f a l l cancers except leukaemla cannot be made f o r
t h l s serles.
An e s t l m a t e o f the whole-body dose does n o t e x l s t . andp r o b a b l y cannot be e s t l m a t e d g l v e n t h e n a t u r e o f t h e exposures.
e/ S h l e l d e d kerma.
-T a b l e

51

Sutnnary of assumptions used In the prolectlons

Mlnlmum latency

for leukaemla:
for all other sltes:

2 years
10 years

Plateau

for leukaemla:
for all other sltes:

4 0 years
Llfetlme

Extrapolatlon models

For leukaemla:
For all other sltes:

Addltlve and multlpllcatlve
Addltlve and multlpllcatlve

Oetrlment lndlcators

Llfetlme excess mortallty For cancer of each slte
Loss of llfe expectancy In person-years

Populatlon exposed

1.000 persons

Exposure

1 Gy to each slte at a hlgh d o s e rate

Basellne mortallty

Cancer mortallty tn Japan (1982)
or In the Unlted Kingdom [ W 2 1 ]Wholepopulatlon
Worklng populatlon

Age structure OF the populatlon In 1982
Populatton In 1982
between 2 5 and 6 4 years of age, both sexes

T a b l e

58

Rlsk coefflclents for adults from t h e atornlc bomb,
ankvloslng soondylltls and cervical cancer serles(These coefflclents were used for the calculatlons In Tables 59 and 60.)

Atomlc bomb
study a/Mallsnancv-

Cervlcal cancer
serles c/

Sex
nuitlpllcatlvee/Addltlvef/

nuittpllcatlve-e/Addltlve

nuittpllcatlvef/e/Addltlve
f/

3.7
3.8

5.0
2.9

3.5

2.0

f

0.88

0.61

Average

3.8

3.9

M
F

0.24
0.4

15
17

Average

0.35

16

Leukaemla

Othermallgnanclesp/

Spondylltts
serles b/

0.14
-

4.7

OS86; average values o f 25-29. 30-39. and >40 welghted by t h e proportlonsof the Japanese populatlon ulthln these age groups. f r o m [S49]. appendlr
tables 5a and 58. Part 11.
b/ from [021] and [Llb].
C/ From [836], page 1307.
Excess relatlve rlsk per Gy.
f/ Excess deaths per 10) PYGy.

i/

T a b l e

59

ProJectlon of excess llfetlme mortality
for an adult populatlon of both sexes (1000 males or 1 0 0 0 females1
exposed to 1 Gy of orqan absorbed dose of low-LET radtatton at hlqh dose rate
PLATEAU = 4 0 years

Spondylltls
sertes b/Atornlc bomb
study a/Hal lgnancy

Sexnuit\pllcatlve

Addltlve

f

9.0
8.1

13
7.0

Average

8.6

10

f

37
46

29
39

Average

42

34

51

44

Leukaemla(1)

Cervlcal cancer
serles b/

H
C/

Other
mallgnancles
(2)
a/

H

Total ( 1 ) + (2)(average)

nuit\pllcatlve

Addltlve

14

4.4

-

nuitlpllcatlve

Addltlve

2.8

1.4

21

35

12

PLATEAU = llfetlme

Atomlc bomb
study a/Hallgnancy

Spondylltls
serles b/

Cervlcal cancer
serles b/

Sex
nuit\pllcatlve

Othermallgnanctes
(3)
d/

M

Addltlve

F

41
52

30
42

Average

47

3b

56

4b

Total (1) + (3)multipllcatlve

23

1.8
-

37

12

a/ Reference populatlon: Japan, 1982.
b/ Reference populatlon: United Klngdom, 1982.

c/ Assumed latency tlme:

2 years.

d / Assumed latency tlrne: 1 0 years.

Addttlve

Hultlpllcative

Addltlve-

T a b l e

60

Projection o f l o s s o f l t f e e x p e c t a n c y
f o r an a d u l t p o p u l a t l o n of b o t h sexes (1000 males o r 1000 females)
exposed t o 1 Gy o f organ absorbed dose o f low-LET r a d l a t l o n a t h l q h dose r a t e

PLATEAU = 40 years

Atomlc bombs t u d y a/kllgnancy

Spondylltls
s e r l e s b/

C e r v l c a l cancers e r l e s b/

Sex
Uultlpllcatlve

Addltlve

F

140
120

290
170

Average

130

230

f

400
530

500
700

Average

470

600

600

830

Leukaemla
(1)
C/

Other
mallgnancles
(2)
dl

U

M

Total ( 1 ) + ( 2 )(average)

