GENETIC AND SOMATIC
EFFECTSOF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
1986 Report to the General Assembly, with annexes

UNITED NATIONSNew York, 1986

NOTE

The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Forty-first Session, Supplement No. 16 (A/41/16).
The designations employed and the presentation of material in this publication do
not imply the expression of any opinion whatsoever on the part of the Secretariat of theUnited Nations concerning the legal status of any country, territory, city or area. or of its
authorities, or concerning the delimitation of its frontiers or boundaries.

UNITED NATIONS PUBLICATION
Sales No. E.86.IX.9
ISBN 92-1-142123-3004800P

ANNEXB

Dose-response relationships for radiation-induced cancer

CONTENTSParagraphs

INTRODUCTION •.•..••••.. _......... ..
I.

DOSE-RESPONSE RELATIONSHIPSFOR RADIATION-INDUCED CANCER ....•.•.............•.........
A.
B.

The independent variable ........ .
The dependent variables in experimental work ..................•
C. The dependent variables in epidemiological studies .....•............
I. The risk expressed in absoluteterms .................... .
2. The risk expressed in relative
terms .................... .
D. Temporal relationships .......... .
I. Latent period ............. .
2. Relationships between dose andtumour-free lifetime lost as aresult of induced cancers .... .
E. Summary and conclusions ....... .

II. ASSUMPTIONS AND LIMITATIONS
OF EXISTING MODELS .......... .
A.

B.

C.
D.
E.
F.
G.
III.

Basic phenomena and influence ofmodifying factors ...•...........
The threshold dose for cancer induction ......................... .
Unicellular versus multicellularorigin of neoplastic growth ...... .
Autonomy of target cells for tumour
induction ...........•..........
Number of cells at risk •.•........
Population heterogeneity and susceptibility to cancer induction . . . . .
Summary and conclusions . . . . . . . .

1-18

B.

Derivation and characteristics of
dose-response models ........... .
1. The linear model .......... .
2. The linear-quadratic model .. .
3. The quadratic model .......•
Summary and conclusions ....... .

109-147
109-116
I 17-142
143-147
148-157

DOSE-RESPONSE RELATIONSHIPSIN EXPERIMENTAL SYSTEMS ....

158-341

19-63

C.

24
25-36

IV.

37-50

A.

42-48
49-50
51-57
52-56

B.
57
58-63

64-104

64-74
75-76
77-78
79-89
90-92
C.
93-97
98-104

DOSE-RESPONSE MODELS OF
RADIATION-INDUCED CANCER

105-157

A.

106-108

Introduction ......•.•..........

Paragraphs

V.

Phenomena observed at the cellularand subcellular level •....•....... 158-228
160
I. Mutations in germ cells ..... .
2. Mutations in somatic cells ... . 161-170
3. Chromosome aberrarions ... . 171-178
4. Oncogenic transformation ofcells in vitro ....•........... 179-228
Tumours in experimental animals .. 229-321
I. Myeloid leukaemia ......... . 232-241
2. Thymic lymphoma ......... . 242-248
3. Other reticular tumours ..... . 249-252
4. Tumours of the thyroid ..... . 253-258
5. Mammary tumours ........ . 259-274
6. Lung cancers .............. . 275-282
7. Lung adenomas ...•.......• 283-285
8. Ovarian tumours .......... . 286-289
290
9. Pituitary gland tumours .... .
JO. Harderian gland tumours ... .
291
11. Skin tumours ............. . 292-301
12. Bone tumours (internal irradiation) ................. · · 302-311
13. Liver .................•.... _ 312-313
14. Combined tumour data andindirect inferences ......... . 314-321
Summary and conclusions . . . . . . . . 322-341

DOSE-RESPONSE RELATIONSHIPSFOR TUMOURS IN MAN . . . . . . . . . .

A.

Leukaemia ................... .
I. Direct studies ............. .
2. Indirect evidence .......... .

342-471347-355
347-353354-355

165

Paragraphs

B.

C.

D.

E.

Cancer of the breast ............ .
1. Radiotherapy for mastitis ... .
2. Pneumotherapy patients .... .

356-377361-363364-377

Tumours of the thyroid ......... .
1. Direct studies ............. .
2. Indirect evidence .......... .

378-398378-385386-398

Cancer of the respiratory tract ..•.
1. The risk expressed in absoluteterms . . . . . . . . . . . . . . . . . . . . .
2. The risk expressed in relative
terms . . . . . . . . . . . . . . . . . . . . .

399-432428-432

Bone sarcoma ................. .
l. Direct studies ............. .

433-456434-450

2.

The model of Marshall andGreer .................... .
Interspecies comparisons ........ .
Summary and conclusions ....... .

451-456457-462463-471

VI.

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

472-491

VIL

RESEARCH NEEDS .............. .

492

F.
G.

401-427
Page

Introduction
1. It has long been recognized by UNSCEAR thatradiation-induced malignant diseases are the mostimportant late somatic effect in human populations
exposed at high doses for which direct observations
are available [U6, U7, U9-Ul2. U24]. For evaluationof radiological risk or detriment [12] this importancederives from the fact that these diseases are often
lethal and they are the only statistically verifiable
cause of radiation-induced life shortening at intermediate and low doses [B 17, B 18, JI. K39, K40, U24].
Radiation-induced cancer belongs to those radiobiological effects whose frequency of occurrence (but not
severity) is believed-as a rule-to correlate withdose. a The postulated probabilistic nature of therelationship between dose and frequency of malignancyb
has led to the acceptance of the term "stochastic" foreffects of such type.

2. Assessment of risk. from environmental andoccupational radiation sources in the dose region fromfractions of mGy to a few tens of mGy, would begreatly facilitated by knowledge of the shapes of thedose-response relationships for radiation-induced
cancers in humans. This knowledge is not available atpresent and is not likely to be obtained by direct
observation. Two features of the dose-response relations are most important for evaluation of the risk at
low doses: the possible presence of a threshold dose
below which the effects would not occur, and theshape of the dose-response curve.
3. Lack of threshold for a given effect is usuallyassumed if the response for this effect, plotted against
the independent variable (causal factor. or, specifically,dose). permits extrapolation by eye to the origin of
the coordinate system. or when the calculated regres~For brevity, the term "dose" is used here instead of the morecorrect "absorbed dose".

hin this annex, the term "carcinogenesis" is used to include
carcinoma, leukaemia or any other form of malignancy (sarcoma,
lymphoma, etc.). The word "malignancy" is used when thereference is to all such malignant conditions, while "cancer" or"malignant tumour" refer only to solid or focal malignancies. The
term "tumour" is used without qualification when it is either clear
from the context, or unimportant, whether a malignant or a benign
tumour is intended.

166

Paragraphs

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

245

References ............................. .

248sion line intercepts the abscissa at values that are
not significantly different from zero. Conversely. athreshold is usually assumed when the fitted regressionfunction crosses the abscissa at a value significantly
greater than zero. However, proving or disproving athreshold below the levels of direct observation may
be impossible, due to statistical fluctuations of the
spontaneous level and of the presumably induced
response. Therefore, assumptions regarding a threshold
are based essentially on theoretical considerationsof the mechanisms of radiation interaction with thebiological targets for initiation of neoplasia. supplemented by empirical observations to support the
hypothesis. Although absence of the threshold is often
assumed, this has not been proved for any formof radiation-induced malignancy [U6] and must be
regarded as a working hypothesis.
4. In annex I of the 1977 UNSCEAR report [U6].
the available data concerning experimental radiation
carcinogenesis in numerous animal species were reviewed. The large variation of susceptibility to cancer
induction in different tissues was emphasized. Physicaland biological factors modifying the frequency of
induction were discussed in great detail and interactions of other agents (e.g., viruses) with radiation
were also reviewed. The extreme complication andunsatisfactory understanding of the pathogenesis of all
forms of cancer, including those induced by radiation.
were particularly stressed.
5. Various physical factors. such as dose, dose rate,
and quality of radiation, were also considered, andgeneral patterns could be recognized in cases wheresuch factors were systematically studied in a given
strain of animals, and for specific tumour types.
Among the patterns identified, were a sparing effect ofdose fractionation and protraction of low-LET radiation (x or gamma rays) upon the frequency of induced
cancer and the absence, or even reversal, of suchan effect for high-LET radiation (neutrons, alphaparticles).
6. Current theories of cancer induction by radiationand some other agents (viruses. chemicals) were also
briefly reviewed in the 1977 UNSCEAR report [U6].
None of these was able to accommodate all the known
facts and to allow development of a theory or of

comprehensive models of cancer induction by ionizing
radiation. It was recognized, however, that known
carcinogens have a common target within the susceptible cells, which is most likely the nuclear DNA or
genome.

as to whether such tumours may represent adequate
models of corresponding human diseases. Similar
doubts would also apply to some observed forms of
dose-response relationships. In some cases. doseresponse relationships differ from species to species.
although in many cases consistent patterns have beenfound. For these reasons, the increased incidence perunit dose of a given form of cancer cannot-as arule-be extrapolated between species.

7. Since the 1977 report [U6], new information has
been published on experimental induction of cancer
by radiation. Some of it refers to observations atintermediate and low doses. Of particular importanceis the information dealing with high-LET particles(mostly neutrons). This is reviewed here when it appears
relevant to models of radiation-induced malignancies.

10. For dose-response relationships of category (a)some regularities were pointed out that appeared toconform to other radiobiological phenomena occurringin single cells (e.g., cell killing, induction of mutations
and chromosome aberrations). These common features
were as follows:

8. In annex I of the 1977 report [U6], the response
relationships as a function of single acute doses forvarious forms of experimental radiation-induced
cancer-both after whole-body and localized irradiation-were reviewed thoroughly. Tumours could bebroadly subdivided into three categories:(a)Those showing an increasing incidence withincreasing dose up to a maximum, with a decline
following that maximum (most forms):(b)

Those displaying a negative conelation between
incidence and dose, as observed in tumours withan unusually high spontaneous frequency:(c)Those showing no clear rise with increasing dose
up to several Gy.

For occupational and environmental exposure of man,type (a) is the most relevant. Schematic examples ofdose-response curves are shown in Figure I.

(a)

The RBE values for densely-ionizing radiation
relative to x and gamma rays are higher than I
and decrease as doses increase:(b)With acute doses of high-LET radiation thedose-response relationship is closer to linearity
than for sparsely-ionizing radiation, for which
upward concave curvilinearity is usually observed:(c)

The tumour yield often shows little dependence
on dose protraction and fractionation for highLET radiation. while for x and gamma rays theyield usually declines.

11. Since publication of the 1977 report [U6], additional information has appeared on tumour induction
and life shortening in the low and intermediate dose
region. It shows that after acute (high dose rate) highLET exposure, in some cases at intermediate and in
most cases at high doses. the incidence of tumours perunit dose decreases with increasing dose. For low-LET
acute exposures. such a decline is usually observed
only at high doses (above several Gy). These andother observations, together with some notable exceptions. will be discussed in detail in chapter IV.

9. UNSCEAR [U6] also identified a large variabilityof the net incidence of various tumour types atintermediate to high doses between different species
and. within species. between inbred strains. It was also
found that in many cases a particular tumour could be
induced by radiation in only one or two strains of agiven species, an observation that must raise questions

...

~5

·c
:::,

t' 4
"''-

-i...:"'

Curve 1: Downwards concave
Curve 2: Linear
Curve 3: Upwards concave
Curve 4: Threshold type
Curve 5: A high spontaneous
tumour rate
declining with dose

3

u

~
2
u

Cl

u
z

:::.. 1
1-

u

w
.....
.....
u

2

3

4

5

6

DOSE (arbitrary units)
Figure I. Typical dose-response curves for radiation-Induced tumours. Curve 1: Downwards
concave; Curve 2: Linear, Curve 3: Upwards concave; Curve 4: Threshold type; Curve 5: A highspontaneoua tumour rate decllnlng with dose. The shaded area repreaents the spontaneous(control) Incidence.

16712. In annex G of the 1977 report [U6]. UNSCEAR
presented a comprehensive review of epidemiological
data on radiation-induced cancer in man. Absoluterisk estimates of mortality per unit dose were examined
in detail for malignant diseases of various organs, andconfidence limits were attached to these estimates,
derived in most cases from irradiation with doses at or
above 1 Gy. Also, an approximate life-time risk ofmortality from cancer at all sites per unit dose wasestimated from the ratio of incidence of all nonleukaemic malignancies to the incidence of leukaemias
in several groups (atomic bomb survivors. Americanradiologists, and patients treated for ankylosing
spondyli tis and metropathia haemorrhagica ). However.
the previously available dosimetry at Hiroshima andNagasaki has been questioned, and the new dosimetricsystem (DS86) is expected to yield improved risk
coefficients for atomic bomb survivors. who are oneof the most important sources of information.
13. The merit of such risk estimates lies in the factthat thev are derived directly from human data andthus av~id interspecies extrapolations of doubtful
validity. The precision of the 1977 risk estimates was
the best possible under the conditions of exposure andfollow-up then available, but many limitations of theestimates were discussed extensively.

14. Uncertainties regarding the shape of the doseresponse relationships for radiation-induced malignancies, and the related risk estimates in man, derive
mostly from the following conditions:

(a)

(b)

168

The short duration of follow-up of irradiatedpopulations compared to the length of latent
period of most tumours. Whereas 20 to 30 years
may be sufficient for manifestation of leukaernias
and bone sarcomas after short-term irradiation.
it is not so for other cancers. At present, the time
distribution of their latent periods is not known
in detail. and for some cancers it depends upondose (or dose rate for chronic exposure), and also
on age at irradiation. In addition. several. if notall, radiation-induced tumours tend to have an
age distribution similar to that of their spontaneous counterparts. This means that greater
absolute incidence per unit dose will be observedin cohorts of older than of younger ages. On theother hand. the expression of induced cancers
will be truncated in cohorts irradiated at older
ages, owing to their limited survival. Thus. theshape of the dose-response curve may depend
upon the length of follow-up and on the age
structure of the irradiated population. In moststudies, the mean follow-up period is substantiallyshorter than the time needed for full tumour
expression. In addition, a negative correlation
between dose and latent period could. if present.
affect the shape of the dose-response relationship, because it could not permit comparable
tumour expression after high and low dose;
The sex and age composition of the population
under study. Since for certain tumours the age at
irradiation and sex have a pronounced effectupon the risk of later development of themalignancy, a given dose-response relationshipmay not be representative of populations ofdifferent composition:(c)

There is a pronounced geographical. socioeconomic and ethnic variation of the spontaneous incidence of cancers in most organs. (For areview of this point see [D 17, W9].) This suggeststhat epidemiological observations on radiationinduced cancer cannot be applied indiscriminately
to populations of different ethnic. socio-economic
or geographic characteristics. On the other hand.
such differences are not necessarily reflected in
the value of the absolute risk or the shape of thedose-response relationship. For instance. in spiteof large differences in the age-specific incidence.
the age-corrected excess risk of breast cancer anddose-response curves in Japanese atomic bomb
survivors are very similar to those in women
irradiated in the United States for medical
reasons;(d)

Deficiencies of tumour ascertainment in retrospective studies from available records of incidence or specific mortality:(e)Difficulties in the selection of suitable comparisongroups for the calculation of the expected (control)
incidence or mortality due to a given tumour;(f)Presence of confounding variables and modifying
factors (promoters. inhibitors) that. if correlatedwith dose, or per se. could modify the shape ofthe dose-response relation:(g)

Questionable accuracy of dosimetric estimates.
particularly when these involve retrospective
reconstructions of complex situations. Numerous
examples of such uncertainties are given inchapter V. In this category belongs also the very
narrow range of doses to which a population
may have been exposed. as well as the nonuniformity of dose distribution in the target
organs. The latter condition may distort therelationship when the mean organ dose is used as
the independent variable and induction is not a
first-order process;(h)Statistical uncertainties in the estimates of incidence or mortality at given dose levels.

15. Because of such limitations, in view of thepresence of numerous and often unknown biologicalvariables affecting cancer incidence. and of the lackof understanding of the pathogenesis of cancer,
UNSCEAR cautioned against the indiscriminate useof risk estimates under conditions other than those forwhich they had been derived. For example, direct
application of the risk coefficients to doses in therange from I mGy to 0. I Gy involves a procedure oflinear extrapolation, i.e.. an assumption that theincidence per unit dose does not vary with dose. Sucha procedure could, however. lead to over- or underestimates of risk. depending on the actual shape of thedose-response curve. It was generally concluded, inthe 1977 report, that the real risk per unit dose of lowLET radiation at low doses and/or dose rates would
be unlikely to be higher, but could be substantiallylower. than the values derived for the range of a few
tens of mGy. The derivation was based essentially onobservations made above I Gy, but some reduction of
the effect at low doses was already assumed (e.g., forleukaemia by a factor of about 2).
16. The v.'ide confidence limits on the data from man
allow various mathematical functions to be fitted tothe same epidemiological series [B 17. B20, B24, C29,
M31, R21, SSO]. Consequently. the probability of
being able to discriminate between the statisticalgoodness of fit of various alternatives. or to rejectsome of them. is too low. In addition, the extrapolation of a relationship beyond the region of direct
observation is always questionable when the underlying mechanism is not well understood.
17. In view of all these difficulties UNSCEAR has
followed another approach in preparing the present
annex. It has reviewed evidence at the subcellular andcellular level. from which inferences could be made as
to the possible nature of the dose-response for cancer
initiation by radiation. It has also examined how
initiation of cancerous clones. and their progression toclinical tumours. may affect the shape of the doseresponse relationship. Finally, it has reviewed publishedmodels of cancer induction and tested them forcompatibility with epidemiological and experimental
findings. It is hoped that this complex exercise may
help to establish, with some confidence, the shape of
dose-response relationships, and thereby limit theuncertainty in the extrapolation of the risk to low
doses.
18. Thus. the objectives of this annex may besummarized as follows:(a)

To review the critical assumptions involved in
the formulation of models linking radiationinduced cancer to dose;(b)

To review and discuss dose-response re la tionshi psfor effects at the cellular level that could conceptually be linked with malignant transformation:(c)

To discuss models of cancer induction by radiation from the standpoint of resulting doseresponse relationships for tumours of someorgans and tissues;(d)To review the effects of the mode of dosedelivery (dose rate, fractionation) and quality ofradiation upon the dose-response relationships;(e)

To identify possible general trends. and interspecies similarities. brought about by changes in
the above variables upon the dose-response
relationships for various types of cancer.

UNSCEAR wishes to stress that in pursuing thisexercise it does not intend to give more weight or
credit to one or another model of tumour induction,
nor to depart from previously established policies inrisk estimation adopted within the Committee. This
review is meant to be a purely scientific analysis ofdata aiming at an assessment of systematic errors in
the risk estimates derived from existing epidemiological evidence when one or another model is assumed ininterpreting such evidence.

I.

DOSE-RESPONSE RELATIONSHIPSFOR RADIATION-INDUCED CANCER

19. Radiation-induced cancer, as a stochastic phenomenon. can be analysed in terms of probabilistic
concepts such as the distribution function of the timefrom irradiation to the occurrence of cancer. Depending on the data, the event may be assumed to occur at
the time of diagnosis for readily apparent tumours, orat the time of death for rapidly lethal ones. The
definitions and procedures of estimation are similar,
but the two cases should not be confused because this
could lead to serious errors. particularly v.'ith cancers
for which effective therapy is available.

20. In experimental work. the populations understudy consist generally of inbred animals standardized
for species, strain. sex and age. They are irradiatedunder controlled conditions and followed for a specified
time or up to death. Appropriately matched control
groups are followed concurrently under similar conditions. The time of death and, at least in someexperiments. the cause of death, can be ascertained foreach animal. Such data may undergo sophisticatedstatistical treatments.
21. Easily diagnosed or rapidly lethal tumours arereadily discovered. For such '"manifest'· neoplasms,
established mathematical procedures can be applied tocorrect for competing risks. e.g., intercurrent mortality
not related to the tumour incidence. Under these
conditions. the time to the expression of the tumour isknown only for some of the individuals in thecollective, while others die or disappear from observation due to unrelated causes before a tumour isobserved. For these latter individuals one knows onlythat the hypothetical time to the tumour would havebeen longer than the observation time. i.e., it would lie
to the right on the time scale. Hence one speaks of"right censored" data.
22. If tumours are "occult", in the sense that they
are discovered only incidentally in animals killed ordying for other reasons, one speaks of "double
censored" data. In this case, one knows either that thetime to the expression of the tumour is shorter thanthe observed time of death or that the hypotheticaltime would be longer than the time of death,according to whether the dead animals carry atumour, or not. Under these conditions the expression"double censored data" is used (meaning that the data
are both "left and right censored"') and the methods
for a competing-risk-corrected analysis are more
complex (see paragraph 31). There are special difficulties for partly lethal tumours. but a four-point
grading of the tumours is usually practicable andsufficient for the analysis: it ranges from "definitively
incidental" to "definitively manifest (e.g., lethal)"[Pl8. Pl9].
23. In epidemiological work on human populations,the situation is quite different. The series are, in mostcases, retrospective: the final data on morbidity andmortality are frequently incomplete: and the composition of the group is often heterogeneous with respect169to sex, age. socio-economic status, health conditions
and exposure to carcinogenic or promoting agentsother than radiation. Also. the control population isseldom fully adequate; follow-up to extinction israrely achieved owing to the long life span of man;and dosimetry is frequently uncertain. The statisticaltreatment of such data must obviously follow methods
different from those applying to prospective experiments.
A.

THE INDEPENDENT VARIABLE

24. Dose-response curves are functional relationships
between an independent variable, the radiation dose ina given organ or tissue. and a dependent variable
represented by a suitable measure of the response. The
specific energy, z, absorbed in a cell or in its criticalstructures, is a random variable. The mean value of z,i.e., the absorbed dose, D, is commonly used as thequantity of reference. but at equal values of absorbed
dose the distribution of the values of specific energy
can vary greatly, depending on the tissue volume forwhich the specific energy is determined and the valueof the absorbed dose. as well as the radiation quality(see 111.B.2). Furthermore. the same dose may bedelivered at different dose rates. Jn the present
context. the following terminology will be adopted forsparsely-ionizing radiation: low doses,< 0.2 Gy: intermediate doses, 0.2-2.0 Gy; and high doses. > 2.0 Gy.
For densely-ionizing radiation (e.g., fast neutrons)
doses < 0.05 and > 0.5 Gy will be referred to as low
or high. respectively. with intermediate doses falling
between the figures quoted. Low dose rates for allradiations are< 0.05 mGy min- 1: high dose rates are> 0.05 Gy min- 1; and intermediate dose rates fall
between these limits. Other quantities will at times beused as the independent variable, such as the injected
activity of a specified radionuclide, or the timeintegrated concentration of alpha-energy of shortlived radon daughters ultimately to be released in air.
With some oscillations. such quantities are proportional to dose.

B.

THE DEPENDENT VARIABLES IN
EXPERIMENT AL WORK

25. In experimental work on radiation carcinogenesis,
various expressions of the response may be adopted(see annex I in [U6]). The simplest. and mostcommonly used. is the fraction of animals incurring
a tumour after irradiation with a given dose (crude
incidence). It has been stressed repeatedly [FI,GI7-G19. Hl5, M32, R9. S37, U2-U5, U20-U22] thatsuch way of expressing the response leads to erroneous
results. The reason is the interference of competingrisks and of the different duration of life between
animals receiving different doses. Actually, animals
receiving the highest doses tend to die earlier and thus
have less chance of expressing the tumours that may
be induced.

example, in studies by Ullrich and Storer [U2-U5.
U20, U21, U23-U26]. In this approach, the data aretruncated at the time when the group is extinguishedthrough natural death and the observed incidence in thetreated group is corrected by a factor equal to the ratioof the mean lifetime for the control and the irradiatedgroups. This approach can provide approximate age
corrections, but it may be misleading when thefrequency of tumour appearance varies considerablywith time after exposure.
27. Rigorous corrections for age and intercurrent
mortality may be made by following the response ofirradiated and control individuals throughout their life
after irradiation or during a pre-selected post-irradiation period, with appropriate methods of investigation,
including careful post-mortem pathology. The relevant
parameter is then the age- or time-dependent rate oftumour appearance [Cl8, CI9. HIS. K8, S37] or a
related cumulative quantity that can be more readily
determined in the experiment. The basic quantities inthis approach and their competing-risk-corrected estimates for manifest tumours are:(a) The tumour rate, r(t), as a function of age ortime (t) after irradiation. It is the probability attime t per individual to develop a tumour per
unit time. This quantity. r(t). is to be interpreted
as a mean value for the population under study.
Since, for tumours diagnosed during the lifetime.
the actual time of origin of the tumour is
unknown, the time of its first observation is
generally used: the time of death is used for
rapidly developing, lethal rumours. In experimental work one derives r(t) as an average value
in a group of animals at time t. If N animals areobserved (i.e .. are at risk) over the intervalt - A t/2 to t + LI t/2, and n tumours appear
within the interval, the estimate of the tumour
rate is f(t) = Lln/NAt. For incidentally observed
tumours a direct estimate of the tumour rate is
impossible: the tumour prevalence can, however,be estimated (see paragraph 31):(b)

The cumulative tumour rate, R(t). Estimates ofthis quantity are less affected by statistical fluctuations and are therefore more readily derived.
The quantity is defined as the integral of thetumour rate from the time of exposure (t = 0) up
to time t:I

f0

R(t) = r(t) dt

R(t) is the number of tumours per animal up to
time t under the hypothetical condition that one
could keep the number of animals at risk
constant in spite of intercurrent mortality andthe occurrence of tumours. R(t) exceeds, therefore, not only the crude incidence, but also theincidence I(t), corrected for competing risks (seeparagraphs 29 and 30). A competing-risk-corrected estimate of the integral tumour rate is [A I,
N3, S37]:
R(t) =.? (n/N;Lf t) At=.? n/Ni
I

26. Corrections for differences in the distribution ofsurvival times between control and irradiated animals
may be made by approximate methods, as, for170( 1.1)

I( 1.2)

for all i with iAt < t. where ni is the numberof tumours appearing within the time interval(i - I )At to iA t, and Ni is the actual number ofindividuals still at risk at this time, i.e., individuals
still without a tumour. The standard error forequation ( 1.2) can be obtained by the relationship [S37]
O"R(<)= [/ (J; n/Nr)( 1.3)

I

28. If multiple non-lethal tumours occur. estimates of
the tumour rate or the integral tumour rate can be based
also on all observed tumours [S37]. In this case all
animals still at risk are included in N; (equation 1.2),
regardless of whether these animals had developed atumour or not. With this modification. similar estimates
are obtained. provided that the animals without
previous tumour had experienced the same tumour
rate as the animals that had already incurred atumour. This is so because both the numerator andthe denominator in equation ( 1.2) are increased. If, on
the other hand, there are inherent variations of thetumour rate within a population, or if the occurrenceof a tumour increases the probability of subsequent
tumours, the tumour rate estimated from all tumours
will be larger than the rate estimated from first
tumours only. It is mandatory, therefore, to specify
whether the estimates of the integral tumour rate arebased on the first or on all observed tumours. For
partly lethal or rapidly developing lethal tumours theestimate can be based only on first tumours.
29. A frequently used quantity, related to the cumulative tumour rate. is the actuarial incidence. orincidence corrected for competing risks, l(t). It is theprobability of an animal at risk up to time t to haveincurred a tumour. In the absence of competing risks,
the actuarial incidence equals the crude incidence (seeparagraph 25). In the presence of competing risks. andfor manifest tumours, a quantity can be obtained interms of the product limit estimate [Kl]:I(t) = l-J7p - n/N;]( 1.4)

where the product extends over a number of timeintervals (i) up to time t: n; is the number of animals
with tumours appearing within the time intervalt; + 1 - t;; and N; is the number of animals without
tumours still at risk at time t;. The standard error of
the product limit estimate is expressed by the so-called
Greenwood formula:a-l(t)= [l - I(t)] l/ J; n/NrIti::::; l(1.5)

When N is very small the log-rank test is preferable(see paragraph 33).
30. If few individuals incur the tumour. the actuarial
incidence and the integral tumour rate. based on first
tumours only. are nearly equal. At high frequencies.
the actuarial incidence can approach l, and theintegral tumour rate may exceed I. The sum limit
estimate (equation 1.2) is largely equivalent to the
product limit estimate (equation 1.4), i.e., the integral
tumour rate can also be obtained from the productlimit estimate by the relationship:
R(t) =-In [l - I(t)](l.6)

Similarly, the actuarial incidence can be obtained
from the sum limit estimate by the relationship:
I(t) = 1 - exp [-R(t)](1.7)

31. For occult tumours (see paragraph 22). which
frequently occur in short-lived animals. the actuarial
incidence (which is then usually called prevalence) or
the integral tumour rate are more difficult to estimate.
Theoretical analyses have shown that a combinationof serial killing and survival data is required for such
estimates in the case of tumours with unknown degreeof lethality or life shortening [C36. M22, N4, R8]. If
occult tumours are definitely non-lethal, estimates canbe obtained by serial sacrifices at specified times after
irradiation. However. this approach requires large
numbers of animals. As Hoel and Walburg havepointed out [H29]. the method of isotonic regression(see also [B84. K38]) may be used to estimate thecompeting-risk-corrected incidence from survival
experiments. This provides a maximum likelihood
solution with the constraint of monotonicity of theincidence. The algorithm for isotonic regression isstraightforward and has been utilized for the analysisof radiation carcinogenesis [C36]. At present. however,there are no methods to derive standard errors.
32. In most experimental studies in which tumours
are seen in various organs of the same animals, it isusually assumed that such tumours occur independently of each other. However, Storer has shown [S53]that this is not necessarilv so. In irradiated female
BALB/c mice. 21 out of th~ 66 pairs of tumours tested
showed significant positive or negative correlations.
Some of the negative associations were due to rapid
lethality caused by one of the tumours, and this could
be corrected for by appropriate methods allowing forintercurrent mortality. Of the remaining 13 significant
correlations. 6 involved tumours known to be endocrine-related. and 7 applied to tumours of otherorgans. Alterations in host factors were believed tobe responsible for the observed associations. Thesepossible complications should be borne in mind in theanalysis of dose-response relationships on the assumption of random, i.e .. independent. tumour occurrence.
33. The Jogrank test. the Breslow test. or the widerclass of non-parametric generalized rank-sum tests are
suitable for the comparison of tumour rates in two or
more groups in the case of manifest tumours [K37].
Analogous tests do not exist for double censored datafrom survival experiments. i.e .. for tumours foundincidentally. With such data. one must use tests basedon the assumption of the equality of competing risks
in the two groups under comparison, or one requires
knowledge of the degree of difference of competingrisks. For experiments with serial killing, suitable
standard tests exist.
34. The quantities discussed in paragraphs 28-29 are
not based on specific models. In experiments where
various groups. exposed to different doses. are compared. estimates may be used that are also nonparametric but are based on models. Most frequently.
the proportional hazards model is used. This model isbased on the assumption that the tumour rate or the
integral tumour rate in non-irradiated animals isincreased by a dose-dependent factor:r(t,D) = },(D) r 0(t)orR(t,D) = }.(D) Ro(t)
(1.8)
171

where ro(t) and R 0(t) are the tumour rates and integral
tumour rates for the non-irradiated animals, andr{t,D) and R(t,D) are the tumour rates for theindividuals exposed to dose D. By equations (I.I) and( 1.6) one could express this model in terms of theactuarial incidence. I{t). However, such expression
would be more complicated. The reason is thattumour rates and cumulative tumour rates fromindependent causes are additive. while the incidence isadditive only when its value is small. For manifest
tumours. there is a relatively straightforward algorithm
for calculation of the proportional hazard coefficients.
l(D), employing the method of partial likelihood[K37]. For incidentally observed tumours, one must
make use of more complex methods. requiring computer algorithms for non-linear optimization, with theconstraint of monotonicity [C36. K38]. The analysis
can also be based on the model of accelerated failure
times by use of the non-linear optimization methods.
This model assumes that the competing-risk-corrected
incidence. I(t.D). rises earlier in a way that can be
described by a dose-dependent acceleration of theincidence Io(t) for the control groups:
I(t,D) = lo [a(D)t]and

R(t.D) = R0 [a(D)t]( 1.9)

A similar model is that of time shift [C36], whichassumes that the tumour rates, the integral tumour
rates, or the incidence may attain the same values at
earlier times, in a manner that can be described by aforward shift in time:l(t.D) = I 0 [t+s(D)]andR(t.d) = R0{t +s(D)](1.10)

With both the accelerated time or the time shiftmodels, algorithms for non-linear optimization are
required for either manifest or incidentally foundtumours.
35. As a further step towards the derivation ofcoherent time and dose dependencies, parametricmodels have been used. Particularly important among
these is the so-called Weibull model [K37], which
postulates tumour rates. and integral tumour rates,
increasing as a power of time:r(t) = c tP

and

R(t)=ctP+ 1/(p+ l)(I.II)

The coefficient c is assumed to depend on dose, while
the exponent p may or may not be treated as aparameter that varies with dose. The Weibull model isa special case both of the proportional hazards modeland of the accelerated time model. Another frequently
used model envisages a log-normal distribution of thetimes to the tumour. i.e., of a competing-risk-corrected
incidence that depends on time as a log-normal sum
distribution. Various other models. for example thelogistic model, have also been utilized.
36. The preceding paragraphs refer only to acuteirradiation. In case of continuous or fractionatedlong-term exposure. additional complexities are introduced. Under such conditions. the dose increases withtime and it may be difficult to identify the relevant
value of the accumulated dose. The process of cancer
172

induction is followed by a period of growth until thetumour becomes observable. The dose absorbed during
this period is not relevant to the appearance of thetumour. Corrections may therefore be applied bysubtracting from the total dose the portion received
after the presumed onset of neoplastic growth.

C. THE DEPENDENT VARIABLESIN EPIDEMIOLOGICAL STUDIES
37. Whereas experimental studies use inbred animals
that are uniform as regards sex. age at exposure andother conditions. no comparable uniformity is everencountered in epidemiological human studies. Moreover. various human populations are often subject toa spectrum of influences, of which onlv some are
known or accounted for. In an ideal ca~e. a multivariate analysis should be used to assess the relative
importance of factors other than radiation. As this isseldom possible. Jess rigorous analyses must frequently
be accepted which, in addition to the basic quantities
previously discussed, use other, somewhat cruder
ones. In epidemiological investigations, the follow-up
may start shortly after irradiation (prospective studies)or at later times when some or all of the expectedtumours may have occurred (retrospective studies).
Reliable data collection is more easily achieved in thefirst case. but the majority of epidemiological studies
arc based on retrospective analyses.
38. It is not the objective of this annex to deal indetail with all factors and variables affecting theaccuracy of risk assessment of radiogenic cancers.
However, for the understanding of the following text
it is necessary to discuss briefly the expression of the
response in absolute and relative terms. The questionof risk projection beyond the period of direct observation is intimately linked to the use of so-called
absolute and relative risk projection models. These
will not be discussed in detail in this annex.
39. As mentioned above. the occurrence of radiationinduced neoplasms may depend on time after irradiationand on the absorbed dose in a variety of ways. In
epidemiological investigations it is possible, ideally. toenvisage two different situations frequently referred toas the absolute or the relative risk model.
(a)The radiation-induced excess tumour rate-or
the incidence rate, as more frequently determinedin epidemiological studies-after a latent period
increases independently of the spontaneous incidence but as a function of absorbed dose, i.e ..
the spontaneous and induced rates are additive.
Panel (a) of Figure II illustrates this caseschematically;(b)

The excess tumour rate. or the net incidence rate.
is proportional to the spontaneous age-specificincidence rate. i.e .. the dose results in a multiplicative effect of the spontaneous tumour rateover the life span. This relative risk model.
corresponding to the proportional hazards 111odel
described in paragraph 34. is shown in panel (b)of Figure II [C29].

Lifetime Expression, Comparison of Absolute and Relative Risk Models

b. Relative Rilka. Absolute Riskwu

Incidence afterzw

Irradiation

r;

0

u
z

'I

r

,-

'I

/

;1
/
/

~ Spen11,,..,u,

I

I

I

I

I

/

.,,,.-'//~

Incidence/0x, + e

x.

0

90

x.

90

Limited Expression Time, Relative Risk Model,
Comparison of Two Age·at•Exposure Groupsc. Irradiation at Younger Age

d. Irradiation at Older Age

w

u

z
w
0

I

u

z

I

I

I

/

,,..Radiogenic

ExcessRadiogenic

Exceu

0

x,

Xt + 2

0

90

x,

X +

•

e

90

AGE'

AGE'
•xe is ag-e at expowra, Q t1 1ht minim1r laten1 period.

Figure II.

Radiation-Induced cancer Incidence superimposed on spontaneous cancer Incidence,by age. Relative and absolute risk models.

[C29)

40. For most human tumours. the spontaneous
tumour rate is a steep function of age. but quantitatively this dependence varies. For radiation-induced
tumours with relatively short latent periods and full
expression within a short interval (leukaemia andbone sarcoma) one may distinguish between absoluteor relative risk models. A simple absolute model will
apply when irradiation at any age is followed by atemporary increase of the tumour rate that does notdepend on the magnitude of the spontaneous agespecific rate. A relative model will be preferable when
the temporary increase of the tumour rate becomeslarger with increasing age at exposure. The latter caseis illustrated in panels (c) and (d) of Figure II.

The relative risk projection model implies thatthe absolute (attributable) risk increases with age; on
the other hand, the absolute risk model implies thatthe excess risk when related to the spontaneous
incidence rate, decreases with age. Actually, epidemiological data often show an intermediate pattern.
and a decision as to which. model is most appropriate
for risk estimation is not always possible [C29, Tl2].
However. recent evaluations of cancer incidences inatomic bomb survivors lend rather strong support to41.

the relative model. This is so because. for the same age
cohort, excess deaths from cancer other than leukaemia
increase with age at death in proportion to the agespecific death rate from these cancers in the populationof Japan [K39, S59]. A similar conclusion was reachedwhen the time pattern of appearance of second
cancers, presumably radiation-induced, was studied inwomen treated by radiation for carcinoma of thecervix [B93]. Constancy of the relative risk of lungcancer with time after irradiation was also noted in
Swedish iron-ore miners [R41] and in United States ofAmerica and Czechoslovak uranium miners [15]. The
two projection models have been used for predictionof the numbers of various tumour types in a population having an age distribution similar to the one in
the United States, assuming a series of dose-response
relationships and applying the appropriate corrections
for intercurrent mortality by the life-table technique[C29]. When considering the risk of radiation-induced
cancer, whatever the model applied. it is being
currently assumed that the distribution of the sensitivity in human population is unimodaL although thecharacter of the distribution is virtually unknown. The
question of the possible exceptionally elevated susceptibility of some individuals is discussed in paragraphs 93-97.
173

1.

The risk expressed in absolute terms

42. The tumour response of an irradiated population
may be characterized by the time average net incidence
rate, i r,,,, which is defined as the number of additional
tumours diagnosed per person-year (PY) at risk. Thisquantity should reflect a net increase above thespontaneous incidence rate in suitably matched controls. It is calculated from the formula
iTA = X/P- J/Q( 1.12)where X is the number of persons with a diagnosed
tumour in the exposed group: P is the number of
person-years in this same group, obtained by summing
the number of years at risk for all individuals: J is
the number of persons with the same type of tumour
in a control group that is matched or corrected forsex, age and calendar years: and Q is the number of
person-years in the control group.
43. The period at risk for an irradiated subject is thetime. usually in years, from irradiation to cancer
diagnosis, or death. or to loss from observation, or
termination of the survey. For cancers other than
leukaemia and bone sarcoma, an assumed minimum
latency is usually subtracted from the time at risk. The
value of iTA is given as "cancer cases/person-year atrisk", or more generally as the annual probability ofoccurrence of a specified cancer in a given population.
The dose, D, will commonly be an average of thedifferent doses that the members of the population
have received.
44. If a suitable control group is not available. ageand sex-specific incidence rates of tumours in thegeneral population may be used. Under these conditions, however. rumour ascertainment in the groups
may not be fully comparable, and possible selection
by conditions that prompted irradiation, or by otherco-variates, may result in gross errors.
45. In order to obtain the time average net incidence,
ITA- the value obtained from equation (1.12) ismultiplied by the average time at risk, i.e., by theaverage period of observation or, for predictions
beyond follow-up, by an assumed time for full
expression of the malignancy. For leukaemia andbone sarcoma, this time is known not to exceed
significantly 30 years (see chapter V). For otherradiation-induced tumours. the period of expression is
unknown. In order to derive meaningful projections, acorrection for intercurrent !'10nality becomes necessary,i.e., average life expectancies have to be used. Whenthe distribution of the population by age and sex is
known. life tables can be used to this purpose. as in[C29]. As the quantities iTA and ITA can be affectedby significant errors, due to several circumstances,
they must be used with caution. First, as the latent
period is not known precisely, the correction for it can
only be, at best, an approximation. Secondly (andapart from the above correction) it is unrealistic toassume constancy of the incidence rate over time; if
the observation periods for two collectives exposed todifferent doses do not coincide. then the observations
cannot be strictly comparable.

174

46. Annual risk coefficients for radiation-induced
cancer can be expressed in terms of the time average
net incidence rate per unit dose, FTA, that is, theprobability per unit time per unit dose per person thata tumour can be seen in the observation period. Thisrisk may depend on sex, age at irradiation, genetic
disposition. the organ exposed, and a variety of otherfactors. The quantity is obtained by dividing iTA by
the mean absorbed dose received in the exposedgroup. Numerical values are commonly given in"cases 10-6 a-• Gy-1".

47. In order to obtain the life-time risk coefficient(net incidence per unit dose), FTA, the quantity FTA ismultiplied by the time at risk, i.e .. by an assumed
average time of full expression of the malignancy. The
considerations in paragraph 45 that refer to thequantity ITA apply also to FTA·
48. When the risk coefficients FrA and FrA are
calculated for groups exposed to different average
doses, changes of these quantities with increasing dose
may provide approximate information about the shapeof the dose-response curve. Thus, constancy of thecoefficient indicates proportionality between responseand dose within the range of doses studied; a rise or adecrease with increasing dose may result from an
upward or downward concavity of the dose-response
curve. However. if the radiation dose is correlatedwith a variable that affects the response (e.g .. age)spurious effects may be seen and normalization
procedures are called for. Furthermore, if the doseincidence relationship is not linear, expressing theobservations in terms of a probability per unit dose
distorts the data and introduces additional inaccuracies
if individual doses within the exposed population
deviate substantially from the average dose to the
population. For instance, if the dose relationshipcontains a dose-squared component, the contribution
to the response by individuals with high doses isgreater than if linearity applies.

2.

The risk expressed in relative terms

49. When the risk is expressed in relative terms, theresponse is related to the risk of spontaneous cancers(incidence or mortality) in an unirradiated control
population. The response variables used are thestandardized mortality ratio (SMR), defined as theratio of mortalities in the exposed group to themortality in a control group multiplied by 100; and/or
the relative risk (RR). which is the ratio of risks
observed over expected (each expressed, for instance,
per 10- 6 person and over a given follow-up time).
The latter quantity may be applied both to theincidence and mortality indices. The proportional
hazard model specifies that if ).i is the incidence rate ofa disease, or the mortality rate for a specific cause ofdeath among subjects in dose group i, it can be
expressed as),;= Aw (RR;), where ).iO is the backgroundor spontaneous rate of mortality or incidence (i.e., therate experienced by subjects in the absence of exposure
to radiation) while RR 1 is the relative risk associated with dose group i. The starting point for investigation of a radiation dose-response is the function

RR; = l + yD;. where y represents the excess relativerisk coefficient ((RR -1) per unit dose). Variation ofy with dose provides information as to the form of the
RR-dose relationship.
50. Various statistical methods. including multiple
regression analysis. have been used to obtain doseresponse relationships, and are presented and discussed in detail in numerous publications, e.g .. [G36,J8. K42, S60. W 17]. Careful corrections for sex, age at
irradiation. attained age at observation and otherconfounding variables (e.g., ethnicity, exposure toother carcinogens and promoters) are necessary when
the shape of the dose-response curve is the object of
the study.

D.

TEMPORAL RELATIONSHIPS

51. As pointed out in preceding paragraphs, thetumour rate, the cumulative tumour rate and theactuarial incidence depend on time after irradiationand on other factors, such as age at exposure or
absorbed dose. It has already been mentioned that theabsorbed dose may change the time dependence in avariety of ways. It is necessary, therefore, to consider
temporal relations in somewhat more detail.

I.

Latent period

52. The latent period is the time between irradiation(e.g .. single acute exposure) and manifestation of atumour. It may be divided conceptually into truelatency (the time required from initiation to thebeginning of unrestrained growth) and tumour growth(time until the neoplasm can be diagnosed). Reported
data are usually latent periods, i.e., the sum of theabove times. The length of true latency may beobtained by subtracting an estimated time of tumour
growth from the observed latent periods. There areconsiderable differences between the latent periods ofvarious tumours. Two malignancies in man. leukaemia
and bone sarcoma, appear to have relatively shortlatencies and show an upper limit of the latent
periods. so that their full distribution in a population
having a normal age structure can be observed. For
other tumours the distribution of the latent periods is
unknown. because it extends to very long times; thedistributions are then usually truncated by the lengthof the observation period. Median times recorded so
far are of the order of 20 to 30 years, but they should.
increase with extension of the follow-up of therespective groups.
53. If the follow-up is shorter than tht; minimum
latent period. radiation-induced tumours cannot be
expected. For more extended studies an inferred
minimum latent period is frequently subtracted fromthe total time at risk. as mentioned before. The
minimum latent period is often identified with thetime after irradiation at which the incidence rate
becomes statistically significant at a given level ofconfidence above the control values. Figure III shows.
however. that, for statistical reasons. the minimum
latent period so estimated must vary with dose even

Q

,_

....

,cc
c::
c::

iS

:c
::,

....

C
0

:;
"'
:.;

"',_,_

~
C

QI

4J

"'
,_:::,

Q

"'
C:

-Q

TIME AFTER SINGLE ACUTE IRRADIATIONC:·e ...,e

...J

QI

....

Figure Ill. Presumed effect ol the magnitude of dose upon estimate ol minimum latent period.
Two doses (D 1 < D:z) produce different absolute effects, which have similar time distributions ol
the latent periods. Shaded area: spontaneous (control) Incidence rate; Broken line: upper
confidence limit ol the spontaneous Incidence rate.

175

under the assumption of the proportional hazard
model, i.e .. when the tumour rate is increased by aconstant factor without change of the underlying
temporal dependence. Similarly, shorter minimum
latent periods are estimated if the number of individuals in the observed population is larger, because
predetermined levels of statistical significance arereached earlier in a larger sample. Other statisticalprocedures have been developed to analyse the dependence of the latent period on dose [L32].
54. For some cancers. the minimum observablelatend periods may change with age at irradiation. as
suggested. for example. by studies of human breast
carcinoma [826, Ml 7, Sl6. TI2. T23] and lung cancer
incidence in Japanese atomic bomb survivors [K39].
These radiation-induced tumours appear with highfrequency at ages when the spontaneous incidence isalso relatively high. It follows, therefore, that latency
is longer for cohorts irradiated in childhood andadolescence than for individuals exposed in their
twenties or thirties. If so. the follow-up to include acomplete (i.e., life-time) expression of the effect mustvary with age at exposure for different cohorts. It is
not known whether this observation can be applied ina general sense to all forms of radiation-induced
tumours with long latent periods.

55. In cohorts of advanced age, the life expectancy
may be shorter than the average latent periods, andonly a fraction of induced neoplasms will be seen. The
younger the age at irradiation, the fuller the expression of induced tumours. In the common case ofneoplasms with a distribution of latent periods extending significantly beyond the follow-up. the doseresponse relationship cannot be based on complete
data. The estimate of ITA will then change with theduration of the observation period; however. for thosecancers for which the relative risk model appears
adequate. the relative risk should be a less susceptible
quantity in this respect. Analogous changes of thedose-response relationships have been shown in experimental work [S37]. Whenever the distribution of latent
periods varies with the absorbed dose. the form of thederived dose-response relationships will depend critically on the length of the observation period. At low
doses, the minimum latent periods may exceed theaverage life span of the individuals and it has been
postulated that so-called practical thresholds may
result [E3, M8, MI 0, R28]. This inverse relationshipbetween latency and dose is most common in studies
of continuous long-term irradiation. It was firstdescribed for bone sarcoma induced by long-lived
isotopes [848. E3. E4, F8, M4, Rl8-R20]. The present
evidence does not substantiate the existence of such
relations for other tumours commonly induced byradiation in man. for which sufficiently detailed data
are available, namely cancer of the breast [K39, L22],of the thyroid [S38), and of the lung and stomach[K39. L32]: an inverse relationship between absorbed
dose and latent period may exist for leukaemia [L24],
but has not been definitely proved.
56. All the above factors must be borne in mind inany discussion of the accuracy and reproducibility of
dose-response relationships. Except for tumours with176

short latencies. such as leukaemia and osteosarcoma.
there is generally a lack of data extending to follow-up
periods long enough for the dose-response relationship to be assessed with reasonable completeness.