Uultlpllcatlve

Addltlve

140

79

Uultlpllcatlve

31

200

Addltlve

28

120

-

340

200

-

PLATEAU = l l f e t l m e

Atomlc bombs t u d y a/

Spondylltls
s e r l e s b/

C e r v l c a l cancers e r l e s b/

Sex

Malignancy

Uultlpllcatlve

Addltlve

U
F

420
570

510
710

Average

490

61 0

620

840

Other
mllgnancles(3)d/Total ( 1 ) + (3)(average)

Uultlpllcatlve

Addltlve

210

120

350

200

a/ Reference p o p u l a t l o n : Japan. 1982.
b/ Reference p o p u l a t t o n : U n l t e d Klngdom. 1982.
-

c / Assumed l a t e n c y tlme:
2 years.
/; Assumed l a t e n c y t l m e : 1 0 y e a r s .

-Uultlpllcatlve-

Addltlve

T a b l e

61Prolectlon of loss of llfe expectancy
for a populatlon of both sexes 1 5 0 0 males and 5 0 0 females1
exposed t o 1 Gv of organ absorbed dose of low-LET radlatlon at hlqh dose rate
as a functlon of age uslnq an age-constant rlsk coefflclent

ADDITIVE MOOEL
Age at exposure
Organ or tlssue

Leukaemla
All cancers
exceptleukaernla

640

530

420

310

210

120

62

24

2360

1750

1230

800

470

240

93

22

Age at exposure
Organ or tlssue

Leukaemla
All cancers
exceptleukaemla

250

240

250

260

240

190

130

63

920

930

920

880

790

620

370

130

T a b l e

62:

P r o e c t l o n s of excess llfetlme mortallty and loss of llfe expectanc
populatlon of both sexes (500 males and 5 0 0 females) and all a&forexposed to 1 Gy of orqan absorbed dose of low-LET radlatlon at hlqh dose rateuslng aqe-speclflc rlsk coefflclents
Rlsk coefflclents at ages 0-9 and 10-19 a r e glven In the text;
rlsk coefflclents for aaults are glven ln Table 58.
All rlsk coefflclents are based on the Japanese atomlc bomb survlvors.
(Based on the populatlon of Japan In 1982.)
EXCESS LIFETIME MORTALITY
Uultlpllcatlve
rlsk projectlon
mdel
Leukaemla a/
Other mallgnancles b/

1097

All mallgnancles

107

Addltlve
rlsk projectlon
model

42

LOSS OF LIFE EXPECTANCY
Uultlpllcatlve
rlsk projectlon
model
Leukaemla a/
Other mallgnancles b/

260
1110

All mallgnancles

1370

a/ Plateau: 4 0 years.
b/ Plateau: llfetlme.

Addltlve
rlsk projectlon
mode 1

T a b l e

63

P r o j e c t l o n s o f excess l l f e t l m e m o r t a l i t y and l o s s o f l l f e expectancy
f o r a p o p u l a t l o n of b o t h sexes I 5 0 0 males and 500 females) and a l l doese x ~ o s e dt o 1 Gv o f organ absorbed dose o f low-LET r a d l a t l o n a t h l a h dose r a t e
u s l n a an lac-averaaed r l s k c o e f f l c l e n t
The r l s k c o e f f l c l e n t s a r e based on Japanese a t o m l c bomb s u r v l v o r s .
R l s k c o e f f l c l e n t s g l v e n I n T a b l e 54 a r e averaged
over a l l c l a s s e s o f age a t exposure a c c o r d l n g t o t h e s l z e o f each c l a s s .
(90% c o n f l d e n c e intervals I n parentheses.)
EXCESS LIFETIME MORTALITY

Multlpllcatlver l s k projectlon
model
Leukaemla
Other m a l l g n a n c l e s

9.7
61

A l l mallgnancles

71( 7.1-13)(48 -75)

Addltlve
rlsk projectlon
model
9.3 ( 7.7-11)
36( 2 8 -44)
45

LOSS OF LIFE EXPECTANCY

Multlpllcatlver i s k projectlon
mode1

Addltlve
rlsk projectlon
model

Leukaemla
Other m a l l g n a n c l e s

220 (160-270)
730 (570-900)

300 (250-360)
910 (710-1110)

A l l mallgnancles

950

1210

T a b l e

64

Demoqraphlc c h a r a c t e r l s t l c s o f countries used t o compare r l s k p r o l e c t l o n s[W21 IL l f e expectancy ( y e a r s )I n f a n t r n o r t a l l t y ( p e r 1000 b l r t h s )Percentage o f p o p u l a t l o n under 15 years
Percentage o f p o p u l a t l o n over 64 years
Cancer m o r t a l l t y r a t e a/ (1985)
Death r a t e s a/ (1983-1985)
a/ Age-standard1 zed.