2.

Relationships between dose and tumour-free lifetime
lost as a result of induced cancers

57. As mentioned above, various malignancies may
be characterized by different latent periods. For somemalignancies and modes of irradiation the latent
periods (mean, median) may vary with dose, the meanvalues normally increasing with decreasing dose. A
quantity that may provide a first approximation to acommon denominator for assessment of the harm per
induced neoplasm is the tumour-free lifetime lost [16].
The relationship between this quantity and dose is
therefore of interest. Very few papers provide information on the subject, but this will be reviewed. when
it is available. in relation to different types of tumour.

E.

SUMMARY AND CONCLUSIONS

58. Cancer, as a stochastic radiation effect, can bestudied for its dependence on dose and time after
irradiation. Different degrees of precision are attainable in experimental and epidemiological studies ofradiation-induced tumours. The methods for theestimation of dose-response relationships reflect thesedifferences.
59. The absorbed dose in the relevant tissue is theindependent variable for dose-response studies. The
magnitude of the dose and its temporal pattern ofdelivery (dose rate. fractionation) may vary greatly. In
the present context. low doses are taken to be those up
to 0.2 Gy of low-LET radiation. while those in theinterval 2.0-3.5 Gy are regarded as high doses. with
the intermediate doses lying between these ranges.
Low and high dose rates are taken to be below
0.05 mGy min- 1 and above 0.05 Gy min- 1• respectively.
Intermediate rates are those in between these values.
For high-LET radiation low and high doses are
assumed to range up to 0.05 Gy and down to 0.5 Gy,
respectively. Dose rates may be classified in the same
way as for low-LET radiation. In certain studies, more
readily measurable quantities that are proportional toabsorbed dose-at least over some range-may be
used as the independent variable.
60. In experiments on radiation carcinogenesis,
various measures of the response may be used. The
crude incidence, uncorrected for mortality. is not
infrequently applied, but it is unsatisfactory because it
neglects differences in life span after different exposures: accordingly, it may be strongly affected byintercurrent mortality due to causes other than cancer.
Competing risk corrected quantities such as thetumour rate. r(t), the cumulative tumour rate. R(t), or
the actuarial incidence or prevalence, I(t,D). can beused for more meaningful expression of the response.
These quantities are always dependent on the postirradiation time, and must be reported accordingly.
They are obtained from the observed time sequence oftumour appearance and from the variable number ofindividuals at risk during the observation period. They
may be calculated by appropriate algorithms that are
different for manifest tumours. i.e., rapidly lethalor readily discovered tumours, and for incidentallyobserved tumours. i.e .. tumours that do not contributeto lethality and that are found only at necropsy. Onlya few experiments have so far been analysed according
to the requirements of the competing risk theory. andthis circumstance has often reduced the potentially
useful information from numerous studies.
61. In epidemiological surveys, the response is. inmost cases, assessed retrospectively, but less accuracy
can be achieved than in well-designed controlled
experiments. The genetic composition, the distributionsof ages and sex. the forces of selection, and the followup periods are often different in irradiated and control
groups and require appropriate adjustments. Furthermore. the doses to individual members of a cohort areusually subject to substantial variation, making it
necessary to group exposed individuals over broaddose intervals. Also, the less rigorous quantities usedin epidemiological studies, ITA• FTA, and their rates.
are complex functions of time post-irradiation. The
scoring of radiation-induced tumours depends therefore, in a complex way, on the age at irradiation.
duration and completeness of follow-up, latent period,and life expectancy of the population. The duration offollow-up may especially influence the magnitude of
the response and the shape of the derived doseresponse relationship in terms of the absolute (attributable) risk. If the tumours of interest show anincrement of the relative risk per unit dose that is notstrongly dependent on age at irradiation, the shape ofthe observed dose-response relationship is Jess susceptible to duration of the follow-up. provided theminimum latent period has been exceeded. the numberof tumours is sufficient for verification of the postulated
models. and other relevant co-variables have beencorrected for.
62. Human tumours with relatively short latent
periods. e.g., leukaemia and bone sarcoma, are notexpected to appear after about 30 years. For thesetumours, the dose-response relationships in young
cohons can be based on complete manifestation of theeffect. For other tumours. of longer and unknown
latency, dose-response relationships must be based on
the incomplete information resulting from truncationof the response by the short follow-up. A possible
dependence of latent periods on dose is of criticalimportance in determining the shape of the doseresponse curve. When mean latent periods decrease
with increasing dose, the shape of the relation depends
on the observation time and, in some cases. practicalthresholds may apply. However. except for 226Rainduced bone sarcoma. little information of thisnature is available from data on man.
63. Projection of tumour incidence or incidence rate
beyond the period of follow-up for tumours with Jonglatent periods may be achieved by two alternativemodels: the absolute and the relative risk projection
model. ln its simple version, the first is based on theassumption that the rates of spontaneous and ofradiation-induced tumours are independent. so that therate of radiation-induced tumours does not increase
proportionally to the age-dependent rate of spontaneous incidence. The second model in its simplest
form assumes that irradiation has a multiplicative
effect on the spontaneous tumour rate and that therate of induced tumours is a dose-related multipleof the spontaneous rate. Recent data from several
epidemiological studies have shown that, in manycases. the relative risk projection model provides abetter fit to the data than the simple absolute risk
model. For numerous tumours. however, no firm
conclusions can be drawn as yet.

II.
A.

ASSUMPTIONS AND LIMITATIONS
OF EXISTING MODELS

BASIC PHENOMENA AND INFLUENCE OF
MODIFYING FACTORS

64. Common features of malignant cells are theunrestrained growth, the ability to infiltrate neighbouring tissues. and often the capacity to give rise tometastases. ln a general sense. cancerous cells transmit
their malignant characteristics from one generation ofcells to another. and therefore somatic mutation could
be one of the mechanisms involved as an underlying
factor [B71. C32, Fl4. K20, K29, M50, R31. S43]. On
the other hand. epigenetic factors such as dis-differentiation. expression of previously suppressed genes,
activation of oncogenes (see annex A to this report) orothers [B71, K26, S43, R31, S55] may be envisaged,
alternatively or in parallel. Continuous growth throughcellular divisions might result either from inactivationof operating or regulatory genes. or from the inabilityof malignant cells to receive or recognize divisionrestraining signals. whatever their nature might be.
65. Owing to poor understanding of the origin ofcancer. quantitative predictions regarding the effectsof ionizing radiation (dependence on dose. dose rate,quality of radiation) cannot be developed from basic
principles. Formulation of simplified hypotheses under
the form of models is at present a practical step
towards understanding basic issues. To this end.
detailed knowledge of mechanisms of cancer initiationand promotion would be valuable. but even thiscannot be secured at present in a comprehensive form.
Quantitative models of cancer induction have beenreviewed recently by Whittemore [W8] and Parfenov[P2].
66. Before reviewing selected models, it is necessary
to discuss the concept of multi-stage development ofcancer. Since the classical studies of Berenblum et al.
on chemically induced skin cancer in mice (discussed
recently with regard to in vitro oncogenic transformation by Borek [B76]) this concept has gained wide
acceptance. The subject has been repeatedly reviewed[B71, C32, Dl8, Fl3. Fl6. F20. M50, R31, R42. S43].
It is commonly assumed that cancer induction isstarted by a phenomenon of initiation, occurring most
likely in one cell, although participation or modifying
influences from neighbouring cells cannot be excluded.
Further development into a cancerous clone probably177requires several stages. covered under the concepts ofpromotion and progression. which result eventually inan overt malignancy. These concepts have beenreviewed by the Committee in annex I of the 1977
report [U6].
67. Cellular phenomena that take place during development of a cancerous clone are not well understood.
Direct involvement of DNA in oncogenic cell transformation has been demonstrated [B 14, L33. L34].
Lesions affecting its structure and function must
therefore be relevant. Somatic mutation(s)-such aschanges of the DNA base sequence: transposition.
deletion, translocation and transfection (from one cellto another) of genetic material: enhanced instability ofDNA, leading to facilitation of non-repairable DNA
damage; induction of recombination between nuclear
and mitocondrial DNA; disturbances of DNA methylation: activation of oncogenes-may be involved. But
some of these mechanisms are largely hypothetical[871, 883. F21. G33. R3J, S43, S45, S55. V2. V3].
Initiation is followed by a Jong latent period, during
which secondary influences (systemic. exogenous) may
influence the final outcome of the process. During thisperiod, the action of secondary factors may accelerateand stimulate (promote) or inhibit. or even reverse theprocess (anti-promoters, suppressors of malignant
transformation). Arguments have recently been presented which show rather convincingly that not all
initiated cells, or their clones. will eventually give rise
to diagnosable tumours [F22].
68. Whatever the nature of initiation, be it radiationinduced somatic mutation in the classic sense (induction coefficient of 10-s to 10- 6 Gy- 1 of low-LET
radiation per locus at risk), or any other phenomenon
similar to in vitro cell transformation (induction
coefficient of 10-2 to 10- 4 Gy- 1), the yield of recovered
malignant tumours per irradiated cell in viva is lower
by many orders of magnitude. The possibility of asymmetrical "tumour-specific" chromosomal translocation was advocated [F21] as a very rare event thatwould remove part of this difficulty. However, recent
studies in vitro and in viva (chapter IV) suggest that
initiation may not be a rare event when expressed percell at risk. Therefore. if it is assumed that theseprocesses operate in viva with comparable efficiency,
even for a small fraction of the susceptible cells 00- 4
to 10- 6), a significant number of cells would betransformed every day because of background irradiation alone [M31].
69. The theory of sequential development of cancer
may help to explain the discrepancy between data in,.;tro and in vivo, and the rarity of radiation-induced
cancer. If a series of consecutive rare events isrequired for the initiated cell to become malignant. thefinal probability of emergence of the malignant clone
will be the product of the probabilities of each event.
Assuming that only the first event (initiation) is
radiation-induced, and that the subsequent ones arerare phenomena, perhaps independent of irradiation.
clinical cancer could be many orders of magnitude lesslikely than initiation itself. Yet, clinical cancer could
show a relationship with dose similar to that of
initiation, even though (owing to the multi-stage
178

nature of the process and possible systemic interferences) Jess regularity would be expected than thatobserved for stochastic radiation-induced phenomena
in single cells under controlled conditions. That thismay actually be the case is suggested by the reproducibility of dose-response relationships for somecancers in animals of selected strains. Also, supporting
this contention is the fact that the absolute risk
coefficient for cancer of the same organs derived fromepidemiological observations of different populations(see chapter V) are often similar. although there are
exceptions to this rule (see. for example, Figure
XXVIII). This may imply that the modifying influenceof secondary factors may not greatly change the final
probability of induction and the reproducibility of thedose-response relationships. It has been postulated
that for some forms of malignancy, such as leukaemias.
radiation may be the causal factor. not for the first,
but for the last event in a series of rare phenomena[L24, K39]. In any case. initiation is a necessary step.
although only a small fraction of initiated cells may
develop into a viable clone and into a clinical tumour.
70. The principal aim of a model is to predict theshape of the incidence curves as a function of dose,
dose rate, quality of radiation and possibly otherfactors. Ideally, a model for radiation-induced cancer
could provide some basis for the evaluation of risk at
low doses [D9. Fl2, Tl5] if it could characterize thefollowing processes:(a)Probability of malignant transformation of adefined target cell. This will most likely vary withthe organ, dose, quality of radiation. and temporal pattern of dose distribution. In this respect,
the model should include theoretical concepts
concerning the nature of the initiating event(s)and not be purely empirical. Mathematical formulations should be compatible with generalknowledge of radiation and cancer biology;(b)

Probability of interaction at the systemic level
between transformed cells or between developing
clones;(c)

Probability of cell killing with dose. as nonviable cells cannot give rise to cancerous clones.
This factor, as discussed in chapter Ill, depends
certainly upon the tissues concerned. some ofwhich are particularly susceptible, and upondose, dose rate and quality of radiation and onother irradiation conditions (in vitro. in situ)[D7, GJ4, GI6, H8, HIO, M31. M52, R2, S26,
S27. U6. U7, UI7]:(d)

Effect of numerous host factors. discussed inannex I of the 1977 UNSCEAR report [U6].
Among promoting factors, cell division is perhaps
a good example [B36, 885, M6. N6. P22].
Enhanced proliferation can be induced by various
mechanisms, including radiation-induced cell
death. a phenomenon which is likely to produce
a threshold-type dose response. Other factors
could be the differentiation of initiated cells,
immunological surveillance that suppresses development of malignant clones with antigenic
characteristics foreign to the host-system. andhormonal influences:(e)Effect of exogenous promoting agents leading tomore rapid appearance of tumours, to an increasein tumour yield. and perhaps also to changes inthe shape of dose-response curves. as shown by
several experiments [F21. L26] including thoseon in vitro oncogenic transformation [H22. L26].

71. Immunological surveillance may be impaired bynumerous factors. including ionizing radiation. The
degree of impairment would certainly depend on dose.
on whether the whole body or only part of it isirradiated, and then on what part and what proportion. It may be postulated that a reduction of
immunological capacity of the organism follows athreshold-type response to irradiation. The importanceof the immunological suppression in the low andintermediate dose range remains to be establishedalthough recent evidence points to a limited role of theimmune system. Studies of Mole et al. [M52] on
induction of acute myelogenous leukaemia in CBA/H
mice, suggest that, at least in this tumour-host system.
impairment of immunological surveillance is not very
important. Similar conclusions were also reached by
Nolibe et al. in respect to Jung cancers induced by
239Pu0 2 in rats [N9].
72. Hormonal dependence is well known for somecancers [U6]. By partly or totally inactivating endocrineorgans and creating a hormonal imbalance. radiation
may accelerate or impair malignant growth in otherorgans (e.g .. breast, thyroid, ovary). Again, it is likelythat this type of response would show pronounced
dose thresholds. Hormonal influences could also be
responsible for the association of various tumours, as
observed in experimental animals [S53].
73. In summary. the action of modifying factors
might change the resulting dose-response relationships. It is a basic weakness of the models discussed inchapter III that mathematical functions relating cancer
incidence to dose reflect only initiation and sterilizationof the initiated cells. This is because the precise effectof other modifying factors on tumour induction-as afunction of dose-cannot yet be described withreasonable credibility. even if some attempts havebeen made [M4. P22]. Models, therefore, provide
greatly simplified concepts. based on plausible assumptions and hypotheses. which may help in understanding the role of dose, dose rate and radiation quality.
The relative importance of the parameters reflecting
these quantities in a model can be deduced bycomparing data with predictions. However, some ofthe parameters are the compounded expression ofseveral elementary phenomena that cannot be resolved
at present.
74. From available models. risk coefficients for man in
the range from about I mGy up to about 0.1 Gy can only
be obtained by extrapolation from the recorded values(in most cases above 1 Gy) to zero dose. Effects of thehost factors discussed above (cell renewal, immunological surveillance, hormonal balance) and exogenous
modifying factors upon dose-response relationships
are uncertain, and only approximate evaluations may
be given. For the purposes of the present annex, thelevels of acute doses of low-LET radiation can bebroadly separated as follows:< 0.2 Gy. At this level, data for most tissues are(a)

not directly available, but the damage to tissue
functions is considered negligible. Therefore.
dose-response relationships could be very close
to those postulated by models that disregard hostfactors;(b)0.2-2.0 Gy. Damage to tissues, cell proliferationand influence of other host factors would not be
expected to play a dominant role. Distortions in
the dose-response relations should be relatively
minor. and would not grossly bias the extrapolations;(c)2.0-10 Gy. Damage to tissues. to immunological
functions (for irradiation of the whole or most of
the body) and to hormonal feed-back systems
may play a significant role. Extrapolations to low
doses must therefore become more complex,
particularly from the upper end of this range.
Great caution is needed to avoid extrapolatingfrom data that are already strongly affected bykilling of initiated cells. as this might result irt asubstantial under-estimate of the risk at low
doses;(d)> 10 Gy. Severe damage to tissues and organs
will dominate the response. Data in this dose
region are most difficult to evaluate and socomplex that extrapolation to low doses could bemeaningless. Induced cell repopulation may also
become a complicating factor for irradiation
times longer than a few days.

A corresponding approximate classification of fastneutron doses would include the ranges: (a)< 0.05 Gy;(b) 0.05-0.2 Gy; (c) 0.2-2.0 Gy: and (d) > 2.0 Gy. Itshould be noted that the relation between these rangesof low- and high-LET radiation may not be interpreted in terms of RBE.

B.

THE THRESHOLD DOSE FOR CANCERINDUCTION

75. It has already been mentioned that for many
types of cancer the epidemiological and experimental
information available does not suggest the presence ofa threshold dose. If initiation is at least partly
autonomous. i.e., if it affects a single or very few cells.
present understanding of the mechanisms involved
suggests that:
The nature of radiation interaction with thecellular target for cancer initiation is stochastic,in the sense that each increment of dose carries agiven probability of effective interaction;(b) The error-free repair of the DNA, which is themost likely target involved, leaves some fractionof the damage unrepaired and the error-prone
repair may produce misrepaired sequences in the
DNA structure.

(a)

As the product of two probabilities greater than zerocannot equal zero, the presence of a threshold cannot
be assumed.
179

76. A different situation obtains when the lifetime
lost per cancer case (instead of the incidence) is related
to dose or dose rate. Few malignancies show a definite
inverse relationship between dose rate and latent
period (see III.B.2), particularly at chronic exposure.
In such cases (e.g., bone sarcomas induced by 90Sr or
long-lived radium isotopes) practical thresholds may
exist below which no life shortening occurs and a very
low probability of tumour appearance applies.

C.

UNICELLULAR VERSUS MULTICELLULAR
ORIGIN OF NEOPLASTIC GROWTH

77. Under the simplifying assumption that doseresponse relationships for radiation-induced cancer
reflect mainly the kinetics of initiation, they should
include both the dose-dependence of the relevant intracellular phenomena and the interactions of individual(contiguous) cells. if indeed the latter play any role in
the process [G30]. Therefore. the question whether amalignant clone arises from transformation of a single
cell or of several contiguous cells is of criticalimportance for the formulation of models. Because
understanding of the biological process of carcinogenesis is limited, this question cannot be resolved
unequivocally at present. However, most experimental
and human observations tend to support-even if
indirectly-the monocellular origin of neoplasms.
Furthermore, the alternative multicellular hypothesis
allows the development of models resulting in such avariety of dose-response relationships as to render the
exercise of model-fitting totally meaningless.
78. All these problems were reviewed in depth by
Fialkow [F3, F4, F6]. Nowell [N5] and others [B60.
FI3, F14). It appears from their work that the
monocellular alternative is gaining increasing acceptance, except for some rare hereditary tumours insubjects with inborn predispositions (e.g.. multiple
neuro-fibromatosis [F5]) and other rare tumours. suchas condylomata acuminata [FlO]. Three main lines ofevidence support the unicellular hypothesis [F3. F6.
N5]:
(a)

(b)
(c)

The isoenzyme pattern of glucose-6-phosphate
dehydrogenase in cancerous cells derived fromtumours of heterozygous women, in accordancewith the hypothesis that the same X-chromosomeof the homologous pair is functioning in all cellsof a given neoplasm. A similar pattern wasobserved recently in 3-methylcholantrene-induced
fibrosarcomas in Pgk-P/Pgk-1 b mice carrying
X-chromosome inactivation mosaicism for thephosphoglycerate kinase (PGK-1) gene [Tl7]:
The homogeneity of immunoglobulins producedby almost every case of myeloma;
The common cytogenetic markers frequently
detected in the cells of a single tumour.

This evidence is limited, indirect and compatible withthe alternative hypothesis that selection of one clone
from among several initially transformed cells mightlead to an apparently monoclonal composition of thetumour. So far, however. this possibility has not been
widely supported.
180

D.

AUTONOMY OF TARGET CELLSFOR TUMOUR INDUCTION

79. Conceptually, even if initiation is taking place in
one cell, the multi-stage nature of cancer development
and possible influences of tissue and systemic origin
could introduce random fluctuations into the expression of cancers in viva. For radiation-induced cancer.
therefore, such regularity and reproducibility of doseresponse relationships as that seen for stochastic
radiobiological phenomena in cultured cells would not
be expected. Much of the information from animal
experiments shows nevertheless that dose-response
relationships are reasonably reproducible. Proportionality between initiation frequency and expression may
therefore be assumed as a plausible hypothesis.
80. On the basis of microdosimetric considerations
Rossi and Kellerer [Rl7], Rossi [Rl5, Rl6] and Rossi
and Hall [R43] have pointed out that the observed
curvilinear dose-response relationships for neutroninduced mammary tumours in rats and other tumours
in mice are inconsistent with autonomous response
because at low and intermediate doses there should bea direct proportionality (linearity) between dose andtumour incidence. Therefore, if the dose response is infact non-linear. this must mean that either initiation
or expression are modified by dose-dependent factors,
implying a lack of "cell autonomy". If such a
conclusion should generally apply, theories concernedwith the response of single cells may not be relevant todose-response relationships for cancer induction.
81. In the original experimental data of Shellabarger
on Sprague-Dawley rats [S15), 14 months after anacute x-ray exposure, the incidence of all mammary
tumours (adenomas plus carcinomas) per rat showed
an approximately linear relationship with dose, up to
0.84 Gy, whereas 0.43 MeV neutron irradiation, withdoses from 0.001 to 0.064 Gy. resulted in a tumour
incidence roughly proportional to the square root of
the dose [Sl5]. Rossi and Kellerer argued [Rl7] that.
since cell killing would be negligible at such low
neutron doses, the form of the observed relationshiprequired the interplay of radiation effects in several
cells. For mammary fibroadenomas, such an interaction leads, apparently, to a reduction of the tumour
rate per unit dose even at neutron doses of a few tensof mGy.
82. Earlier data by Shellabarger et al. [S 15) werelater extended, with follow-up of the animals to about1000 days [S37]. Tumours scored included fibroadenomas and adenocarcinomas. the latter malignant
forms being 9-16% of the total. The data expressed as
crude incidence or mortality-corrected indices, r(t,O),R(t.D), at various post-irradiation times, essentiallyconfirmed the previous findings. A very high RBE wasseen at low neutron doses for both tumour types(about 100 at 0.1 mGy) and the dose-response for the
combined tumours was concave· downwards for neutrons and approximately linear for x rays. There wasalso a significant shift of the age-specific r(t) cul'Ve in
the irradiated animals (acceleration).

83. When the net R(t) values at 800 days (the latest
follow-up time for all but one dose groups) wereconsidered separately for fibroadenomas and adenocarcinomas, the following conclusions could be drawn:(a)

For all tumours combined the downward concavity of the curve after irradiation with neutrons
results essentially from a low point for the
fibroadenomas at 0.064 Gy. Such an effect is notseen for the adenocarcinomas. where the relation
is approximately linear, although the experimental scatter precludes accurate assessments inthis case:(b)

At 800 days, the departure from linearity of R(t)for the fibroadenomas is much less pronounced
than at 400 days [S 15] or than that for theincidence of adenocarcinoma [S37];(c)

No account was taken of cell killing in theseexperiments, although this may have not been
negligible already at 0.064 Gy.

84. In view of their high spontaneous incidence (80%throughout the lifetime in females), the mammary
tumours in Sprague-Dawley rats must be regarded as
an unusual model. This view is confirmed by the facts
that only a minor part of these tumours is histologicallymalignant [Sl2, Sl3, S14, Sl5, Ul7. V4, V5] and thatthe very high sensitivity of the Sprague-Dawley rat tothe induction of mammary tumours is not seen inother rat strains [B43. B92, C15. S7, Sl 1. VlO].
85. In summary. the shape of the dose-response
relationship reported for neutron- and x-ray-induced
fibroadenomas at low doses in the mammary gland of
Sprague-Dawley rats in one study is rather exceptional
among all data on radiation-induced tumours. The
low yield of adenomas per unit dose at 0.064 Gy,
which has been interpreted to show an inhibitory
influence by the neighbouring cells. may also be
explained in terms of cell killing. Therefore, theobservations discussed do not necessarily imply thatmalignant tumours arise from more than one initiallytransformed cell, or from interaction of several cells.
86. Other data on benign lung adenomas in RFM
mice [U21, U22] may be discussed in this context.
Pathogen-free animals were irradiated locally over thethorax with graded doses of fission neutrons (0.05 to
1.5 Gy) and the number of tumours in dissected lungs
was counted 9 months after exposure. The effect was
fully manifest at 6 months after 0.5 Gy, and intercurrent mortality was negligible. A peaked response,with a maximum around 0.25 Gy, was seen following
single neutron doses. Splitting of the dose into two
equal fractions. given at 24-hour or 30-day intervals.
resulted in no sparing effect of fractionation. Plotting
the mean number of adenomas per animal at 9 months
against dose gives a slightly upward concave curve inthe range of O to 0.25 Gy. A quadratic model fits thedata very well (P > 0.99) but non-threshold linearity is
not excluded (P > 0.8): also, a threshold of 0.05 Gycannot be rejected, particularly since the gamma-ray
curve suggests such a possibility. It is also possiblethat increasing doses of neutrons up to 0.25 Gy may
have an enhancing effect, interpreted either as accele-ration or promotion. Such an effect, however, is the
opposite of that seen for mammary fibroadenomas inSprague-Dawley rats. Results of other experimentswith neutron induction of various tumours in BALB/cmice [U23] were also advocated as evidence thatinduction cannot be treated as a phenomenon related
to autonomous cells. However, a correction for sterilization of initiated cells could result in approximately
linear dose-response curves up to 0.2 Gy.
87. There is yet another explanation for the above
data, i.e., that single-cell initiation is modified byenhancing or inhibiting dose-related effects. The natureof these effects (direct or abscopal, cellular or humoral)
cannot be specified at present. Tumours requiringhormonal stimulation for their development (as in thecase of the ovary) often have threshold dose-responses.
In essence, therefore, none of the data discussed areincompatible with the hypothesis that tumour initiation
by radiation may take place in a single cell. whichfrom this stand-point must be considered relatively
autonomous.
88. It has been pointed out [G 15] that the simultaneous initiation of cancerous growth in several
interacting cells would be equivalent to a multi-target
event. If so, the sigmoid shape of the curve should
become more pronounced with an increasing numberof participating cells. There is, however. little data to
support such a possibility and no known experimental
system to test such hypotheses.
89. It may be concluded that if the curve is not
obviously sigmoid or threshold-like upon visual inspection, the idea of a monocellular origin of the tumour
may be accepted. The argument of a mono- versus apluri-cellular theory, as well as the question of thedegree of cellular autonomy in the origin of cancer,
will not be finally resolved as long as the understanding of tumour pathogenesis remains unsatisfactory. As a rule, however. there appears to be nosolid biological evidence against the monocellularorigin of neoplasms. The assumptions that malignancy
is initiated in a single cell, and that there is areasonable proportionality between tumour inductionand expression. have been incorporated-explicitly or
implicitly-into most models of cancer induction byradiation. This view is explicitly accepted here as aworking hypothesis, even though it is recognized thatdifferent opinions have been expressed [B83, M52,
R43].

E.

NUMBER OF CELLS AT RISK

90. The number of cells at risk of cancer induction in
any organ is not known. When discussing this subject.
most authors argue that the number of cells in which
initiation takes place must be proportional to thenumber of cells at risk in a given tissue. and that thelatter is proportional to the fraction of tissue irradiated.
Most models or theories of cancer induction byradiation have accepted this assumption. It does notfollow from it that tumour incidence, spontaneous orradiation-induc·ed, is proportional to the total numberof cells in any organ. or in the body of various animal
181

species [849, M9], because there is no obvious
correlation between body size in various species andincidence of tumours.
91. Epidemiological data on leukaemia in man. after
irradiation of various fractions of the total active bonemarrow. are broadly consistent with the notion thatthe probability of induction is proportional to thenumber of irradiated cells at risk, on the assumptionthat these are uniformly distributed throughout themarrow. Absolute annual risk coefficients derived
from various studies fall within a range which isnarrower than the variation of the fraction of theirradiated tissue (annex G in the 1977 UNSCEAR
report [U6]). The same conclusion may be derived
from experiments on cancer induction by total andpartial irradiation of the mammary tissue in rats [828.
SIO. Sl2] and by various areas of skin in mice [Hll.
Hl2, HI3].
92. An important and related question is the effecton tumour incidence of a non-uniform tissue dose
distribution. The extreme case is that of the so-called
hot particles, i.e., particles with very high concentrations of radionuclides that are deposited in an
organ such as the respiratory tract or the liver. Under
such circumstances. the dose averaged over the entire
organ would be much lower than that in the immediate
vicinity of any such particle. Several authors addressed
this question by studying carcinogenesis in the lung[I3. L35, S54]. In all cases, as expected from theoreticalpredictions [M9. MI OJ, hot particles were found to beless effective than similar doses of the same radiation
quality distributed in a more uniform manner.

F. POPULATION HETEROGENEITY
AND SUSCEPTIBILITY TO CANCER INDUCTION
93. Baum [B 16] raised the question of whether linear
extrapolation of the risk from the high dose and doserate region of low-LET radiation to the low-dose
domain is always conservative, in view of a possible
difference in susceptibility to cancer induction between
groups in the general population. To exemplify thesituation, Baum [B 16] constructed a model in which
three population sub-groups, represented to 1. 10 and
89%, varied in susceptibility (expressed as D 0 values)in the ratio of 100: I : 0, respectively. For each of the
sub-groups he postulated a dose-response relationshipof the form
(2.1)
94. For the most sensitive sub-group (l %) he assumed
that cancer induction might be a single-target effect(n = l) with Do of 0.01 Gy; 10% would exhibit alower sensitivity (D 0 = 1 Gy); and for the rest of the
population D 0 =oo. According to Baum. the composite
response of the total population is dominated in the
low-dose region by the highest sensitivity of the 1%
sub-group. In the range from about 0.01 Gy to a few
Gy, the relationship would be a curve. concave
downwards. with response roughly proportional toD 0·5. The risk per unit dose above I Gy would be lessthan below 0.01 Gy.
182

95. It is not easy to envisage why susceptibility
between groups should be reflected only by D 0. and, if
so. why by a factor as large as 100. Moreover, theassumption that the bulk of the population should be
totally non-susceptible to induction of malignant
disease(s) lacks justification in Baum's paper [B 16].
No epidemiological evidence supports this contention.
even though it is known that incidence of radiationinduced cancer in man is generally low. Examples ofdose-response relationships advocated by Baum tosupport his argument do not stand up in the faceof criticism. The author presented data for acuteleukaemia at Nagasaki, and for all cancers. allleukaemias, stomach, lung, and breast cancer at
Hiroshima. where incidences rise with a power of dose
between 0.1 and 0.8. At present. dosimetric uncertainties preclude a more detailed discussion of atomic
bomb survivor data. but preliminary evaluations[K39, S46] of the dose-response relationships forleukaemia, breast cancer and total malignancies forthe period up to 1978. using new dose estimates [L27].
do not support the above conclusions (this information is still tentative). Therefore, Baum's hypothesis isneither satisfactory on theoretical grounds nor supported by epidemiological observations. The subject
itself, however, is obviously important and warrants
some exploration.
96. Progress in cancer genetics has shed some lighton possible mechanisms of differential susceptibility
to cancer development in individuals with various
inherited traits [G 12. M35]. The relevance of these
phenomena to radiation-induced cancer requires attention. The relationship between genetic heterogeneityand incidence of spontaneous cancer, and cancer
induced by radiation or other carcinogens, was discussed. in detail in annex I of the 1982 UNSCEAR
report [U24]. It is again reviewed in annex A to thisreport. The homozygotes for some genes (ataxia
telangiectasia. Fanconi's anaemia and several others)
have a significantly increased natural incidence ofsome forms of cancer and an enhanced sensitivity toother cellular and subcellular radiation effects. Various
forms of impaired DNA repair are seen in most ofthese conditions. In view of their rarity. the affectedsubjects do not pose a public health problem, but theheterozygous carriers of these genes could also havean increased risk of developing spontaneous cancer.
Calculations have shown [V6] that a few percent of
individuals in the general population should carrysuch genes in a heterozygous state. If their capability
for DNA repair should be reduced, this might resultin an increased proneness to cancer development.
Although it is not known at present whether theseheterozygous subjects may also be more prone toradiation-induced cancer, this possibility should not
be overlooked.

97. If risk coefficients at low doses were higher thanthose reported in most studies at about I Gy. thenperhaps such evidence could be interpreted to suggest
the presence of population groups particularly susceptible to cancer development. A higher effectivenessof low doses was claimed by Mancuso et al. [M3. K 17.
K32], who studied the mortality of workers employedin the Hanford works, Richland, United States, dying

with cancer from 1944. for whom death certificatesand data on personal radiation dosimetry were available. This information was reviewed by several authors[A 7. 014, G5. G25. H20. M30, R3. S2] who pointed
to the low statistical power of the original data and tonumerous other difficulties in their interpretation.
From careful examination of all the evidence, itappears that these data are at present inadequate toprove or disprove that the risk of radiation-induced
cancer at low doses is higher than estimated by
UNSCEAR in its 1977 report [U6]. This matter will,
however, be kept under review.

G.

SUMMARY AND CONCLUSIONS

98. The pathogenesis of tumours, both spontaneousand radiation-induced, is at present poorly understood. The probability of cancer induction cannot
therefore be derived from general principles. The data
available indicate that carcinogenesis is likely to be acomplex, multi-stage process. Initiation at the cellularlevel is followed by a long period of latency. during
which numerous changes take place until the tumour
becomes clinically manifest. The probability of someof these changes is very low, and during the intermediate stages numerous exogenous factors could
accelerate or inhibit the development of potentiallycancerous cell clones.
99. There is considerable variation between organs
and tissues in the process of cancer development,
presumably related to numerous endogenous factors.
Among these. the hormonal and the immunologicalfactors are known to be of importance. at least forsome forms of cancer. Significant cell killing in tissues
may stimulate compensatory cell proliferation andtherefore increase the probability of cancer development. The ways in which. and degrees to which,radiation could modify such mechanisms. particularly
in relation to dose, are not well understood. It appears
likely. however. that dose thresholds such as those
operating for non-stochastic effects might apply. This
would imply that low or intermediate doses (below
approximately 2.0 Gy of gamma rays and 0.3-0.5 Gyof neutrons) delivered acutely might have little or no
modifying effect.
100. Under the circumstances described, for predictive purposes the use of simplified models of tumour
induction becomes one of the possible choices. eventhough the degree of simplification is usually such as
to exclude consideration of the above modifying
factors. This important limitation of the models
should be kept in mind.
10 I. In view of the multi-stage nature of the phenomena described. and of the small probability ofoccurrence of each step. the proportion of initiallytransformed cells giving rise to an overt tumour must
be extremely small. It may be postulated that at low
doses and dose rates, where the host factors mentioned
above are not expected to modify primary events
appreciably. there is a broad similarity of relationships
between dose and tumour incidence. on the one hand,and between dose and probability of cell initiation andsurvival. on the other. Exogenous modifying factors(e.g., promoters and inhibitors) could alter the slope,and perhaps the shape, of the dose-response curve insome instances; in man very little is known in thisrespect, apart from the effects of tobacco smoke onlung cancer induction.
102. Monocellular and monoclonal hypotheses areusually assumed in models of radiation carcinogenesis.
Most biological data support the notion that cancer.
as a rule, starts from a single cell. but unequivocal.
direct evidence to support this point is lacking. andalternative interpretations are possible. The monocellular hypothesis is critical in extrapolating the risk
from high to low doses. The alternative hypothesis.
that concomitant initiation or interaction of several
cells is required, lacks sufficient experimental supportand makes extrapolation from intermediate to low
doses difficult or impossible at present. The postulate
of monocellular origin of cancer must be treated. forthe time being. as a working hypothesis.
103. The number of cells at risk of radiation-induced
malignant transformation is usually assumed to be
proportional to the fraction of an organ or tissue
irradiated. The experimental evidence in favour ofsuch an assumption is very strong, but. again. it must
be regarded simply as a plausible working hypothesis.
Gross non-uniformities of the tissue doses. such as
those resulting from deposition of the so-called hot
particles, normally result in a lower tumour incidence
than for comparable doses distributed uniformly.
104. It has been proposed that sensitive sub-groups
in the general population might invalidate any linear
extrapolation of cancer risk to low doses of radiation,a procedure hitherto believed to provide upper valuesof the risk. It is known that the very rare homozygous
carriers of particular genes (e.g .. ataxia telangiectasia.
Fanconi's anaemia) are more prone to cancer and that
their cells are particularly sensitive to other effects ofradiation, such as cell killing. It is also true that thehealthy carriers of these same genes in the heterozygous form (a few percent of the general population)
are at greater risk of developing spontaneous tumours
and also have a slightly enhanced sensitivity to otherradiobiological effects. Whether these same individuals
may also be at a higher risk of radiation-induced cancer
cannot be proved at present and this question requires
further study. The epidemiological evidence in favour of
the notion that higher risk coefficients per unit dose of
low-LET radiation may apply at low, rather than at
high. doses appears at present unconvincing.

III. DOSE-RESPONSE MODELSOF RADIATION-INDUCED CANCER
105. Although in principle a large variety of mathematical expressions and models could be fitted toexperimental and epidemiological data on radiationinduced tumours. for the purpose of this annex theCommittee decided to limit the analysis only to thosemodels that appear to be supported by generalknowledge of cellular and subcellular radiobiology.
183

A.

INTRODUCTION

106. When either the crude or the actuarial incidenceof various radiation-induced experimental tumours isplotted against a wide range of doses. then, for low-LET
radiation. a peak incidence is normally seen atintermediate doses. followed by a decline at high doses.
For high-LET particles, the essentially linear initialslope gradually decreases with dose. In some cases, iteven becomes negative. The bulk of data is consistent
with this generalization [U6]. Evidence in man is muchless certain because only a few series cover a sufficiently
wide range of doses. Nevertheless. the incidence per unit
dose of bone sarcoma [M29, R 18], lung carcinoma [K22.
S3] and cancer of the breast [S 16] decreases at very highdoses. Thus. a model of radiation-induced cancer
should allow for two opposing trends: a rise ofprobability of induction with dose and then a decline.
resulting presumably either from killing of irradiatedpotentially malignant cells [G 16. M52, R2]. or, in somecases. from increased mortality rate at high doses (15.
17]. Mathematically, this trend may be simulated bymultiplying the induction dose-response function by aterm describing the probability of cell {or organism)
survival as a function of dose.
107. Conceptually, there are two possible approaches
to the formulation of models. The first is based onradiobiological considerations, relating. by analogy. theradiation-induced cancer incidence and the influence ofvarious parameters (dose, dose rate, fractionation) toother effects in single cells. Broad similarities have been
observed in numerous cases. The alternative approach isan empirical one, aimed at approximating the data
{incidence versus dose) by simple mathematical functions. In practice, the two approaches are often appliedin combination.
108. There is no reason why any model might be valid
for all radiation- induced malignancies: actually. a morereasonable approach would be to determine separately
which model is applicable to which type of cancer, aconclusion supported by the bulk of experimental data.
There are examples of radiation-induced cancer withpronounced thresholds {e.g., the chymic lymphoma of
the C57BL mouse, ovarian tumours in many mousestrains). Indirect mechanisms (destruction of an overwhelming part of target cells in the thymus: killing of alarge fraction of hormonally-active cells in the ovary)
may explain such sigmoid relationships. Similar data
are exceptional in man (see chapter V). Thus, even
if threshold-type relationships cannot absolutely be
excluded, the most easily induced human tumours, suchas those of breast, thyroid and lung (undifferentiatedsmall cell type), as well as leukaemia, do not indicate theexistence of a threshold. Therefore. models used forthese malignancies do not postulate a threshold. In
principle, the models discussed below have beenformulated in terms of the absolute risk, but they seem
equally applicable to a relative risk increment.
B.

DERIVATION AND CHARACTERISTICS OF
DOSE-RESPONSE MODELS
1.

The linear model

109. The simplest and oldest linear model wasdeveloped for x-ray-induced point mutations in Dro184

sophila [G24, M46]. It was based on the postulate thateach energy deposition in a cellular target carries aprobability of changes in the genome (mutations) andthat these may be either irreparable or the result of
misrepair. Since radiation energy is transferred indiscrete events. all effects should ultimately be linearwith dose at low doses when only few cells absorb someenergy and their number is directly proportional todose. The probabilities of an effect assumed to be an
all-or-none phenomenon in relation to each dose
increment should be additive. and dose rate or
fractionation would not be expected to alter themagnitude of the final effect.
110. In the course of time it became obvious that thelinear model must be limited to effects showing singlehit kinetics after low- or high-LET irradiation. However. the postulated additivity of effects and the doserate independence does not always apply to single-hit
effects [EIO, H35], showing that in such cases repair
processes must also operate to make an otherwise linear
relationship dose-rate sensitive. It appears that when a
track passing through the sensitive volume is not 100%
effective, then its effects may be subject to repair. In
other words. the presence of dose-protraction or dosefractionation effects may not be incompatible withsingle-hit kinetics.

111. For high-LET radiation, the linearity of theinitial slope, modified by phenomena of saturation orcell inactivation (killing), has been widely accepted[B20. II, M66. U6, U7, U9, UIO]. The dose response isdescribed by the following equation:(3.1)

If cells are sensitive to inactivation. the relationshipwill depart from linearity, even at low or intermediate
doses. owing to cell killing. The lower the mean lethal
dose (l/(J 1), the more downwards concave the relationship will be. Recent experiments on neutron-induced
tumours in animals (see chapter IV) suggest that thisphenomenon-or others [S37. U23. U25, U26]-doesin fact operate. causing departure from linearity. evenat a few tens of milligray or a few tenths of a gray.
This is explained by the fact that cell killing by highLET particles is very effective with exponential nonthreshold survival curves.
I 12. If equation (3. I) reflects the kinetics of tumour
incidence as a function of the high-LET dose, extrapolation to low doses would tend to under-estimate
the risk by a factor of e-P,D. Examples and limitationsof this postulate will be discussed in chapter IV, in thelight of available experimental data.

113. Alternatively, the data can normally be fitted
over some range of doses by an equation of the type:l(D) = a 1\ID

(3.2)

Such a purely descriptive model implies no linear
slope at low doses, even for very radioresistant cells.
This seems unlikely. however, on radiobiologicalgrounds. In this latter model. as in any other model
involving a downward concavity of the dose-response
curve, dose fractionation would produce an increased

incidence of tumours if the intervals between fractions
were sufficiently long for the effects of each fraction
to be considered independent [R37]. By a similar
mechanism. the effects at low dose rate could also beenhanced, in comparison with the high dose rate.
114. An interesting variant of the linear model isthat developed by Mayneord and Clarke [M9]. They
discussed dose-response curves and their relationshipwith time. in regard to both dose rate and latency inthe appearance of tumours. This is of importancebecause irradiation time and latency may be comparable with the life span of an exposed individual andcould, therefore, affect the manifestation of the
response. Their point of departure is that irradiation
confers a probability of cancer appearance in the
future [B48]. following a stochastic process. This
probability may be estimated by integrating the
response of single cells as a function of dose over thenumber of cells at risk. A linear relationship between
the probability of malignant cell transformation anddose was assumed at low doses where cell killing isirrelevant. Because much experimental evidence fromchemically- and radiation-induced tumours [B48, E3.
E4, F8] pointed to an increase in latency withdecreasing dose rate. this particular feature was also
incorporated into the model [M9, M JO].
115. The result of the analysis was that in all cases.
assuming a linear relationship between each incrementof dose and risk (the latter distributed in time). nonlinear (concave upwards) dose-response relationships
were obtained. often with an apparent threshold. Thisis due to the inverse relation assumed between time oftumour appearance and the dose. According to thismodel. therefore. in most situations a linear extrapolation of the risk from high to low doses and dose
rates is likely to yield a conservative risk estimate. The
dose-response relationships should tend to linearity
for: (a) long observation times. compared with themedian latent period; (b) very heterogeneous populations, i.e., populations with a wide distribution of thelatent period after single irradiation; (c) little variationof the median tumour appearance time with the dose. In
general. however. the theoretical analysis of Mayneord
and Clarke [MI OJ does not support an overall linear
relationship between dose and cumulative tumour rateover finite time intervals in populations having astandard age distribution.
116. Inverse relationships between the mean latent
period (from the start of exposure to tumour diagnosis)
and dose (or dose rate) are seen mostly for irradiationsof long duration. for instance in dogs and mice
injected with 226Ra and 99Sr [M33, R28, R32]: inChinese hamsters. in which the latent period of liver
tumours decreases with increasing activity of injected
239Pu [B87]; in rats injected with thorotrast. which
produces tumours of liver and spleen [Wl5]; or rats
exposed over periods of weeks or months to various
concentrations of radon resulting in lung carcinomas[C34]. Finally, a negative correlation of latency versus
mean dose rate was seen in human dial painters with
226Ra and 228Ra body burdens [E3, E4. Ml 4, PI I,
Rl8]. It is interesting to note that the inverse doselatency relationship was much less pronounced for

induction of bone sarcomas after single injections ofshort-lived 224 Ra in rats [M67]. For brief exposures
such as for atomic bomb survivors. there is, at least in
the younger cohorts, a suggestion that the mean
induction period for leukaemia is negatively correlatedwith dose [L32], although the reference in question
seems to compare mostly radiogenic cases with mostly
naturally occurring ones. Such a relationship was notdetected for breast. stomach and lung cancer inatomic bomb survivors [BI7, L32. Ml7, K39. Tl2]
and for breast and thyroid cancers resulting frommedical irradiation [B26. S16, S38]. Moreo\'er. of allcases showing an inverse relation of the latent period
against dose. an unequivocal departure from linearity
was found only for 9oSr-induced bone sarcomas. The
situation for human osteosarcomas induced by 226 Ra
and 228 Ra is not totally clear. and the dose-response
relation for leukaemia in atomic bomb survivors isstill not available. In conclusion. the inverse relationship between latency and dose does not apply to many
tumours. Thus, an upward concavity of the doseresponse relationship as a result of this factor alone
cannot be viewed as a general phenomenon.

2.

The linear-quadratic model

117. For the bulk of experiments on single-cellsystems, and for many end-points. the prevailing formof the dose-response curve after acute low-LET
irradiation is concave upward. the response rising witha power of dose of between l and 2. Broadly similar
shapes were also observed for tumours induced by thesame radiation. This form of the response is thought
to imply that for the occurrence of the final effect theinteraction of two elementary effects, usually referred
to as sublesions [K4], is required. Repair phenomena
and dose-rate effects are usually accounted for by theinteraction of these sublesions in time and space [L4,S39. S40], but other interpretations were also proposed[G29. G32]. For effects showing curvilinear responses
to low-LET irradiation. linear dose-responses are
frequently observed with densely-ionizing particles.