Japan

UnltedKlngdom

Puerto
Rlco

76.6
8
23.5
9.3
108.4
4.2

73.7
12
20.3
15.3
150.0
5.8

73.9
17
32
8
93.9
5.6

T a b l e

65Comparlson of prolectlons of llfetlrne excess mortality
ln three reference countrles
for 1000 persons of tne general ~opulatlon
exposed to 1 Gy of orqan absorbed dose of low-LET radlatlon at hlqh dose rate
Excess rlsk coefflclents derlved from atomlc bomb survlvors (Table 56)
and the assumptlons glven In Table 57.

Japan

Unlted Klngdom

nuit\pllcatlve Addltlve

nuitcpllcatlve

Addltlve

Puerto Rlco
multipllcatlve Addltlve

Leukaemla
Other mallgnancles

9.7
61

9.3
36

13
63

8.5
31

9.4
49

9.7
40

Total

71

45

76

40

58

50

T a b l e

66

Comparlson of projections of loss of llfe expectancy
In three reference countrles
for 1000 persons of the general population
exoosed to 1 Gy of orqan absorbed dose of low-LET radlatlon at hlqh dose rate
Excess rlsk coefflclents derlved from atomlc bomb survlvors (Table 56)
and the assumptlons glven ln Table 57.

Japan

Untted Klngdom~ultlMultlpllcatlve Addltlve pltcatlve

Puerto Rlco

Addltlve

Hultlpllcatlve

Addltlve

Leukaemla
Other mallgnancles

220
730

300
91 0

200
740

260
7 50

200
580

360
1090

Tota 1

950

121 0

940

101 0

780

1450

T a b l e

67

Excess relatlve rlsk per 1 Gy of orqan absorbed dose In the low dose ranqe[ 549 I

Dose range (Gy)Type of cancer

Leukaemla
All cancers
except leukaemla
StomachLung
Female breast
Colon

< 6.0

< 1 .

< 0.5

> 0.5 a/5.21 b/3.96 b/2.44 d/5.53

0.41 b/0.27 b/0.63 b/1.19 b/0.85 b/0.46 b/0.41 c/0.83 c/1.78 c/-0.10

0.37 d/0.45 g/1.06 a/
0.82
-0.52

0.41
0.26
0.60
1.21
0.98

-a/ Excess relatlve rlsk for doses > 0.5 Gy compared todoses < 0.5 Gy ls slgnlflcantly dlfferent only forleukaemla (p < 0.05) and for colon cancer (p < 0.1).
b/ p < 0.001.
c/ p < 0.01.
a/ p < 0.05.
g/ p < 0.10.

T a b l e

b8lunq cancer rlsk from chronlc exposure to radon dauqhters
Indoors and outdoors(111 I

txcess frequency of lung cancers
per mllllon persons per year
Sourcednd

locatton

Equll lbrtum
Annualequlvalent
exposure
concentration

Excessrelatlve
Reference population
risk

(105
( Bq/m3

Non-smokers~q h/m3)

(%)

ales

FemalesTotal(averageboth sexes)

0.90
0.23
0.040

9.0
2.3
0.52

54
3.1

11
2.7
0.62

32
8.1
1.9

7.2
1.8
0.42

1 .Z

11.8

71

14

42

9.4

0.030
0.00750.0020

1.0
0.25
0.bb

6.0
1.5
0.40

1.2
0.30
0.079

3.6
0.90
0.24

0.80
0.20
0.053

0.040

1.3

7.9

1.6

4.7

1.05

13

79

16

47

10.5

Radon-222 daughters
Indoors p/
Indoors b/
Outdoors

15
15
4

Subtotal

14

Radon-220 daughters
Indoors a/
Indoors b/
Outdoors
Subtotal
Total

a/ At home.

b/ Elsewhere.

0.5
0.5
0.2

T a b l e

69

Projectlon of excess llfetlme mortality for speclflc cancers
for 1 0 0 0 persons exposed to 1 Gy of oroan absorbed doseof low-LET radlatlon at hlgh dose rate
(Based on the populatlon of Japan.
90% conftdence Intervals In parentheses.)