{a)

The microdosimetric approach

118. Microdosimetric considerations are importantbecause the distribution of absorbed energy divided by
the mass in the volumes believed to be the primarytargets of radiation action (i.e., cells or cell nuclei) isvery inhomogeneous at low and intermediate doses[F7]. Thus the distribution of specific energy, z(energy absorbed divided by the mass of thesevolumes). may be more relevant for the analysis of theeffects than the organ or tissue mean dose, D.
119. Many experiments indicate that for a number ofeffects the probability of occurrence. E. after low-LET
radiation, rises with a power of dose close to 2. Thismay be accounted for by the theory of dual radiation
action which assumes that the induction of two nonspecified sublesions is necessary for the production of
the effect (lesion). In the approximation that was firstdeveloped in detail [K4], it was assumed that theprobability of sublesion interaction does not depend
185

on their distance within a certain volume (the site).
Consequently. the probability of effect should rise inproportion tQ_ the mean of the square of the specificenergy, i.e., z 2 , in the site. It was shown also that z 2 isa function of the absorbed dose. D:
z 2 = (D + D 1(3.3)

where the ( is a weighted average of the specificenergy deposited by single events (energy depositionsin the critical structures by individual charged particles). Thus, the probability of a radiobiologicaleffect, E. should be
E = K((D + D2)(3.4)

The quantity ( has the dimension of dose and its value
denotes the dose at which the contribution of thelinear equals that of the quadratic term. For x andgamma rays. and for sites of I µm diameter, the valuefor ( falls within the range of 0.3-0.8 Gy; for mediumenergy neutrons, it is as large as 16 Gy. For smallersites. the values of ( are considerably larger. but theratio of the values for neutrons and for sparsely
ionizing radiation is less dependent on site size.
120. Consideration of the values of ( for radiations
with different values of LET and their comparison withbiological data. indicates that intracellular distances atwhich sublesions can interact must be of the order of
0.1 to 1 µm [K4]. High values of ( for neutrons andalpha particles (relative to x and gamma rays) accountfor a bulk of radiobiological observations. They showthat the REE of high-LET radiations varies as aninverse function of the square root of their dose andthis can be understood on the basis of microdosimetricconcepts. This type of dependence can hold down todoses where the response to both radiations becomeslinear and the REE reaches a plateau.
121. Suitable time functions can be inserted into thebasic equation (3.4) to describe the interaction probability during the time interval between the formation of two sublesions [R 12). One of the conclusions isthat the linear term for single events in equation (3.4)
should be independent of dose rate. Therefore. any
effect of time distribution may only result in a
modification of the quadratic term. This relationshipbetween irradiation time, T, and mean time between
induction of a sublesion and its repair. r, is reflectedby a reduction factor, G, that affects the quadraticterm:
G = 2(r/T) 2 (1/r - 1 + e-Tlr)(3.5)
In the presence of recovery, the curves of RBE versus
absorbed dose do not change in shape, but are shifted
towards higher doses by a factor depending on thedose distribution in time and the recovery time. r. For
a constant dose rate, if the exposure time is much
longer than the recovery time, the yield of elementarylesions becomes simply proportional (linear) to dose.
122. The theory of dual radiation action has been
applied by several authors to the interpretation of
biological results, for example to cell inactivation byionizing radiation [B62, F7]. In this model. the slope
186of the survival curve depends explicitly on radiation
quality through the quantity ( [K4]. The theory has
also been used as a theoretical basis for the linearquadratic model for many effects. including mutations,chromosome aberrations and initiation of oncogenictransformation. However, experiments with ultrasoft xrays [C23. G9. G JO. G 11] and with spatially correlatedions [888, G3I. G32, K4I. R38] indicate a strong
dependence of the interaction probability of thesublesions on distance, with a dominance of shortrange interactions (much less than 0.1 µm) for denselyionizing radiation. The applicable version of thetheory [K5] is a model of higher complexity that is Jesseasily tested experimentally.
123. Alternative explanations were considered forthe commonly observed RBE-dose and dose-response
relationships for low- and high-LET radiation. In
agreement with earlier ideas of Haynes [H27]. Goodhead et al. [G29, G32] put forward the notion that a
number of cellular and subcellular radiation effects
depend both on the production of the primary lesions
and on a dose-dependent inactivation of repair mechanisms. Whereas the probability of the primary lesions istaken to increase linearly with dose, impairment of therepair system would depend on absorbed dose andspecific energy. It has been postulated that the degreeof impairment of repair should display a pronounced
dependence upon dose and/or dose rate of low-LET
radiation. For high-LET particles there would normallybe no error-free repair, independently of dose. Therefore, basically linear dose-responses would be expected
for induction at the cellular level of each of thevarious effects separately.
124. The above concepts have not been widely
tested. A variety of factors have been reported that
may influence the expression of potential damage. andthus change linear dose-effect relationships to curvilinear ones, and vice versa [Fl8, H22, L26].

{b)

Characterisrics of rhe linear-quadraric model

125. Upward concave dose-response curves that fit
well the cumulative cancer incidence as a function of
acute doses of low-LET radiation are in themselves noproof that cancer is actually initiated in accordancewith a linear-quadratic relationship. Curvilinearity
could well result from an inverse relationship between
dose and latent period [MIO]. However. when followup data show a constant latent period with dose. it
may be assumed, as a working hypothesis, that the
upward concavity reflects a linear-quadratic kinetics
of initiation.
126. A generalized linear-quadratic dose-response
relationship for radiation-induced cancer would be as
follows:

where I(D) is the incidence (in an ideal case corrected
for intercurrent mortality): D is the dose; a 0 is the
spontaneous incidence: a I and a 2 are coefficients forthe linear and dose-squared terms of cancer initiation;and S(D) is the probability of survival of transformed
cells and may be written as
S(D) =e-<JJ,D + /J,DJ(3.7)

In the equation (3.6), initiation may also be treated asa simplification of a more general expression, which
includes some repair at low and intermediate doses
and dose rates [B95].
127. To test compatibility of the model with experimental and epidemiological data, the parameters inequation (3.6) must be assigned some value. This canonly be done by: (a) reasonable analogy with cellularradiobiological effects: or (b) deduction of the values
from empirical studies. As to the parameters for cell
survival. these are known for many cell lines (e.g.,
Barendsen [B5. B6, B9-B 12, B45]; Goodhead et al.
[C23. G9. GlO]: Elkind [E2]: and others [Al7. B19.
B27, Cl, C37, D3, D8, F2, Fl9, H2, H6, 16, K2. K24,
L6, Ml6, M60, R39. S33, Tl8, Tl9, W6, W7]), but are
not necessarily applicable to specific tumours.
128. The number of unknown coefficients in equations (3.6) and (3. 7) is too large to permit theircalculation without some constraints. One of these isthat all parameters should be positive or equal to zero[C29]. However. this is often insufficient for reasonably
stable estimates of fJ I and {J 2, particularly when a I anda 2 are estimated at the same time. Attempts were
made, therefore [B7, B47], to derive independently thequotient a/a 2. which facilitates calculations by lowering the degrees of freedom.
129. Assuming that the theory of dual radiation
action [K4] applies to the initiation of cancer. there
must be a subcellular structure in which the sublesions
appear and an interaction distance below about I µm
where the final lesion leading to malignant transformation is produced. Kellerer and Rossi [K4-K7.
Rl2] did not specify the relevant structure for celltransformation. but the most likely target of radiation
action appears to be the genome. In the light of thisassumption, and of available evidence. it is not
unexpected that models postulating a linear-quadratic
relationship presuppose a direct action of radiation on
DNA or make reference to phenomena involving
DNA (chromosome aberrations, mutations) for derivation of the relevant parameters.
130. Barendsen [B7] selected the values for a I and a 2
on the basis of dose-response relationships for chromosomal aberrations in lymphocytes and the roundedvalues of a/a 2 for x and gamma rays were set at
0.5 and 1.0 Gy, respectively. On a similar principle,
Abrahamson [A3] and Brown [B47] assumed that. if
human radiation-induced cancers are due to mutations
or chromosome aberrations in single cells, theninformation on the quotient a 1/a 2 could be derived
from extensive data available in the literature. However, the large variability of the quotient precluded theuse of numbers at their face value (e.g .. mean ormedian). Brown showed also an inverse relationshipbetween the DNA content per haploid genome in cellsof various species and the a/a 2 quotient, the values
extending over ranges of 103 and 10 4, respectively.

131. For mammalian cells, a/a 2 values for mutations
and chromosome aberrations, as reviewed by Brown[B47]. clustered around I Gy (geometric mean, 1.27 Gy).
The values of the PifP2 ratio for cell sterilization weregenerally much higher. with a geometric mean of
7. 76 Gy. The difference is due mainly to higher rnluesof the linear parameter for cell killing, in accordancewith conclusions [B9. BI I] that at low doses there
must be a substantial component in cell killing thatcannot be identified with the induction of chromosomal
aberrations. Brown concluded that if the initialradiation lesion triggering a human cancer is ofmutational or cytogenetic nature. then risk estimatesderived at 1-2 Gy of low-LET'high-dose-rate exposure
would, as a maximum. over-estimate the cancer risk at
low doses and dose rates by factors of about 2 andabout 4, respectively.
132. Concerning cell survival. it has been pointed
out repeatedly [B7. E2. F2. K2. M21. Sl7] that the
low-LET survival curves can be described by various
models and, among others, by functions of the''single-target" plus "multi-target-single-hit" type
S(D) = e-(Dl1Dol (1 -(I -e-DlnDo) 0 ](3.8)

where S(D) = SofS 0 , 1D 0 and 0 D 0 are mean inactivation doses for single and multiple targets. respectively.
and n is the target multiplicity. Alternatively. thelinear-quadratic form may be applied. as in equation(3.6).
133. Whether for each cell type there is an initialslope [PI in equation (3. 7) and (e- 01 1°0) in equation(3.8)] is still a matter of debate. but this question israther immaterial in the present context as both
functions describe satisfactorily the experimental data
for surviving fractions between 1.0 and 0.1 [B9. Bll.
F2, M21]. Equation (3.6) has been most commonlyused in relation to the linear-quadratic model ofcancer induction (see [U6, annex G] and [B7. C29.
M31]). For high-LET radiation the contribution of thequadratic term is negligible.
134. As a first approximation. for low and intermediate doses, particularly of low-LET radiation,
the killing term S(D) may be neglected. This could
be justified under the assumption that repopulationof the target cells after irradiation has a promoting
effect on the development of radiation-induced cancer
roughly proportional to the degree of cell killing[P22]. If. in addition, some of the terms in equation(3.6) and (3. 7) are omitted, a transition is possible
from the linear-quadratic model to the pure linear orpure quadratic ones (Figure IV). As can be seen fromequation (3.6), the model does not assume thepresence of a threshold.
135. There are many methodological and biologicalfactors [BIO, Cl, D8. H6, K24. L6]. which make it
difficult to select appropriate survival parameters. In
particular, cells irradiated in situ might exhibit higher
survival capacity than when irradiated in culture or insuspension [G14. H8, HIO, M60] (however, for acontrary view, see [A 17]). By using a range of survival
parameters suitable to describe the most and least
187

Genera 1 fonn

linearI (D)=a 0+a 1 D

w

w

u
z

u

z

Cell killing~
attenuates I(D) u

w

Cl

u

z

z

I(D)=(a.0+a. 1D+a2 D2 )exp(-~ 1 D-~ 2 D2 )DOSE (D)DOSE (D)

Quadratic

Linear-quadratic

I (D )=a. 0+a2 D2I (D)=a. 0+a 1 D+a 2 D2

w
u
z
w

w
u
z

u

u
z

w

Cl

Cl

z

DOSE {D)Figure IV.

DOSE (D)Various types of dose-response curves.
(C29]

sensltlve cell lines, one may examine the degree towhich cell killing may affect the shape of the tumour
incidence data and. hence, the reliability of extrapolation from the intermediate to the low doses. Thisshould provide some indication of the degree of overor under-estimation of the risk, within the range ofvalues selected for the parameters in question.
15 10 3136. In an independent analysis. UNSCEAR selected
two values of the a/a 2 quotient applying to x andgamma rays: 0.5 and 2.0 Gy. For survival. the bonemarrow stem cell was selected as the most sensitive. Its
survival curve is described by /J 1 = 4 10- 1 Gy- 1 and/3 2 = 8 10- 2 Gy- 2 [B6]. For the least sensitive cell. ahypothetical line was assumed with survival parameters /3 1 = 10- 1 Gy- 1 and /3 2 = 8 10- 2 Gy- 2 [B6]. In
addition, other survival parameters for radiationinduced human leukaemia cells (Table l from[Ul 7]) were used. as follows: /J 1 = 3 10- 1 Gy- 1, and/Ji= 10- 1 Gy- 2• To normalize the calculated data. it
was further assumed that the lifetime cumulative
incidence at 3.0 Gy may be 15,000 cases per 10 6 (5000
10-6 Gy- 1). The results in terms of the yield of cases
from 10- 3 to 3 Gy for all combinations are plotted in
Figure V.

wuz:::g 10 10 3uz

5 10 30

2

3

DOSE (Gy)137. From such an analysis. the following tentative
conclusions may be drawn. First. the sensitivity to cellkilling has a more pronounced effect on the shape ofthe dose-response relationships than the a 1/ a 2 quotient.
(Similar conclusions were reached by Mole [M31].)
Secondly, for the cells most sensitive to killing, the188

Figure V. Expected cumulative Incidences of a radiationInduced cancer according to a linear-quadratic model with
a1/a2 quotients= 0.5 and 2 Gy and cell survival functions Smax
and Smtn as given In paragraph 136. Incidence normalized to
15,000 cases per 10s at 3 Gy. For full explanation, seeparagraphs 136 and 137.

relationship is concave downward, with maxima at
2-2.5 Gy. Since such curves are not observed forhuman cancers after low-LET irradiation. it is possiblethat the assumed sensitivity is too high for in vivo
irradiation. This would be in accordance with thelower sensitivity of single cells irradiated in situ. whichis due mostly to a wider shoulder of the survival curve[D7, G14, H8. HlO. M60. S26. S27]. Thirdly. for thecells least susceptible to killing (the carcinomarous
cells according to Barendsen [B6. B7]), the overestimate of the tumour yield per unit dose from
1-2 Gy to 1-10 mGy (relative to linear extrapolation)
ranges from 4.0-2.6 at aifa 2 = 0.5 Gy, to 1.6-1.3 ataifa 2 = 2 Gy, respectively. The maximum over-estimation of the risk will result from totally neglecting thecell-killing effect. In such a case. extrapolation from
2 and I Gy down to about 10 mGy would involve thefollowing over-estimate:a/a 2O\•er-esrimare by a/actor of"(Gy)from 2 Gy

from l Gy

0.50
2.00

4

3
1.5

2

The above differences for a if a 2 of 0.5-2 Gy could not
be easily-if at all-detected between estimates derived
from I or 2 Gy and the exceptional estimates available
for doses of a few tens of mGy per single dose. The
lack of statistically significant difference is therefore
compatible with both the linear or the linear-quadraticmodel.
138. Inspection of equations (3.6) and (3. 7) indicatesthat cell killing may alter significantly the incidence ofa given cancer through interaction with the spontaneous
incidence, a 0• At very high levels of the latter andwith high sensitivity of the cells to sterilization, adose-related decrease of the incidence would be
expected. This in fact was seen in experiments withanimals, showing a negative slope of the doseresponse relationships for the so-called reticulum cellsarcoma [MI9].
139. The slope of the dose-response curve in thecomplete linear-quadratic model will be described by adifferential:
d/dD i(D) = [(a 1 + 2a 2D)- (/J 1 + 2P2D) (ao + aiD ++ a 2D2)] e-<P1D + P2D&J(3.9)
As D approaches zero this equation simplifies to:
d/dD i(D) = a 1 + 2a 2D - P 1a 0 - D(/J 1a 1 + 2P2ao)(3.10)To examine the interaction with dose of a 0 , a 1 and P,
and its influence on the curve at low dose, two humancancers were selected: breast carcinoma, with a highspontaneous incidence and moderate sensitivity to cellkilling of initiated cells; and leukaemia, with rather
low values of a0 and high sensitivity to sterilization.
The notional parameters selected were:
Breast cancer:
a 0 = 8 10- 4 a- 1
a 1 =3.210- 4 a- 1 Gy-'a 2 = 3.7 10-4 a- 1 Gy- 2/1 1 = 2 10- 1 Gy- 1
P2 = 8 10- 2 Gy- 2

Leukaemia:
a0 = 5 10- 5 a- 1
a 1 = I 10-4 a- 1 Gy-I
a 2 = I 10- 4 a- 1 Gy- 2(J 1 = 4 10- 1 Gy- 1/12 = 8 10-2 Gy-2

When the values of d/dD i(D) were calculated at 1. 10
and 100 mGy, their ratios to the respective values of
a 1 were:
Dose (Gy)

Leukaemia:
Breast cancer:

0.001

0.0/

0./

0.80
0.50

0.82
0.52

0.94
0.64

Thus, at very low doses interaction of cell killing.
predominantly with the spontaneous incidence. would
introduce some degree of over-estimation of the risk,
if this interaction should be neglected in the extrapolation procedure. It appears unlikely. however. that thisover-estimation might exceed another factor of 2, overthat estimated in paragraph 137.
140. When extrapolation is made from intermediate orhigh doses of low-LET radiation. delivered at low dose
rates or in small fractions (of size much below aifai).
then, due to repair processes, the quadratic termsof equation (3.6) should be reduced. Under thesecircumstances. dose-response relationships approaching linearity would be expected in which the risk
coefficient per unit dose is the same over the range of
low and intermediate doses. For high-LET radiation,
the contribution of the dose-squared component formost effects in single cells is negligible up to a few tensof Gy. Therefore, the model may be treated as linear,although for some effects the slope of the line may not
be dose-rate independent (see III.B. l). Such observations cannot be explained solely on biophysical considerations.
141. It has been pointed out [U17] that the linearquadratic model of cancer initiation is a simplistic
concept and not a pathogenetic theory. The greatcomplexity and the interaction of various phenomena
at the cellular level preclude its acceptance as a
generalized theory of cancer initiation in all tissues
and under all circumstances. The dose dependence ofthe many modifying mechanisms operating at thetissue and systemic level is still too obscure to allow
quantitative predictions over the entire range of doses.
However. as discussed in chapter II, it may be
postulated that the influence of modifying factors
might not be very important in the range of doses up
to 1-2 Gy of low-LET radiation (or their high-LET
equivalent). Under these circumstances, appropriate
extrapolation may be acceptable down from the dose
region of 1-2 Gy of x or gamma radiation (or anequivalent dose of neutrons) to obtain risk estimates
for the low-dose domain.
142. With all these reservations in mind, the linearquadratic model has been applied to the results of
selected animal tumour experiments where dose. doserate, dose fractionation, dose protraction and LET
were systematically investigated (see chapter IV). In
several cases [B7. P22, U2, U3, U25, Yl] the results
were in basic agreement with the model's expectations.
189

3.

The quadratic model

143. This model is based on the assumption that for
the induction of a given effect two consecutive events
are necessary·. or rwo concurrent events separated inspace in such a way that their production by a single
ionization track is extremely unlikely. Except forirradiation of flattened bone lining cells (see V.E.2.),
this assumption is difficult to justify on microdosimetric grounds for low-LET irradiation of normal
cells in situ. In tumour radiobiology, this concept may
be traced back to the theory of bone sarcoma
induction by fJ emitters [M26. M45, M47]. Proportionality to the square of the dose has been noted forvarious cancers [Hl2. Hl3. M26. M52, Rl8]: this does
not exclude the presence of a linear component, but
simply assumes that it may neither be demonstrated
nor ruled out on statistical grounds. Therefore. if
present, such a component must be relatively small.
144. Recently. Mole et al. [M52] have shown that
dose-response relationships for radiation-induced acuteleukaemia in CBA/H mice may be characterized by
an approximately pure quadratic or linear initiation
term for x rays or neutrons, respectively (see IV.B.l).
On the basis of microdosimetric considerations theapparent absence of a linear term in the dose-response
equation for x rays is difficult to explain when the
diameter of a nucleus is of the order of few µm. The
proposed hypothesis [M52] was that the interaction of
two neighbouring cells is necessary for the initiation ofthis cancer. Initiation by neutrons is in direct proportion to dose and this was explained by the fact that asingle recoil track could cross the nuclei of twoneighbouring cells. However, for neutrons of maximum
effectiveness (400 keV) the range of the secondary
protons is less than most nuclear diameters.
145. The experimental basis of these hypotheses isstill debatable, and needs further experimental testing.
Moreover. the postulates are difficult to reconcile withthe results of transformation experiments of cells in
vitro. irradiated at low density (see chapter IV) where
it is unlikely that two neighbouring cells may becrossed by a single recoil track or may interact duringoncogenic transformation by x rays. Explanations
other than the microdosimetric ones must be found toaccommodate all these facts.
146. When fitted to the experimental data obtained
at intermediate or high doses. the quadratic model will
predict effects at low doses to be much less than
implied by the linet1r or the linear-quadratic models
within the usual range of a 1 and a2 values. The
influence of the time pattern of dose administration
cannot be specified a priori for the quadratic model: if
repair is fast and dose-rate-dependent. dose protraction or fractionation could lead to a considerable
reduction of the effect. and zero effect could not be
excluded.
147. The quadratic model has been used by theCommittee on the Biological Effects of Ionizing
Radiation (BEIR Committee) [C29] to obtain thelower boundary of likely linear-square dose responses
at low doses. Three special models have recently been
190

proposed which assume. or derive from experiments,
the basic postulate of the dose-squared concept. They
refer to leukaemia in CBA mice [M52], skin cancer inrats [VI] and bone sarcoma in man [M4]. They arereviewed in chapters IV and V. respectively.
C.

SUMMARY AND CONCLUSIONS

148. Quantitative models of radiation-induced cancer
must allow for two facts: first, that tumour incidence
rises with dose at low doses: and, second. that at highdoses the effect usually declines (either in absoluteterms or per unit dose). This shape of the curve may
be modelled by the product of two terms: an initiation
term increasing as a function of dose, and a cellsurvival term declining with it. The laner term can beneglected at low doses. but this simplification may
lead to misinterpretations as the dose increases. Thereis no reason why any one model should be universally
applicable to all radiation-induced types of cancer.
Models should be tested in each instance by statistical
criteria. In each given tumour system. they should
allow for the effect of the main radiobiologicalvariables, such as dose, dose rate. dose fractionation,
radiation quality.
149. The linear model implies direct proportionality
between dose and the probability of tumour induction.
Absence of dose-rate and fractionation effects wasthought to be an inherent feature of the linear model,
because the biological lesion is assumed to result froma single-track effect. However, examples are known
where this is not true, and linear dose-response
relationships show shallower slopes with decreasing
dose rate. There are few examples of cellular or
carcinogenic effects following linear kinetics after lowLET irradiation, while the effects produced by highLET particles often conform to these characteristics.
However. there are examples where dose-rate effects
for neutrons are found. in an opposite direction(enhancement) from those normally seen for low-LET
exposure. The linear model may be regarded as an
upper boundary for the more general linear-quadraticmodel when the doses at which the linear equals thedose-squared components are high or very high.
150. The model of Mayneord and Clarke assumes
linearity between dose and cancer initiation at thecellular level. It also assumes a log-normal distribution of the latent periods for overt tumours and an
inverse relationship of latency to dose. Solution of thismodel for observation times comparable to humanlife expectancy results in dose-response relationships
which are upward concave. sometimes with apparent
thresholds. The critical assumption leading to such
results is the shortening of the mean latent period withdose. If this were a general rule, then extrapolationof risk from high to low doses would always lead toover-estimates. However, for some radiation-induced
tumours in man (thyroid, stomach, breast. lung), thelatent period is not obviously dose-dependent; also,
curvilinearity is not seen in several cases where there isan inverse relation of the latent period with dose.
Thus, it is impossible to generalize the notion that justfor this reason curvilinear responses would normally
apply.

J51. When corrected for cell killing, numerous biological end-points induced by low-LET radiation insingle cells show an exponential dependence on dosewith exponents of between I and 2. On the contrary,
the same end-points for high-LET radiation show
essentially linear dose-responses. Consequently, theRBE is an inverse function of dose. Low-LET
radiation shows pronounced influences of dose rate
and fractionation, in contrast with high-LET. forwhich such phenomena are seldom observed or are
observed to a lesser extent. Most of these facts may be
accounted for by microdosimetric considerations. They
predict that, as a rule. linear-quadratic dose-responses
should be expected. where the relative contribution of
the two terms is comparable (for low-LET). Thisprediction is in accordance with numerous experimental data on single cells, and so are the effects ofdose rate and dose fractionation that may be deduced
from the kinetics of repair of the sublesions postulated
in the linear-quadratic model.

152. Recent data on ultra-soft x rays, however, do
not conform to the predictions of the theory of dual
radiation action in its early approximate formulation.
The disagreement could be reconciled in the generalizedversion of the theory [B98], assuming that someparameters of the biological effect previously taken to
be invariable are actually subject to some variability:or that. in case of low-LET radiation, the rate of
repair depends on dose and on dose rate. Which ofthese two alternatives is likely to apply remains to beanswered.
153. The linear-quadratic model may be characterized
by the quotient of the induction constants (a/ai).
which varies with the radiation quality and the specificbiological effect. For high-LET particles, this quotient
is so high that the contribution of the dose-squared
term may normally be neglected. The model thenbecomes linear. For low-LET radiation (considering
chromosomal exchanges. mutations and induction ofsome malignancies) the a/a 2 quotient is between
0.5 and 1.5 Gy. The over-estimation of the probabilityof effects at about 10 mGy from single-dose data at
1-2 Gy (acutely delivered) by linear (as opposed tolinear-quadratic) extrapolation would vary from 1.5 to
3.0 for an assumed reasonable set of parameters.
154. Similar over-estimations would apply to theeffects of low-LET radiation delivered at low dose
rates, irrespective of the total doses below the level
when cell killing becomes important. This would
result from the disappearance of the quadratic component of the dose-response curves owing to repair ofsu blesions.
155. Introducing a cell-killing term into a linearquadratic model leads, in general. to a lesser degree ofrisk over-estimation at low doses. The effect of such aterm may be analysed by applying a range ofexperimental cell-survival parameters. Since the killing
effect of a given dose might be less in vivo than invitro. the over-estimation involved in the extrapolation
to low doses and dose rates would probably fall
between that obtained from typical cell survival
parameters in vitro and that obtained by neglecting
cell killing entirely.

156. For fission neutrons and alpha particles, thea/a 2 quotient is of the order of several tens of Gy andthe microdosimetric linear-quadratic model predicts a
linear curve, relatively independent of dose rate. At
doses where departure from linearity becomes substantial. a significant under-estimation of the risk
must result from linear extrapolation to zero doses.
Fractionation or protraction of dose may result inenhancement of the effect even at low and intermediate
doses, contrary to what is seen at intermediate doses forsparsely-ionizing radiation, where the effect decreases
upon fractionation and protraction. These observations, related to high-LET particles, cannot be
explained on biophysical grounds.
157. Dose-response curves after low-LET irradiation
have been reported for some tumours that suggest
either the absence of. or a very small, linear term. In
such cases. the curve approaches the purely quadratic,
indicating perhaps a very low probability of interaction of lesion in two targets crossed by a single
ionizing track. or the presence of highly efficient dosedependent repair processes. Quadratic models havebeen proposed for leukaemia in CBA mice and cancerof the skin and bone. They predict a very pronounced
reduction of the effect by lowering the dose rate or bydose fractionation. Substantial over-estimation of therisk would derive in these cases from linear extrapolation to low doses and dose rates from high orintermediate single doses.

IV.

DOSE-RESPONSE RELATIONSHIPSIN EXPERIMENTAL SYSTEMS

A. PHENOMENA OBSERVED AT THE
CELLULAR AND SUBCELLULAR LEVEL
158. In recent years. there has been good progress inunderstanding the role of oncogenes, and of related
phenomena at the macromolecular level, in the causation and development of cancer. The newest data arereviewed in annex A to the present report. This
progress. however, has left a considerable gap in theunderstanding of how these phenomena may be linked
to mechanisms of radiation carcinogenesis. and what
are the relevant molecular targets [G34]. From qualitative analysis of the available information it appears
that a rather wide spectrum of radiation interaction
with genetic material should be considered.
159. The present section, therefore. discusses doseresponse relationships for radiobiological effects, atthe subcellular and cellular level. that might berelevant to the induction of malignancy. Some effects,
such as in vitro cell transformation, are probably
closely related to in vivo carcinogenesis; the relevanceof others is not yet well established, but is not
implausible. Among the latter effects are mutations,because there is strong evidence of involvement of the
genome in both the process of malignant transformation and of cancerous growth (see II.A). Mutational
events that could be linked with carcinogenesis may
include point mutations, chromosomal deletions and191

translocations, as well as transposition of the genetic
material [B7 I, B72, C32, F 14, S43, S56, Y3]. It has
been postulated [F21] that ··tumour specific" symmetrical chromosomal translocations may be particularly relevant for two reasons: first. there arecancers whose cells consistently show aberrations of thistype (e.g., chronic myelogenous leukaemia, Burkitt's
lymphoma); second, this chromosomal aberration iscompatible with the cell's continuous ability to divide,a pre-condition for a transformed cell to develop intoa cancerous clone.

a:

~

1.0

Constant high dose rate,
varying dose, x rays

0.1

• experimenta 1 points
at high dose rate......
u'I
.....
:z:

w

>
w

0.01

""

:z:
a.
0

w

u

~

l.

l\lutations in germ cellsc:,::; 0.001a,o160. The frequency of point mutations as related todose in germ cells of male and female mice. and ofother species, was reviewed in depth in annex H of the
1977 UNSCEAR repon [U6] and in annex I of the1982 UNSCEAR report [U24]. The most recent
findings are dealt with in annex A to this report. In
summary. there is an unquestionable effect of dose
rate and fractionation upon specific locus mutations
induced in germ cells of male and female mice by lowLET radiation. Interpretations of these findings differ
coilsiderably. Abrahamson and Wolff [A2, A3] postulated that mutational lesions are both one- and twotrack events, and tried to fit linear-quadratic equations
to the data. The attempt was criticized by Russell[R24. R25. R26] who has long been advocating analternative hypothesis, namely, that mutations themselves are single-track phenomena. and the apparent
multiple-track events reflect damage and saturation of
the repair processes at higher doses and dose rates.
UNSCEAR reviewed both hypotheses in detail and, inthe light of present evidence, accepted that of Russell
as a more likely explanation.

2.

:\lutations in somatic cells(a)The Tradescantia system

161. The data obtained on plant cells of the species
Tradescantia are very valuable because: (a) mutations
can be scored down to 3 mGy of x rays (andcorrespondingly lower doses of neutrons); (b) theamount of data on the effects of dose. dose rate andradiation quality is far better than for any othercellular system: (c) the effect is e,·idently a somatic
mutation (although its molecular mechanism is notclear) and the underlying lesion is most likely chromosomal; and (d) the form of the dose-response curve issimilar to that for dicentrics and deletions in mammalian T lymphocytes.
162. Dose-response relationships for somatic mutations in Tradescantia, induced by acute.250-kVp x rays,
are plotted on a log-log scale in Figure VI [N2, S20,
UI9]. Below 0.1 Gy. the curve is linear, but thenits slope increases up to I Gy, where a dose-squared
component sets in. leading to an upward concavity of
the curve. Above 1-2 Gy, the curve bends anddeclines, reflecting. perhaps. preferential killing of themutated cells (the effect is scored in terms offrequency per surviving cell). The data points below
192

I. ~.,~

0.0001
10- 3

,0-2

10-1

100

10 1

DOSE (Gy)Figure VI.

Dose-response curve for induced pink mutations In
Tradescantia.

[B99]

I Gy are well fitted by a non-threshold regression
equation of the type I= a 1D + a 2 0 2, where a 1 and a 2
arc constants, presumably for single- and two-track
events. Mean values of a 1 and a 2 deduced from threestudies [S20, N2, UI9] amounted to 5.1 (range 4.6-6.4)
10- 2 Gy- 1 and 6.5 (5.5-17.3) 10- 2 Gy- 2, respectively[NI]. In terms of the linear-quadratic model, the a 1/a 2
quotient for x rays varied from 0.33 to 0.83 Gy. For
gamma rays. u 1 and 11 2 are 2.1 10- 2 Gy- 1 and5.2 10- 2 Gy- 2 • respectively [NI]. Studies with monoenergetic neutrons (0.065-13.4 Me V) produced a linear
dose-response up to 0.05-0.1 Gy (S19, UI3] of theform I = a 10. At high and intermediate doses. theRBE of neutrons versus x rays was inverselv proportional to the square root of the neutron dose.
163. Reduction of the neutron dose rate had almost
no effect upon the yield of mutations [N2, U 13].
When the x-ray dose rate was reduced from about
I Gy min- 1 to 5-0.5 mGy min- 1, the frequency ofmutations was an increasingly linear function of thedose, approaching a linear response of the form
I = a 10. When the dose rate of x or gamma rays was
progressively lowered [M 18]. and a constant dose of
0.8 Gy delivered over increasing time intervals. lower
mutation frequencies were observed approaching
asymptotically the limiting value of the respective a 10
for gamma rays. Fractionation of an x-ray dose of
0.6 Gy into two acute fractions of 0.3 Gy each [M 18]
produced no reduction of the mutation yield up to a
15-minute fractionation interval, but the yield declinedwith further spacing of the fractions up to 24 hours.
Splitting an x-ray dose of 0.05 Gy into two 0.025 Gy
fractions given at 5 hours from each other did not
reduce the response any further [U27).
164. The influence of fractionation of two x-ray
doses (0. 7 and 4 Gy) was studied upon induction andrepair of two types of somatic mutations (pink andcolourless) in this system (Wl6]. The intervals between

the two fractions varied from 0.5 to 12 hours.
Recovery for the two types of mutations differed. inthat pink mutations showed recovery at both doses,
whereas colourless events showed some recovery at
lower doses, but an increased effect at higher doses.
Thus, two types of mutations induced by x rays in thesame system may have different dose and time
kinetics.
165. In summary. the effects of dose, dose rate.
fractionation and quality of radiation upon Tradescantia mutations provide. in general. a good exampleof the linear-quadratic model of radiation action.

(b)

Mammalian somatic cells

166. In recent years, significant progress has been
made in the methodology of studies of point mutations
in somatic cells in culture. Enzyme deficiencies are
induced by mutagenic agents. and mutant cells arescreened for resistance of developing clones tosubstances that are toxic to normal cells, e.g .. to8-azaguanine, 6-mercaptopurine or 6-thioguanineinhypoxanthine-guanine-phosphoribosyltransferase(HG-PRT) deficient mutants. Biochemical mechanisms
and methods of investigation were reviewed in detailin annex H of the 1977 UN SC EAR report [U 6] and inannex I of the 1982 UNSCEAR report [U24] and are
discussed again in annex A to the present report.
167. In summary, both linear and curvilinear (concave upwards) relationships have been observed for
induction of J:{G-PRT deficiency in various cell lines
by sparsely-ionizing x or gamma rays, and thecharacter of the dose-response curve is evidently
related to the genome of the cell studied and not only
to the quality of radiation applied [Al 3, A 14, B42.
CIO, C23. C24. E8, Kl6]. In cases of curvilinear
dose-response relationships, after acute x or gamma
irradiation there was also a pronounced reduction of
the yield of mutations by dose fractionation. For
densely-ionizing radiation (alpha particles. helium,boron and nitrogen ions). the dose-response relationship for induction of HG-RPT deficiency, both inhuman and hamster cells, was essentially linear [C20,Tl8]. Induction of forward mutations in Chinese
hamster cells by x rays resulted in curvilinear doseresponse relationships (concave upwards): moreoverpronounced dose-rate effects were observed [S25].
168. Experiments on radiation-induced mutations
resulting in HG-PRT deficiency show some correlation between the shape of the survival curve for lowLET radiation and the kinetics of induction ofsomatic mutations in the same cell lines. This observation has been generalized by Thacker et al. [TIO.
T9, T8], Munson and Goodhead [M36]. Leenhouts
and Chadwick [L3. C2] and Goodhead et al. [G29] on
different radiations and cells in various stages of thecell cycle. in the sense that there is a relationship of
the type lnS = -K.M where S is the cell survival(SofSo), and M the frequency of induced mutations.
This correlation is corroborated by other studies (e.g ..
[R5]). Thacker [T8] has shown that it applies toexponentially growing cells of several species (man,hamster and mouse) with the same proportionality
constant K. However. the mutation frequency perlethal lesion seems higher for high-LET radiation andlower for ultrasoft x rays [G34].
169. When Thacker et al. studied the same relationship [Tl 9], by irradiating V-79-4 hamster cells grown
to plateau phase without re-feeding (most cells in theG 1 phase), they found a similar association of
frequency of induced mutations with (log) survival.
This was true both after high (1.7 Gy min- 1) and low
dose rate (down to 3.4 mGy min- 1) gamma irradiation.
There was considerable repair of sub-lethal and submutational damage with decreasing dose rate. However, when the cells were held for 5 hours after
irradiation, before trypsinization and seeding. thepotentially lethal damage was effectively repaired,
whereas that leading to mutation (HGPRT locus)
remained unaffected. Goodhead et al. [G29] interpreted all this to show that the average number ofmutagenic lesions in a cell is proportional to theaverage number of lethal lesions induced by a given
radiation. However. results on repair of the potentiallylethal damage show that phenomena involved in cellkilling and mutation induction can be separated.
170. This conclusion remains to be confirmed. However, if the correlation were generally valid, a linear
relationship between frequency of induced mutations
and dose of low-LET radiation would be exceptional.
because exponential cell-survival curves for x andgamma rays are also exceptional (Al7. B63, C9,
C21-C23, F2, K21. N8. P7. Pl5. S33. W6. W7]. sigmoid
cell survival generally being the rule [B5. B9-BJ2, B19.
B27. B45. CJ, C37, 03, 08, E2. Fl. F2. Fl9. H2. H6,
K2. K24, L6, Ml6, M60, S33. Tl8, W6, W7]. In mostcases studied after neutron and alpha-particle irradiation. the survival of diploid mammalian cells is. with few
exceptions [HI. C20]. a simple exponential function ofdose [B5, B9-BI2. B29. B45. J6, K2. K3, R39, Tl8].

3.

{a)

Chromosome aberrations

Translocarions in germinal cells

171. As discussed in annex Hof the 1977 UNSCEAR
report [U6]. the frequency of chromosomal translocations induced by x and gamma rays in spermatogonia,
spermatids and oocytes shows a pronounced dose-rateand dose-fractionation effect, and data can be fitted toa linear-quadratic equation. On the other hand,neutrons produce essentially linear dose-reponse relationships without any significant protraction or fractionation effect. These conclusions have been confirmed
by more recent data reviewed in annex I of the 1982UNSCEAR report [U24] and in annex A to thepresent report.
{b)Somatic cells

172. Studies of chromosomal aberrations in human
lymphocytes have been reviewed in the past by
UNSCEAR (1969 report, annex C, [U9]). and byothers [B15, Ll3, LI2. 04]. In most cases, the yield of193

easily identifiable dicentric chromosomes and acentric
fragments. induced in G 0 cells, was studied against thedose of various radiations. The asymmetric exchanges
are not compatible with cell survival over many
generations: however. the yield and kinetics of induction are accepted as representative of symmetricalchromosomal exchanges. The latter may be relevant topresent considerations. The subject of dose-response
relationships for induction of dicentrics has beenthoroughly reviewed by Lloyd and Edwards [L36].
The review included re-calculation of the dose-response
functions from original data (62 experiments) using astandardized maximum likelihood method for fitting alinear-quadratic equation. The main conclusions are:(a)

For low-LET radiation. the yield decreases withdecreasing dose rate (or the extension of irradiation time) and with increasing fractionationintervals. This effect is attributed to the repair ofinteracting lesions. whose mean life appears to beabout 2 hours. although some of the lesions may
have a much longer life. Available experimental
data and their theoretical interpretation suggest
that, for very long irradiation times, the a 2
coefficient would be zero and the a I would
remain unaffected (linear relationship);(b)

For neutrons. no effects of dose protraction or
fractionation were seen.

(a)

For gamma rays and high-energy electrons. thevalue of a 1• in the region of 2-2.5 10- 2 dicentric
per cell and gray, appears to be consistent withmost observations:(b)

For x rays (180-250 kVp), a representative valueof a 1 of about 5 10- 2 dicentric per cell and grayseems to apply:

174. The RBE of neutrons versus x or gamma rays isinversely proportional co the square root of theneutron dose. The limiting value at low dose rates
may be obtained from the ratios of the relevant a 1
coefficients.

(c)

The a 2 coefficients for gamma rays. x rays andelectrons show less variation than the individual
reported values of a 1• and they cluster within therange of 4-8 10- 2 dicentric per cell and graysquare:(d)

For fission neutrons, no significant a 2 term wasobserved. Typical a 1 values would be 40-90 dicentric per cell and gray. The coefficient tends toincrease with lowering of the particle energy. to apeak at about 350 keV (about 160 dicentric per
cell and gray);(e)

In several studies [K36, VI 1, Zl]. the yield ofchromosome aberrations in human lymphocytes
was studied after doses well below 0.5 Gy ofx rays. When the data on dicentrics from thesestudies were pooled [Z l], they fitted a linear
function of dose passing through the origin, as
would be expected from the values given above.
The response for acentric fragments was similar.
even though less regular:(f)

At neutron energies above 15 MeV, a significant
value of a 2 appears:(g)

For protons with energies > 7.4 MeV, the a 1
coefficients are very similar to those for x rays.
The a 2 values are rather lower than for typical
low-LET radiation:(h)For alpha particles, all dose-response relationships (excluding one study with possible methodological complications) are linear. but a I values
scatter widely. owing probably to systematic
dosimetric inaccuracies;(i)

When the value of a 1 is correlated with LET,
the coefficient increases with the latter above
5 keV/,um to a maximum at about 70 keV/µm,
and then falls off sharply at still higher values of
the LET. The a 2 value is roughly constant for
low-LET radiation. but virtually absent for highLET particles.

175. This was also noted when whole blood wasirradiated by adding tritiated water prior to initiationof blastic transformation. Doses between 0.2 and 4 Gy
/3 radiation were delivered over 30 minutes or
24 hours. Whereas the dose-response curve for
30-minutes exposures was practically the same as thatafter acute x rays. the response was close to linearity
after longer exposures (the linear component remained
unchanged while the quadratic one decreased by afactor of about 3 [P20]).
176. Similar relationships were obtained for dicentrics in the lymphocytes of all mammalian species
studied so far (marmoset [B41]. Chinese hamster[B41], rabbit [BI. B2. S5]. pottoroo [S5]. swine [BI.
B4L L7]. sheep [L7]. goat [L7]. mouse [823. B41],
rhesus monkey [B61]. and other primates [H9, M37]).
With protraction or fractionation of x- or gamma-ray
doses. the linear term prevails [S4. L9]. With irradiation times exceeding 24 hours the relationships fordicentrics after exposure to gamma rays tend to
approach linearity.
177. For acentric fragments. a linear-quadratic
relationship is usually observed. but the results are lessreproducible [B2, LI3]. As these aberrations include
both interstitial and terminal deletions. classified
together. the relationship does not contradict linearity
for single-break aberrations.
178. In conclusion. induction of chromosomal aberrations of the one- and two-break type. in somatic
cells in G 0 or G 1• is in broad agreement with thelinear-quadratic model for low-LET and with thelinear models for high-LET particles. This agreement
refers to dose and to the effects of dose rate andfractionation. For single-break aberrations. a linear
model should fit the data. but methodological problems make the demonstration difficult.
4.

Oncogenic transformation of cells in vitro(a)173. The effects of dose rate and fractionation upon
dicentric yield in lymphocytes may be summarized asfollows:
194

General179. Studies of transformation from the normal tothe oncogenic state, on cells in vitro. are very relevant

to the purposes of the present annex. They allow
investigation of the mechanisms of cancer initiation
without interference of other factors at the tissue andsystemic levels. In addition. killing and transformation
may be measured in the same target cells. allowing therelative importance of the two effects to be studied at
the same time. Morover, in vitro experiments are lessexpensive and time-consuming than studies on irradiated animals and are easier to analyse, owing to theJack of competing risks and the higher precision of
measurements. On the other hand, lack of closeintercellular contact and systemic regulation during
culture growth is an artifact compared with thesituation in situ. and could change-at least quantitatively-the reactions of cells studied. Details of cell
handling, such as whether trypsinization has been
applied to the cultures, or not. in the course of theexperiments, may also substantially modify the results.
So far. observations on cell transformation have been
limited almost exclusively to fibroblasts. whereas
tumours of epithelial origin prevail among radiationinduced cancers in man.

10- 1
-'
-'
I.LI

u

2
10-2

• !

C!l

z
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=:,
Vl

10- 3

~

I.LI

a.
Vl

1-

250 kVp x rays

:z:

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~

o 430 keV neutrons

~

0

u..
Vl

:z:

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I-

95% confidence limits
10_ 6 ...,_~...__~.,.....~~.......~~~.--~~-.10-3
10- 2
10°
10 1
10- 1
DOSE (.Gy)(b)

Dose-response relationships

180. Transformed cells are assessed by scoring characteristic colonies recovered in a culture. This directly
measures the transformation frequency per surviving
cell. Most experiments are reported in this way, but.
with some additional effort, information can beobtained on cell survival as a function of dose. and on
the plating efficiency. The transformation yield per
initial cell at risk may be calculated by correcting thetransformation frequencies per surviving cell for therespective survival values and plating efficiency. Thislatter measure of transformation can seldom becomputed from the frequencies per survivors reported
in the papers, which often makes it difficult to give aprecise description of the dose-response relationships.
Many features of the dose-response relationships
depend strongly upon the time interval between theestablishment of a culture (seeding of cells) andirradiation: new and established cultures should therefore be dealt with separately.

(i)

Irradiation offreshly established cultures

181. Borek and Hall [B33] x-irradiated early-passage
golden hamster embryo cells in vitro, 24 hours aftertrypsinization and seeding. with doses from 0.0 l to
6.0 Gy (a point at 0.003 Gy x rays was added later[B76]). A dose-response relationship per surviving cellis presented in Figure VII, showing a rise with dose up
to l Gy. a plateau between 1.5 and 3.0 Gy, and a
decline thereafter. The dose-response relationship fromthe same and subsequent experiments was also expressed
per initial cell at risk [B29]. It is impossible to say
whether a linear or an upwards concave line would bea better fit of the experimental points along theascending portion of the curve. A linear fit was
assumed by the authors themselves but a linearquadratic fit was also attempted by Chadwick andLeenhouts [L3]. In a linear plot the line tends to passthrough the origin, suggesting no threshold. Below

Figure VII. Dose-response curves for transformation of hamster
embryo cells by neutrons and x rays. The curves were obtainedby non-parametric least-squares fitting.
[B79]

0.5 Gy of x rays and down to 0.01 Gy the yield oftransformants appears to rise with a power of dose
< I. The transformation frequency per Gy of x rays
below I Gy is of the order of 10-2 per cell. which isseveral orders of magnitude greater than for any
somatic mutation [U6] but almost an order ofmagnitude lower than the total yield of chromosomal
aberrations induced by comparable doses of x rays inmammalian lymphocytes [D4]. In a comparison of
300-kVp x and 60Co gamma rays [B76] the RBE of thelatter varied from 0.85 at about I Gy to 0.5 at a few
tens of mGy.
182. Borek. Hall and Rossi [B29] and Borek andHall [B79] irradiated hamster embryo cells withmonoenergetic neutrons (0.43 MeV) and compared thedose-response relationship with that for x rays. The
curves representing the relationships. both per surviving cell or per initial cell at risk, were peaked in shapeand roughly parallel. A fit to the neutron data similar
to that for x rays. but shifted toward lower doses, wasobtained (Figure VII) with no suggestion of a threshold.
Below 0.1 Gy, the transformation frequency could
also be interpreted as rising with a power of doselower than unity. The RBE of neutrons. at transformation frequencies of 10-3 and 5 10-3, was about 12
and about 6, respectively. Measurable transformation
was induced even by I mGy of neutrons. Accelerated
argon ions (429 MeV per atomic mass unit) wereroughly as effective as neutrons [B29].
183. Data were also obtained for cell survival [B29].
For x rays a sigmoid survival curve (Do= 1.47 Gy;n = 6). and for 430-keV neutrons a purely exponential
curve (D 0 = 0.5 Gy), were reported. The RBE ofneutrons varied approximately with the inverse square195

root of the neurron dose, with values from about 30 atdoses below 0.1 Gy to about 5 at 1.5 Gy. At doses
above 2-3 Gy of x rays, cell killing was appreciable.
but the decline of transformation yield per unit dose
above I Gy of x rays and 0.25 Gy of neutrons was
explained by assuming that transformed cells werepreferentially killed by radiation. An alternative explanation of this phenomenon was also proposed [C7,L3].
184. The dose-response relationship for x-ray-induced
transformation of C3H lOTl/2 cells irradiated 24 hours
after seeding was also studied [T7] and expressed per
surviving cell (at cell densities below 3.8 cell cm- 2:
100-kV x rays, 0 to 15 Gy). The transformation
frequency rose rapidly with dose, up to 4 Gy, andreached a plateau at about 15 Gy. At about I Gy. thetransformation frequency was about 0.5 10-4, roughly
2 orders of magnitude lower than for hamster embryo
cells [B33]. The doses required to double the transformation yield along the ascending branch of thecurves for these two types of cells were 1.0 and 0.1 Gy,
respectively. The dose-response curve for C3HIOT1/2
cells showed no apparent threshold and was concave
upwards, the effect rising with a power of dose > 1
and close to 2.
185. In a later study. Miller et al. [M23, M41)
examined, under a similar experimental protocol inthe same C3Hl0Tl/2 cells, the effect of single andsplit doses of 300-kVp x rays. The single-dose response
curve had a complex, curvilinear shape. The transformation frequency was less than proportional todose between 0.1 and 0.3 Gy, almost flat between 0.3
and about I Gy, and then rising with the square. or
higher. power of dose. A plot of the data at 0.1-10 Gyon a log-log scale, per surviving cell, is given in
Figure VIII. Interpretation of the shape of this dose4 10- 3 ·

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u

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c:r::

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z

i

10- 4

0
I.L.

single doses• split
doses

VI

z

0

~
.....