Malignancy

Multlpllcatlve
risk projectton
msdel

AddltIve
risk projectionmodel

9.7 ( 7.1-13)

Red bone marrow
All cancers
except leukaemla

61(48 -75)

Bladder
Breast
a/
Colon
Lung
Multlple myelomaa/
Ovary
Oesophagus
Stomach

3.9
6.0
7.9
15.1
2.2
3.1
3.4
12.6

( 1.6- 7.3)

Remalnder

11.4
11.8

b/
c/

( 2.8-10.5)( 3.6-13.4)( 8.4-23.0)( 0.6- 5.1)
( 0 . 9 - 6.8)
( 0.8- 1.2)
( 6.6-19.9)

Tota 1a/ These values have t o be dlvIded by 2 t o calculate thetotal and other organ rlsks.

b/ Thls value Is derlved by subtracting t h e sum of t h e rlsks
at t h e sltes speclfled from the rlsks for all cancers
except leukaemla.
c/ Thls value Is derlved by flttlng a llnear relatlve rlsk
model t o the baslc cancer data after the exclusion of
those cases of cancer at the speclflc sltes llsted.
(Coefflclent 0.19 excess relatlve rlsk per Gy and 1.87
per 104 PyGy).
d/ Red bone marrow plus all other cancers.
g/ Red bone marrow plus other lndlvldual sltes Includlng
remalnder.

T a b l e

70

P r o j e c t t o n o f l o s s o f l l f e expectancy f o r s p e c l f t c c a n c e r s
p e r p e r s o n e x ~ o s e dt o 1 Gy o f orqan absorbed doseo f low-LET r a d t a t l o n a t h l q h dose r a t e(Based on t h e p o p u l a t t o n o f Japan.
90% c o n f t d e n c e I n t e r v a l s I n parentheses.)

Ualtgnancy

Multlpl\cattve
r l s k proJectton
model

Addltlver l s k projection
model

Red bone marrow
A l l cancers
e x c e p t leukaemla

0.22 (0.16-0.27)

0.30(0.25-0.36)

0.73 (0.57-0.90)

0.91(0.71-1.10)

Bladder
Breast
a/
Colon
Lung
H u l t l p l e myelomaa/
Ovary
Oesophagus
Stomach

0.03
0.11
0.09
0.17
0.03
0.06
0.04
0.15

(0.01-0.06)(0.05-1.90)(0.04-0.15)(0.09-0.25)(0.0 -0.06)(0.02-0.12)(0.01-0.08)(0.07-0.23)

Remalnder

0.14
0.14

b/

0.28
0.17

c/

c/

b/

lotal

a/ These v a l u e s have t o be d l v l d e d by 2 t o c a l c u l a t e t h e t o t a land o t h e r o r g a n r l s k s .

b/ T h l s v a l u e l s d e r l v e d by s u b t r a c t l n g t h e sum o f

the r l s k s
a t t h e s l t e s s p e c l f l e d from t h e r l s k s f o r a l l c a n c e r s
e x c e p t leukaemla.
c/ T h t s v a l u e I s d e r l v e d by f l t t l n g a l l n e a r r e l a t l v e r l s kmodel t o t h e b a s i c cancer data a f t e r t h e exclusion o f t h o s e
Coefftclent
cases o f cancer a t t h e s p e c l f t c s l t e s l l s t e d .
0.19 excess r e l a t l v e r l s k p e r Gy and 1.87 p e r 10 PYGy).
d/ Red bone marrow p l u s a l l o t h e r cancers.
g / R e d bone marrow p l u s o t h e r l n d l v l d u a l s l t e s I n c l u d i n g
remalnder.

4

T a b l e

71

S u m r v of prolectlons o f l l f e t l m e r l s k s
f o r 1000 persons (500 males and 500 f e m a l e s 1
exposed t o 1 Gv o f oroan absorbed doseo f low-LET r a d l a t l o n a t h l q h dose r a t e(Based on t h e p o p u l a t l o n o f Japan.)Total

populatlona/Worklng p o v u l a t l o n(aged 25-64 y e a r s )Adult p o p u l a t l o n( o v e r 25 y e a r s )b/

Rlsk p r o j e c t l o n
model

Excessf a t a l cancers

Years o f l l f e l o s t

Addltlve
Uultlpllcattve

40 c/ - 50 d/
70 $/ -110 c/

950 c/ - 1200 d/
950 !/ - 1400 c/

Addltlve
Uultlpllcatlve

40
70 c/

a/ - 60 c/

880 d/ - 1330 c/
820 c/ - 970 d/

Addltlve
Multlpltcatlvea/ D e r l v e d f r o m T a b l e s 62 and 63.
b/ D e r l v e d f r o m Tables 59 and 60.

C/ A g e - s p e c l f l c r l s k c o e f f l c l e n t .

d/ Constant (age-averaged) r l s k c o e f f l c t e n t .

- 8 0 d/
50 d/
60 d/

840 d/
620 d/

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