0.1

1

10

DOSE. (Gy)Figure VIII. Dose-response relationships for the number oftransformants per surviving C3H10T1/2 cells, following single
or spilt doses of 300-kVp x rays. In the case of split doses, theradiation was delivered In two equal exposures, separated by
5 hours.
[M23]

I96

response relationship is very difficult, particularly inthe dose range below I Gy.
186. Yang, also, studied the transformation of
C3 HI OT 1/2 cells by x rays and energetic silicon ions
(initial energy 320 MeV per atomic mass unit. residual
range in water 4.5 cm, dose average LET= 88 keV/µm)[Y5]. This radiation was more effective than 225 kVp
x rays (RBE not given). Cells kept in a highly
confluent state for some time after irradiation wereable to repair part of the transformation damage
induced by x rays, but not that induced by accelerated
silicon ions.
187. When C3H IOTl/2 cells were irradiated withneutrons (35-Me V d+ - Be). the results were as in
Figure IX [B79]. The dose-response curve is shifted
towards lower doses with a similar dose-independent
plateau as for x rays. The RBE increased withdecreasing dose and was similar for both transformation and cell killing.
188. Lloyd et al. [Ll 5] studied transformation in
C3H lOTl/2 cells by irradiation with 5.6-MeV alphaparticles, showing a higher effectiveness as comparedwith x rays (the relationship of irradiation- andseeding-time is not available). For alpha particles, thedose-response relationship is of a grossly curvilinear(concave upward) character, the effect rising withapproximately the cube of the dose. When expressed
per surviving cell. the maximum transformation rate
was seen at about 2 Gy.
189. C3H JOTI/2 cells were transformed by 100-kVp
x rays, fast fission neutrons (mean energy 0.5 MeV.
8-20% gamma contribution) and cyclotron neutrons(mean energy 38 MeV, 8% gamma contribution). The
dose ranges were: 1.5-11 Gy, 0.5-5 Gy, and 1.5-6 Gy,
respectively [B89]. The cells were irradiated 36 hours
after seeding. For fission neutrons, the response persurvivor was most effective and the initial portion of
the curve was only slightly concave upwards. X rays
were least effective and 38-MeV neutrons produced
curves very similar to those of x rays. For bothradiations. the dose-response curves were grossly
concave upwards at their ascending portions. A
plateau of effect at high doses was reached for allradiations tested. It is worth mentioning that for eachradiation the survival curves had pronounced shoulders. which were roughly proportional to the degree ofcurvilinearity of the dose-transformation curves. The
RBE relative to x rays at the transformation frequencyof 5 10- 4 was 1.2 and 3.8 for 38-MeV and 0.5-MeV
neutrons, respectively .
190. Transformation of BALB/3T3 cells by 238 Pu
alpha particles and x rays was studied by exposure of
freshly seeded single cells or confluent cell monolayers[R39]. The dose ranges were 0.5-2.5 Gy and 0.5-5 Gy
for alpha particles and x rays, respectively. Whencalculated per surviving cell the rise of transformation
frequency with dose was exponential (steeper thanproportional). However. when the results were expressed as transformants per exposed cell, for alphaparticles the highest yield was induced already by adose of 0.5 Gy, with a slight decline thereafter. This

....I
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=:,
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z

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300 kVp x rayso 35 MeV d+... Be neutrons

0

u..
Vl

z
~

95% confidence limits

I-

10- 1
10°
DOSE (Gy)Figure IX.

Pooled data obtained for the fraction of transformants per surviving C3H10T1/2 cell
following Irradiation with x rays or neutrons.
[B79]

may be attributed to highly efficient cell sterilizationby alpha rays. A high effectiveness of the alphaparticles. relative to x rays, was noted. but the precise
shapes of the curves at the lower end of the dose scalecannot be established. Little studied the transformation by x rays of freshly seeded cells (20 hours prior to
exposure) of BALB/3T3 mouse [LIO]. Although there
was some indication of an upward concave curve, thestatistical uncertainty of the data does not allow
precise conclusions.
191. Golden Syrian hamster embryo fibroblasts,
seeded about I 2 hours before, were exposed for 17 hours
to varying concentrations of methyl 3H-thymidine[L33]. The number of transformants per surviving cell(and mutants at HGPRI locus) showed a proportionality to the concentration of the substance. Tritiateduridine. which is not incorporated into DNA. wasineffective in inducing both oncogenic transformationand mutations.
192. BALB/3T3 embryo fibroblasts. synchronized in
the S-phase, were incubated for 16 hours with the
DNA precursors 3H-thymidine and 12s1-iododeoxyuridine ( 125 1-dUrd) [L34]. The incorporation of theradionuclides into cellular DNA was proportional toconcentration in the culture medium. The transformation frequency per survivor. versus concentration ofactivity per cell, was linear in both cases-without
suggestion of a threshold-up to a frequency of about
5 10- 4 _ The ratio of the initial slopes of 12SJ-dUrd
versus 3 H-thymidine dose-response curve was about
25. In the same experimental series, the transformation
by x rays was somewhat irregular, with an approximately exponential increase of the transformation
frequency with dose over the whole range of doses(0.5-6 Gy). The high effectiveness of 12 5I-dUrd was
explained by the release of a cluster of low energy

Auger electrons (about 25 per decay). leading to avery high energy deposition in the vicinity of the DNA
double strand.
(ii)

Lare irradiation of cultures

193. Dose-response relationships for in vitro transformation of cell line C3H IOT 1/2 by acutely delivered
x rays (50-kVp, 0.18 mm Al filtration) and neutrons(fission, mean energy 0.85 Me V) were reported by
Han and Elkind [HJ]. In contrast with the experiments
reviewed above, cells were irradiated 48 hours after
seeding. When the transformation rate was expressed
per initial cell at risk, the decline of the yield beyond
the maximum had the same slope (or D 0) as for thekilling of non-transformed cells. suggesting that sterilization by high doses of normal or transformed cells
was similar. On linear co-ordinates (Figure X). theascending portions of the dose-response curves (perinitial cell at risk) for x rays was concave upwards (atleast above 1.5-2 Gy) but details cannot be establishedfrom the graphs. For neutrons, the ascending portionof the curve appears to be close to linearity. The RBEof neutrons increased with declining doses, and the
maximum attainable transformation frequency byneutrons was higher by about 50% than that for
gamma rays (per initial cell at risk). In contrast withthe data of Miller et al. [M23] (Figure VIII) there wasa significant flattening of the yield above 4 Gy ofx rays. when the data were expressed per surviving cell
[Hl4] (see Figure XI).
194. Watanabe et al. [W 18] irradiated golden hamster
embryo cells 72 hours after establishing the culture.
The exposures varied from 50 to 600 R at exposure
rates of 5, 75 and 600 R/min. Additional exposures(1-50 R) were applied at the dose rate of 5 R/min. The
197

195. Terasima et al. [T24] studied C3HIOTI/2 cells,
x-irradiated (0.23 to 9.3 Gy) in the plateau phase of
growth (contact inhibited). The dose response (persurviving cell) was very similar to that found by others
for the same cell line. After a steep exponential
increase, up to about 1.8 Gy, there was a graduallyslower increase of the transformation frequency with aplateau above 6-8 Gy. Recent data on in vitrotransformation of C3H JOTl/2 cells by 31-MeV protons
were published by Bettega et al. [B3J, showing that thetransformation frequency per surviving cell had amarked change in slope at about 2 Gy .

(x 10- 4 )
16

14
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50 kVp x rays(c)neutrons

0

....
0

V'I

z

4

<

..."'

(i)

2

0

0

2

4

6
8
DOSE (Gy)

10

12

14

Figure X. Changes in transformation frequency of C3H10T1/2
cells after single exposures to x rays or fission-spectrum
neutrons.
[H1]

a:
0

a:

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V,

10- 3

w

Irradiation offreshly established cu/rures

196. Irradiation of cultures seeded 24 hours before
exposure with two doses of 4.5 + 4.5 Gy of x rays at
various intervals (zero to five hours) showed thatsurvival of C3H JOT 1/2 fibroblasts nearly doubled
when the interval exceeded 2 hours, with no further
increase for longer intervals [T4]. For doses of 1.5, 3.0
and 8.0 Gy in two equal fractions at five-hourintervals. the transformation frequency per surviving
cell remained unaltered at the lowest dose, but
declined significantly (p = 0.005) at the two higher
doses.
197. Hamster embryo cells in culture (seeded 24 hours
earlier) showed a doubling of the effect after split, as
opposed to single, doses of 0.5 or 0.75 Gy [B90]. At
the same time, the survival of irradiated cells increased
only marginally. When the experiment was extended[B64] by studying the effect on the transformation
frequencies of splitting 1.5, 3 and 6 Gy of x rays,
no enhancing effect of 2 X 0.75 Gy. as opposed to
1 X 1.5 Gy. was noted. Fractionation of 3 and 6 Gy
led to a reduction of the total effect.

::::
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Effects of dose fractionation and protracrion;
repair of sub-transformation and potential
transformation damage

0..

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-1

1.0 Gy min-1
0.05 Gy min

5
4 10- - - - - . - - . . . . - - - - - - - - - -.......- -....
0
2
14
6
8
10
12
4

D,OSE (Gy)Figure Xl. Frequency of neoplastic transformation of
C3H10T1/2 cells expressed per surviving cell as a function ofdose of gamma rays delivered at high or at low dose rate. Error
bars represent the standard errors of the data pooled fromvarious experiments.
[H14]

logarithm of transformation frequency per survivor
was approximately linear up to 100 R, and had a very
shallow increase from 200 R onwards (semi-plateau).
From the graphical presentation of data. it appears thatup to 75 R, at 5 R/min. the dose-response relationshipis linear, with no suggestion of a threshold.
198

198. Miller and Hall [M23] studied dose fractionation
on C3H IOTI/2 fibroblasts. plated 24 hours before
x-ray treatments (0.3 to 8.0 Gy). Their results confirmed the sparing effects of splitting the dose above
1.5 Gy (with a possibly incidental deviation of thepoints at 4 Gy) and an enhancement of transformation
below that dose. The experiment was repeated [M41],
and the dose range expanded to include 0.1 and10 Gy. The results are presented in Figure VIII. In
addition. a dose of I Gy was split into 2. 3 or 4 equal
fractions [H2l]. An almost proportional (2-, 3- and4-fold) enhancement of transformation was observed.
Also. when a dose of I Gy of 60 Co gamma rays wasdelivered at a low dose rate (over 6 hours) the effectwas significantly enhanced, by a factor of about 3, bycomparison with acute exposure (over 10 min) [H21].
In conclusion, using this experimental protocol. in therange 0.3-1 Gy there is an enhancement of the effectby splitting the dose into two equal fractions within
5 hours or by protracting the dose over a similarinterval. At 2 Gy, there is no effect. There is a declineof the yield after fractionation at higher doses.
Approximately the same trend is seen when the data
are expressed per initial cell at risk.

199. LiHle [LIO] reported dose-fractionation experiments on BALB/3T3 cells seeded 24 hours before thefirst exposure with essentially identical results. The
fractionated doses ranged from 0.1 to 3.5 Gy, andsimilar observations were also made in still anotherstudy by Suzuki et al. [S44]. It may be concluded,
therefore. that enhanced transformation (per survivor)
below 1.5 Gy of x rays after fractionation within
5 hours is a phenomenon observable in all cell lines
studied so far, irradiated in freshly established cultures.
Such an effect might be deduced from the curves in
Figure VIII [M23]. In fact. if an independent action of
the two dose fractions is assumed, the decrease above
2 Gy. where the response rises with 02 or with ahigher exponent, is easily understood. Similarly. below
I Gy. over the plateau. where the effect is roughly
independent of dose, fractionation should increase theyield, as observed.

transformation yield was by a factor of about 5 above
6 Gy and by a factor of about 3 at 2 Gy, and was stillpresent at doses of 0.5 and 0.2 Gy [E9. H26].
203. Hill et al. [H30] studied the effects of gammaray fractionation in the same system. Throughout thedose range tested (0.25-3 Gy). fractionation of thedose into 5 daily fractions resulted in a significant
reduction of transformation frequency. Up to 1.5 Gydelivered unfractionated. and up to 3 Gy fractionatedregimes. the dose response could be fitted by a straightline passing though the origin (Figure XII). The yield(x 10- 4 )
8

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a

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a:

=:,

200. Figures VIII and IX show clearly that a linear
extrapolation down from intermediate ( I Gy) andhigh (2-3 Gy) doses of x rays would lead to an underestimate of the real transformation frequency, particularly with respect to the effect of split doses in the
low-dose region. The greatest under-estimate, by afactor of 4-6. would be encountered when the effect of
single doses in the range 1-3 Gy is linearly extrapolated
to predict effects of split total doses of 0.1-0.3 Gy. The
relevance of this finding to tumour induction in vivo
has been commented upon by several authors [B76,
H21. M41].

"'

SLOPE ( Gy - I )CORR, COEFFICIENTSLOPE RATIO (1')

7

I Gy/minO. 5 Gy/min

2.58 10- 4

0.8 10- 4
0.975

0.955
0.31

6

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Gy/mln• 0.5 Gy/min

0
0

(ii)

Late irradiation of cultures

201. Data on fractionation were reported by Han
and Elkind [HI] for x rays (0.75 Gy) and fission
neutrons (3.8 Gy) on C3H IOTl/2cells exposed 48 hours
after seeding. The transformation rate after doses ofthis magnitude was on the declining part of the curvewhen expressed per initial cell at risk. Fractionation of
the neutron dose within O to 16 hours had little. if any.
effect on single-dose survival and caused a slight
reduction of the transformation yield. perhaps within
the limits of experimental error. With x-ray fractionation times up to 5 and 10 hours, the frequency
increased and then declined to the level of the nonfractionated exposure at about 16 hours. The increase
was within a factor of 2 and its statistical significanceuncertain. When expressed per sur,;vor, the transformation frequency after x irradiation declined steadily
to a plateau at 12-16 hours fractionation interval,
reflecting essentially an expected and considerable
effect upon survival of the non-transformed cells. Thisobservation. therefore. confirmed other findings [M23.
M4I) that fractionation of high x-ray doses in this cellline reduces the transformation frequency when expressed per surviving cell.
202. Han and Elkind also irradiated C3HI0Tl/2
cells. 48 hours after plating. with 60Co gamma rays athigh (1.0 Gy min-1) and low (0.05 Gy min- 1) dose
rate [H 14]. The range of doses varied between 0.2 and13 Gy. The transformation frequency per survivor(Figure XI) was consistently reduced at the lower dose
rate. as was cell sterilization. The reduction in

2

3

DOSE (Gy)Figure XII. Transformation frequency of C3H10T1/2 cells per
surviving cell against dose of gamma rays. Open circles: acuteexposure at 1 Gy mln- 1; Dashed line: continuous exposure at
1 mGy mln- 1; Closed circles: five fractions at 0.5 Gy mln- 1.
given at 24-hour Intervals.
[H30]

of transformants per unit dose was 3 times lower after
fractionated than after single doses. and very similar
to the dose-response curve for the lower dose-rate
exposure referred to above [E9. H26]. Increasing thefractionation intervals beyond 24 hours, and reducing
the dose per fraction, led to a further slight reductionof the effect. This suggested that there may be a limit
beyond which further dose protraction cannot reduce
the transformation frequency. Trypsinization per se,or delivery of the dose within 7 days of growth inculture, did not affect the yield of transformants perunit dose, provided they took place at least 40 hours
after seeding. Confluence of the cells was excluded asa possible reason for the observed fractionation effect.
These results of dose fractionation and protraction
below 1.5 Gy are in striking contrast with thoseobserved when the cells were irradiated 24 hours after
seeding [H21, M23]. The difference was attributed toatypical conditions of cellular growth early after
plating and to the action of radiation on parasynchronous cells [H30].
204. Watanabe et al. [W 18) irradiated golden hamster
embryo cells. sub-cultured 72 hours earlier. with x rays199

at various exposure rates: 5, 75 and 600 R/min.
Throughout the whole range of exposures tested(50-600 R), the lower dose rates produced a reduced
yield of transformed cells. even within the 50-100 R
range where the dose-response relationship was practically linear. At equal survival levels (which wereinversely related to dose rate). the transformation
frequency was higher in cells irradiated at higher thanat lower dose rates. Terasima et al. [T24] studied theeffect of fractionating x-ray doses (0.93, 1.86 and3.72 Gy) in C3HTIOl/2 cells irradiated in the plateau
phase. Equal fractions were spaced at intervals of 3.
10 and 15 hours. There was significant reduction of
the yield at all doses tested, as compared with single
doses, the maximum reduction being achieved alreadyat the 3-hour interval.
205. Hill et al. [H26. H34] worked with fissionspectrum neutrons (mean energy 0.85 MeV) at ,·arious
dose rates in C3H!OTl/2 cells irradiated 48 hours
after seeding. There was no discernible effect uponcell survival of neutrons delivered at a low rate
(0.43-0.86 mGy min- 1) versus a high rate (0.103-0.38 Gy
min- 1). At the same time, the low-rate neutron
irradiation enhanced significantly the transformation
frequency at doses below I Gy (by a factor of about
9 at 0.025-0.l Gy) (Figure XIII), an effect that cannot

ls 15

SLOPE (Gy-l)
CORR. COEFFICIENTSLOPE RATIO (\)

~

~

Bl

0.38 Gy/min

0.00086 Gy/min

5.96 10- 4

53.o ,o- 4
0.998

0.990

8.89

....

C:

0.

>-

~

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....

10

C:
.....

a
,-

i 5
a
.....
V')

~

...

0.38 Gy/min
0.00086 Gy/mfn

0

•
0

0.2

0.4

0.6

0.8

1.0

DOSE (Gy)Figure XIII. Oncogenlc transformation of C3H10T1/2 cells
exposed to fission-spectrum neutrons al high and low dose
rate. Dashed lines Indicate the linear regressions fitted to theinitial portions of the curves.
[H34]

be explained on biophysical grounds. Above doses of
1.5-2.0 Gy. the effect of the dose rate disappeared anddose-response relationships converged to a plateau of
5 10- 3 transformants per surviving cell.
206. The influence of dose fractionation (5 fractions
over 4 days) of fission-spectrum neutrons. delivered at
a rate of O. l Gy min- 1• was studied by the sameauthors. Over the whole range from 0.103 to 1.12 Gy.
an enhancement of effects by fractionation wasobserved. The ratio of linear slopes of the dose200

response curves at low doses was about 8. The
increased effectiveness of the low dose rate and of thefractionated neutron irradiation was explained either
by the induction of more efficient error-prone repair
or by facilitation of the expression of ''sub-effective
transformation damage", whatever this means [H37].
A recent study on transformed mammary epithelial
cells transplanted in vivo to virgin female BALB/cmice suggests that the effect of fractionated neutron
exposures may be analogous to chemical promotion
and is due to an enhanced expression of the transformation damage [U28]. The effects of fractionation
schemes applied to the cells in an asynchronous
growth indicate that x and gamma irradiation-by
analogy with sublethal damage-result in error-free.
reparable. sub-transformation damage. The transformation damage induced by neutrons either does notundergo repair, or is subject to error-prone repair[E 10, H37]; however. why the latter should be more
effective at protracted or fractionated low doses is notclear.
207. Terzaghi and Little [T5] found that irradiating
C3H !OTl/2 cells with x rays in a density-inhibited
state, and delaying plating up to 48 hours substantially
increased survival rates. Delay for 2 to 4 hours caused
marked increase of the transformation rate. Further
delay of plating reduced the yield of transformants tovery low levels after 48 hours. Terasima et al. [T24].
however, did not observe any initial increase of thetransformation frequency. as the potential transformation damage fell over the first 3 hours of delayed
plating. The rate of potential transformation repair in
C3H 1OT I/2 cells depended strongly on a particular
batch of feta! calf serum used in the cell culture
medium, both before and after release from confluence[TI I]. Lack of serum was accompanied by a highdegree of repair (80% over 6 hours) after keeping theirradiated cells (x rays. 3. 7 Gy) in the non-proliferatingstate. Some batches of serum totally prevented theoccurrence of repair. No repair of potential transformation could be found after irradiation with alphaparticles [R39] and accelerated heavy ions [Y5].
208. When potentially lethal damage was studied byholding these cells in confluence after irradiation forvarying lengths of time. a pronounced repair wasobserved for x rays and none for alpha particles [R39].
Equally. no repair of potential transformation damage
was seen for up to 220 hours after alpha particle
exposure. whereas the x-ray-induced potential damage
was efficiently repaired.
209. The results of other experiments [L23] suggestthat two separate processes may be involved in therecovery of damage: first. DNA repair leading toenhanced survival: and, second, a slower error-prone
repair process responsible for changes in DNA andleading to mutation and transformation. It should be
stressed that the frequencies of transformation reported
for most in vitro experiments apply to actively
proliferating cell populations and may not be representative of situations where the overwhelming majorityof cells is in the resting state, as in most organs in
vivo.

(d)

Other factors affecting oncogenictransformation in vitro

210. Numerous factors affect the yield of in vitro
oncogenic transformation. Among these, a basic roleis played by both the time and the density at whichcells are seeded.
211. Studies on three cell lines (hamster embryo.
C3HIOTJ/2 mouse embryo and mouse BALB/3T3
cells), have shown [B34, Kl2, LIO, T6] that several
post-irradiation cell divisions-4 to 6, depending on
the cell line studied-are necessary for expression or
fixation of the transformed state. Of these, at least one
must take place in the first 24 hours post-irradiation.
212. Terzaghi and Little [T7] investigated the influence of cell density on the transformation frequency
per surviving cell. Above 400 viable cells per dish(about 5 cell cm- 2). there was a steep decline fromplateau values of transformation observed at lower
cell densities. The authors suggested that this effectcould be the result of an incomplete expression oftransformation due to early confluence, which lowers
the number of cell divisions during exponential
growth below that necessary for full expression oftransformation [87 L B72, L26]. Han and Elkind
observed, in the same cell line, a similar relationshipbetween the density of seeded cells and the transformation rate after x-ray and neutron irradiation [HI].
Direct cellular contact cannot operate at such celldistances, but a diffusible mediator substance might
prevent occurrence or growth of the transformed
clones [Ll5].
213. Lloyd et al. [LI 6] experimented on co-cultivation of transformed C3H JOT 1/2 cells with nontransformed ones. When transformed cells were seeded
at low densities. together with normal cells, at someratios of the two cell types (1:50 to 1:500. respectively).
expression of the malignant state could be completely
prevented. Adding non-transformed cells in greaternumbers again elicited this response. The experimentpoints clearly to a very complex nature of theinteraction between transformed and non-transformed
cells. even in vitro.
214. The data by Kennedy et al. [K26] are ofimportance because they throw some light on thecomplexity of the phenomena leading to oncogenic
cell transformation in vitro and could modify substantially the current interpretation of this radiation
effect. These authors studied the influence of resuspending C3H IOTI/2 cells after irradiation. once
confluence was reached. When dilutions at the timeof re-seeding were progressively increased, the numberof originally irradiated and inoculated cells per platedecreased to very low values. In spite of that, after aconstant dose of 4 Gy of x rays. the number oftransformed foci per plate remained practically constant. This indicates that the number of transformedfoci per plate is apparently independent of the numberof cells initially irradiated. It is interesting to note thatsimilar results were obtained when the effect of
inoculum size was studied on the appearance oftumours, after in vitro irradiation of monodispersed

thyroid or mammary cells injected into the fat pads ofrats [G30]. These observations are in direct conflictwith the expectation that-if initiation of a cell is arare phenomenon-the probability of observing atumour should rise in proportion to the size of the
inoculum.
215. It has been suggested [K26, G30] that exposure
to radiation results in some change of the cellular state
in many or, after high doses, in all cells. Gould
postulates that initiation is not an all-or-none phenomenon, but that its intensity rises with dose up to asaturation level, which is reached in C3Hl0Tl/2 cells
at 5-6 Gy after 60Co gamma irradiation or 3 Gy ofneutrons. The change is probably transmitted to thewhole progeny of surviving cells. The nature of
initiation-genetic or epigenetic-is unknown, but thelatter would presumably be suggested by these observations. This interpretation is not easily reconciledwith the demonstrated direct involvement of DNA in
the carcinogenic process [814. L33]. Only a secondrare phenomenon (perhaps mutation), would lead to aphenotypically recognizable transformation at confluence of C3HI0Tl/2 cells. The probability of thissecond phenomenon should be in some proportion
with the degree of initiation.
216. A report by Hall et al. [H28] challenged the
hypothesis that commitment of irradiated cells to
the transformed state takes place at confluence. By
re-plating cultures at different times after irradiationand testing for distribution of transformed fociamong the plates. the authors could show thatcommitment takes place within I week of exposure. Thisobservation is in agreement with a study [891] on invitro oncogenic transformation of C3HJOTl/2 cellsby 7P,8a-dihydroxy ,9a, JOa-epoxy, 7.8,9. I0-tetrahydrobenzo(a)-pyrene. The results of this study showed that
acquisition of the ability to form transformed focioccurred within 2 days of exposure to a carcinogen.
Hall's experiments [H28] also showed that increasing
the density of cells in culture probably suppressed
expression of the transformed state. These results do
not contradict the fact that at 4 Gy of x rays theprobability of initiation per cell is close to I. but they,
have been interpreted to challenge the postulated nonstochastic nature of initiation [K26].
217. The presence of thyroxin in the culture medium
at a physiological concentration was shown to bea prerequisite for transformation to occur in Syrian
hamster embryo and C3HI0Tl/2 cells [B73. G26.
G27]. Thyroxin is required for protein synthesis only
within a few hours of irradiation and its action can bereversed by an agent blocking protein synthesis. e.g ..
cycloheximide.
218. Other factors were shown to enhance transformation in culture during or after irradiation.
Extensive investigations were made on a well-known
promoter of in viva carcinogenesis, the active ingredient of croton oil, 12-0-tetradecanoyl-phorbol-13
acetate (TPA). By adding TPA to the cultures within
96 hours of irradiation, Kennedy et al. [KIO] showedenhancement of the x-ray transformation frequency(or its expression) in C3H IOTI/2 mouse embryo cells.
201

The effect was particularly marked after doses of
0.5-1.0 Gy. These data indicate that promoting agenrs
can increase the levels of x-ray-induced transformation in vitro, just as they enhance carcinogenesis invivo. It was also shown [K27] that the most effective
period of exposure to TPA is that of exponential
growth. However. a delay of TPA application, e.g ..
addition to cultures re-seeded after confluence, did
still lead to a significant enhancement of oncogenictransformation.
219. When TPA was added for six to seven weeks (at0.1 µg/ml of medium) to cultures of C3H10Tl/2 cells
irradiated with graded doses of x rays (0.25-4.0 Gy),
there was not only an absolute increase of transformation frequency, but also a change in the shape of thedose-response relationship. from curvilinear (upward
concave) after x rays alone to linear (Figure XIV). The

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communication [H22, TIS]: enhancement of chromosomal rearrangements [K28]; production of shortlived radicals [B76]: and action via mechanism ofcellular differentiation [B74, S43]. Increase of cellular
proliferation is a phenomenon that often accompanies
promotion [F 14], but it is doubtful whether it is at allnecessary. or sufficient [D13, K27]. The TPA promoting effect is apparently not related to any of the
known DNA repair processes [K27].
221. Enhanced transformation of various cell lines
was also noted after addition to the medium of theepidermal growth factor, a natural hormone-like
polypeptide [FIS]: bromodeoxyuridine [R30]; highconcentrations of insulin [U29]; cortisone [K30]: andinterferone [B46]. The particular batch of feta! calf
serum used may also have a profound influence on thetransformation frequency eventually observed [TI l]. A
new promoter, dihydroteleocidin 8, an antibiotic
derivative recently discovered, has a promoting capacity
per unit mass about 100 times higher than that ofTPA[H3I]. A synergism between x rays and a food pyrolysate product 3-amino-1-methyl-SH-pyrido-(4-3b )indol(Trp-P-2), itself a mutagen and carcinogen isolated
from boiled meat and fish, has also been shown[876] in Syrian hamster embryo cells. Hyperthermia(43°C for 60 minutes or 45°C for 15 minutes before
irradiation) caused some increase of the x-ray-induced
transformation frequency in C3HI0Tl/2 cells [C33].
The nature of most enhancing agents mentioned
above suggests that the mechanisms of action are
epigenetic rather than likely to cause structural changes
in the genome itself.

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222. There are also suppressing (inhibiting) factors.
Kennedy and Little [K35] and Little [L26] describedsuppression by the protease inhibitors antipain andleupeptin. In other studies [B65, G28] it was shownthat antipain added to cultures before irradiation
enhanced the yield of transformants. while addition
shortly after exposure reduced the transformation
frequency. and addition 1 or 2 days later wasineffective. Inhibition of radiation-induced oncogenictransformation was also observed when inhibitorsof poly(ADP-ribose) synthesis (benzamide. 3-aminobenzamide) were added to cultures of C3HIOTl/2 andgolden hamster embryo cells [B96].

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DOSE (Gy)Figure XIV. Influence of post-irradiation Incubation with thetumour promoter TPA on x-ray transformation of mouse
C3H10T1/2 cells. O x-lrradlatlon onl,v; t::,. TPA (0.1 µg/ml) added
for the entire period of expression.
[L26]

action of TPA was especially pronounced at doses in
the low and intermediate range [L26]. A very similareffect of TP A on the shape of the dose-response
curves for x-ray-induced and neutron-induced transformation of C3HI0Tl/2 cells was also seen inanother study [H22].
220. Numerous mechanisms of action for TPA havebeen advocated, including inhibition of the cell-to-cell202223. An inhibition (by a factor of 3) of transformation in C3H IOTl/2 cells was observed by adding.
24 hours before exposure. a non-toxic derivative of
vitamin A, trimethyl-methoxy-phenyl, analogue of Nethyl retinamide (Ro-H-1430) and other retinoids[B73]. The retinoids irreversibly suppressed oncogenictransformation when present in culture for only a few
days after irradiation. Later addition of TP A to· theculture remained ineffective. The retinoids may act bysuppressing the carcinogen-induced progression of theneoplastic process [B76].
224. Selenium compounds [B73], actinomycin D[K31] and lymphotoxin [D19. E6, R44] also inhibit
radiation-induced transformation. When superoxide
dismutasc was added to irradiated C3H lOTl/2 cultures from irradiation to expression of transformation,
the frequency of radiation-induced transformants wasgreatly reduced, whether or not the drug was present
during x-ray exposure [M49]. Quantitatively. theeffects of oxygen and misonidazol upon oncogenictransformation and cell killing of C3H lOT 1/2 cells arevery similar [897].

(e)formation experiments with low-LET radiation.
However. in the light of present knowledge-which isstill insufficient-such conclusions are premature, forthe following reasons:(a)

No dose-response relationship has been observed
for tumours in animals with a plateau below
l Gy after single acute doses of x or gamma rays.
It is also quite clear that no enhancement oftumour induction by fractionation or protractionof external low-LET irradiation has ever been
noted at doses below I Gy (with one possible
exception. see IV.B);(b)

The dependence of the dose-response relationships on the length of the culture period before
irradiation shows that the irregular shape of thedose-response curves and the enhancement of
fractionation in freshly plated cultures result
from irradiation of para-synchronous cells andmay therefore be considered an artifact [H37]:(c)

The effects of low-LET dose fractionation andprotraction on established cell cultures are in
general agreement with observations related toother effects at the cellular level (induction of
mutations. chromosome aberrations, cell sterilization).

B.

TUMOURS IN EXPERIMENTAL ANIMALS

Conclusions

225. The oncogenic transformation in vitro of hamster
embryo cells and several established mouse fibroblastlines by ionizing radiation shows numerous similarities
in respect of dose-response relationships, effects ofdose fractionation, and influence of cell density upontransformation frequency.
226. The mechanisms of transformation are still
imperfectly understood and several methodologicalquestions are not yet fully resolved. The subject has
been thoroughly reviewed [B7 l. B76, G34, L26. Y3].
Transformation is probably a complex multi-stage
phenomenon that includes initiation, progression andfinal expression of malignant foci. A number ofpromoting and suppressing factors may affect thefrequency of transformation and therefore the shapeof the dose-response relationships.
227. For these reasons, analysis of dose-response
relationships for low- and high-LET radiation must,for the time being, remain descriptive. After single
doses of x rays or neutrons, the dose-response curves
have some features in common with those seen in viva
for many experimental tumours. For example, when
expressed per initial cell at risk. transformation shows
an initial rise of the frequency with dose, then the
curve reaches a peak and the yield declines at still
higher doses. The lower efficiency of gamma rays at
the low. as opposed to high, dose rates in cultures
established at least 40 hours before irradiation is alsoin accordance with most observations in vivo. The
same applies to the RBE values of neutrons and alphaparticles, which are definitely higher than unity andtend to decline with increasing dose. in agreementwith the general understanding of cellular radiobiology [Bll, K7]. Neutron dose fractionation upon
oncogenic transformation in vitro produces effects
that are similar to those seen recently in some-but
not all-experiments in vivo. There are. however,differences, particularly when comparisons are madewith cells plated shortly before irradiation. The mostimportant is the rise of the transformation frequency
with a power of dose less than 1 at intermediate doses(< 1.5 Gy). This shape of the curve may be linked
with the enhancing effect of fractionation of x ray
doses in the same region. a phenomenon observed in
all cell lines tested so far.
228. If enhancement of transformation by fractionation applied in vivo, the complex nature of the low-LET
dose-response relationship for single doses might imply
an under-estimation of cancer induction when risk
coefficients for man are extrapolated from the intermediate down to the lowest doses. Similarly, in the caseof fractionated exposure. there might be an even greater
under-estimation. owing to the enhancement producedby dose fractionation and protraction in some trans-

229. In its 1977 report [U6]. UNSCEAR reviewed
experimental data on radiation-induced tumours. including an examination of the dose-response relationships then available. The essential conclusions werethat the peculiarities of each tumour model were suchas to prevent large generalizations. There were difficulties in interpreting tumour induction curves on thebasis of simple mechanisms of action. in view of thecomplex interplay of primary and secondary contributing factors. With few exceptions, the data camefrom observations at doses above 0.5 Gy. Data wereinsufficient to define, unambiguously, dose-effect relationships in the low and sometimes also in theintermediate dose region.
230. With the exception of the mammary tumour of
the Sprague-Dawley rat. dose-incidence curves obtained
at high dose rates with low-LET radiation showed aslope that increased with increasing dose, not incompatible with a linear-quadratic trend. With high-LET
radiation, on the other hand, dose-effect relationships
tended to be more linear and their initial slopes
showed relatively little change with dose rate andfractionation. However, with low-LET radiation. a
decrease in dose rate Jed mostly to a decrease of theoncogenic effect, following some inverse function of
the exposure time. It appeared difficult to quantify
this decrease because the shape of the dose-induction
relationships was often altered by the change in dose
rate. It was clear, however, that the sparing effect oflow dose rate or fractionation was higher for lowthan for high-LET radiation. Occasional departuresfrom this general scheme were attributed to thepeculiarity of the model systems tested, rather thanto real exceptions of established radiobiologicalmechanisms.
203231. The National Council on Radiation Protection
and Measurements [NI] evaluated the influence ofdose and its distribution in time on the induction
curves for tumours. with different radiations and awide range of dose rates. The ratio of the linear nonthreshold curves fitted to the high- or to the low-doserate experimental points was taken to be a measure ofthe "dose-rate effectiveness factor" (DREF). DREF
values referring to 10 different experimental tumour
systems varied from I.I to 6.7, the majority of thevalues clustering between 3 and 5. This analysis Jed tothe conclusion that in most cases the risk of low-LET
radiation would be significantly overestimated if nonthreshold linear extrapolation of the data for highdose-rate were applied to low-dose-rate irradiation.
Moskalev et al. [M61, M68] came to the sameconclusion when ·reviewing the available scientific
literature. New data that have become available since1977 are reviewed below.
1.

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Hyeloid leukaemia

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young mice (A8older mice (l

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DOSE (Gy)Figure XV. Final cumulative tumour rate ± standard error
versus dose tor myelold leukaemia In x-lrradlated RF mice.
[R7]

204

233. Petoyan and Filyuskin [P22] tested anothermodel on x-ray- and neutron-induced (high dose rate)
leukaemia in RF mice [U 16]. The basic assumptionsof the model were:
(a)

(b)

Initiation in the bone marrow stem cells is a
two-track phenomenon. perhaps a symmetricalchromosomal translocation;
The sensitivity of initiated and non-initiated stem
cells to killing by radiation is the same:(c)

Most of mitotic cell death is due to asymmetricchromosomal exchanges, which have a functionaldose dependence basically similar to that of thesymmetrical translocations. Therefore. the shapeand parameters of the dose-response functions
for induction of symmetrical exchanges and cell
death should be similar for a given cell line;(d)

The promoting influence of radiation is brought
about through an enhancement of mitotic activity
and. therefore, the degree of promotion should beinversely proportional to the post-irradiation
survival of stem cells;(e)The probability of scoring an overt malignancy
during the remaining life span is a complex
function of the "spontaneous" incidence of agiven malignancy.

Myeloid leukaemia

232. Robinson and Upton [R7] re-analysed part ofthe .original data on radiation effects in RF mice
[UI4-UI6]. correcting for competing risks. About
2000 male mice, irradiated with 250-kV x rays at doses
between zero and 4.5 Gy. were selected. Early causesof death (myeloid leukaemia. M, and thymic lymphoma,T) or late causes (reticulum cell sarcoma, L, or others,R) were analysed separately by a non-parametric
Kaplan-Meier survival function and its logarithmictransform (the cumulative force of mortality, cum.
F.M.). Models were set up for treatment of these twocategories, on the assumption of independence between
the various causes of death. For causes M and T, there
was a significant decrease of the latent period withdose up to 3 Gy. When the effect of dose on the
integral tumour rate of M (which corresponds to thecum. F.M.) was studied. the form of the relationshipfor this cause of death peaked, with a maximum
between 2 and 3 Gy and a further decline up to
4.5 Gy. depending on the age at irradiation of theanimals (which was 5-6 weeks for group A and9-10 weeks for group B) (Figure XV). The model for
fitting the experimental data was such that theestimate of the ultimate value of the cum. F.M.
corresponded to the number of leukaemogenic cells
per animal. These were assumed to have a linear-.......~

quadratic dose dependence for induction, and linearquadratic kinetics for killing. Following Barendsen[B7]. the authors took an aifa 2 quotient of0.5 Gy anda (J if(J 2 quotient of 3 Gy. The fit of the data actually
produced a (J ii/3 2 quotient of 2.4. which is inreasonable agreement, considering the assumptions
involved. It was concluded that the data were consistent with the postulated linear-quadratic dose-responsemodel.

234. The parameters of the model were defined by
selecting from independent sources the survival functions of bone marrow stem cells irradiated with x rays
and neutrons. The model was fitted to experimental
data on the incidence of leukaemia in the RF mouse[Ul6] by the maximum likelihood method. using asingle set of two adjustable parameters; the same set
was applied to x rays and neutrons. A good fit was
obtained, by visual inspection, and the dose-response
curve showed a slight upward concave curvilinearityand linearity of the initial ascending part of the curvefor x rays and neutrons, respectively. Linear extrapolation from 1.5 Gy to the low-dose region would
lead to a small over-estimate of the risk for x rays. but
would be adequate for neutrons. The assumption thatthe dose-response functions for the initiation and cellkilling are similar could be criticized on the basis ofavailable information (B9, BI I]. but the postulate may
be accepted as a first approximation to reality.
235. Mole et al. [M2. M52. M64-M66] studied theinduction of acute myeloid leukaemia by x rays,
gamma rays and fission neutrons in male CBA/H
mice that have almost a zero incidence of this disease.
With little intercurrent mortality from competing
causes of death, this tumour model is also lesssensitive to systematic bias from such causes than thaton RF mice [R7].

236. Mice were exposed to one of ten doses of x rays(from 0.25 to 6 Gy, delivered at the rate of 0.5 Gymin- 1) and then followed until they died [M52, M64].
Median survival in all groups was very similar. Therewas essentially no association between latency anddose. The results were fitted to a four-term polynomialof the general form I= (a 1D + a 2D 2) exp- (jJ 1D + P2D 2)
as well as to four simplifications with three or two
parameters only. All fits were acceptable in a statisticalsense (P for goodness of fit= 0.34-0.44), but only two
equations had all parameters positive and significantlY,larger than zero (p < 0.05). These were: I= a 1D e-P"Dand I= a 2D 2 e-P1D. The former was rejected on the
ground that cell survival depending solely on thesquare of dose is normally not found. The observed
incidence could best be fitted by the latter relationship, as shown in Figure XVI. In another recent studyof the induction of myeloid leukaemia in CBA malemice by whole-body x irradiation (250 kVp, H\!L
1.5 mm Cu) [D3], the age-corrected incidence after
doses of l, 3, 5 and 7 Gy was essentially superimposable on the data by Mole [M52] (see Figure
XVI). A purely exponential survival for haemopoetic
cells is probably a simplification of reality, but
survival curves for bone marrow stem cells usuallyshow only a small shoulder at low doses. For in vivo
irradiated bone marrow stem cells McCulloch and Till
[MI6] found D 0 = 0.95'Gy and n = l.5. Mean values
for 17 measurements of D 0 for spleen-colony-forming
units in different mouse strains irradiated in vivo withx rays were in the range 0.95-1.61 Gy [H32]. The valueof P1 (0. 7-0.11 Gy- 1) found by Mole [M52] is compatible with this range.

adjustable parameters greater than two. one or two of
the parameters were always insignificant. From thesimplified two-parameter models. one had to bechosen on the basis of additional information, andthis implies a constraint a posteriori even if none had
been chosen a priori. In summary, it appears thatcomplete parameters for cell initiation and survival
cannot be estimated, independently and simultaneously,solely from the data. However. when a likely shape ofthe survival function is assumed. the kinetics ofinitiation for low-LET radiation appears, in this case[M2. M52, M64], to be concave upwards with apronounced D 2 component.
238. Induction of myeloid leukaemia in CBA/H
mice was also studied after brief (0.25 Gy min- 1) andprotracted exposure to 60Co gamma rays ( 1.5, 3.0 and
4.5 Gy) [M65]. Protracted exposures were delivered
either as daily fractions (0.25 Gy min- 1• 5 days per week
for 4 weeks) or at a constant rate of 0.004-0.11 mGy
min- 1• The latter two modes of exposure did not differ intheir effectiveness and gave a rather constant response
at 5-6% incidence for doses above zero. The shape ofthe dose-response curve is very similar to that observed
for leukaemias induced by fractionated x-ray treatment for ankylosing spondylitis [S49]. The response
after acute irradiation was higher by a factor of 2.2,
2.8 and 5 for the three doses. respectively. The mosteffective gamma-ray dose for leukaemia induction was
higher than that of x rays.
239. Irradiation of CBA/H male mice with fission
neutrons was performed at high rate (exposure times.
2-20 minutes) with 7 air-midline kerma values in therange from 0.02 through 2 Gy [M66]. The observed
incidence of acute mveloid leukaemia was fitted by theequation I(D) = (4:5 ± 1.25) 10-10 e-n.0 1 ± o.2s10(P = 0.25). Neither a purely linear model without
correction for cell killing. nor the dose-squared modelthat fitted the x-ray data. could be satisfactorilyinterpolated to the neutron data (P for goodness of fit
in either case < 10- 4).

237. A contribution of a dose-linear term (a 1D) tothe dose-response relationship in Figure XVI cannot
be excluded on purely statistical grounds. The a/a 2
quotient estimated for the complete four parametermodel was negative, but the upper 95% confidence
limit was 1.29 Gy: and therefore, values of 0.3-0.5 Gycannot be excluded as very unlikely. Moreover, when
the data were tested on three models with a number of

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DOSE (Gy)Figure XVI. Dose-response relationship for Incidence of myelold leukaemia after brief exposuresof male CBA mice to 250-kVp x rays. Closed circles, data frqm Mole [M52]; Open circles, datafrom DI Malo et al. [03].

205240. In experiments by Ullrich and Storer [U20],
specific-pathogen-free (SPF) RFM/Un mice of both
sexes were irradiated at 10 weeks of age with 137 es
gamma rays at 0.45 Gy min- 1, with doses ranging
from 0.1 to 3 Gy. Myeloid leukaemia was less frequentin the females. in which the age-corrected incidence
reached significance over the control level at 1.5 Gy.
Although both a linear and a linear-quadratic model
provided a satisfactory fit to the data (P > 0.5
and> 0.8. respectively), the dose-squared component
was not significant and linearity predominated between
zero and 3 Gy.
241. In male mice, the incidence was significantly
higher than control, even at 0.5 Gy. and the form of
the relationship was similar to that in females: it could
be described either by a linear (P > 0.5) or a linearquadratic model (P > 0.35), with a very small andnon-significant dose-squared term. The ratio of thelinear slopes for the two sexes indicated that males
were more susceptible by a factor of about 5. Lowdose-rate (0.083 Gy per day) gamma exposure [U3]
was very much less effective in inducing myeloid
leukaemia in the female mice; no significant increase
above controls could be reached even at 2.0 Gy. After
acute and chronic neutron irradiation, the incidence ofthe disease was very low and did not permit any
detailed study of dose-response relationships. In either
case, the peak incidence was observed at 0.47 Gy. but
the results w;re nor significantly different from controls (p > 0.05).
2.

Thymic lymphoma

242. Ullrich and Storer [U2, U3, U5. U20] studied
the dose-response relationship and dose-rate effects
for 137 es gamma rays and neutrons in SPF 10-weekold RFM/Un mice. The response was assessed as agecorrected incidence, standardized to the distributionof the age at death of control animals. In females,
thymic lymphoma was efficiently induced by gamma
rays at 0.45 Gy min- 1: the incidence was significantly
higher than in controls in all groups receiving 0.25 Gy
or more. No simple model could describe the responseover the entire dose range (0. 1-3 Gy). There was asteep rise in the region below 0.5 Gy. followed bya shallow rise at higher doses. Over the range of
0-0.25 Gy (three points). a dose-squared model provided an adequate fit and linearity could be rejected(P < 0.06). From 0.5 to 3 Gy the increase in incidencewith dose was compatible with linearity.
243. In males, the significance of the difference
above controls was reached only at l Gy. A linear
model provided a satisfactory fit over the entire rangeof gamma-ray doses (0.1-3 Gy; P> 0.4). Over 0-1.5 Gy,
both a linear and linear-quadratic equation (with D 2
coefficient not significant) provided a very good fit to
the data (P > 0.95 and> 0.80, respectively). Thus. inmales the dose-response relationship for acute gamma
rays ,vas predominantly linear over the entire dose
range.
244. Lowering the dose rate to 0.083 Gy per day
considerably decreased the incidence of thymic
206

lymphoma in the females and changed the form of thecurve from quadratic followed by linear to linearquadratic with a negative linear component. Simple
linearity could be rejected (P < 0.001). It is quite clearthat in the RFM mouse, after low-LET exposure.
there is no suggestion of the threshold-type response
found by Kaplan and Brown [K33] in e57Bl mice. In
these older data there was a statistically verified
threshold in the dose-response relationship. As may beseen in Figure XVII (kindly provided by G. Walinder).
fractionation of the dose into l. 2. 4 or 8 fractions
with one-day spacing. is without effect upon theincidence of the lymphoma. When plotted against
exposure (either simple or fractionated) the incidence
may be fitted by a linear function of the form
I= aD - b where a= 0.112. and b =-21.6 (significantly
different from zero); the coefficient of correlation isvery high (0.903).
245. In experiments by Maisin et al. [M62]. 12-weekold male BALB/c mice were exposed to single or to
fractionated doses of mes gamma rays ( 10 equal doses
separated by l day) in the dose range from 0.25 to 6 Gy.
The dose-response curve for thymic lymphoma was of athreshold type. the actuarial incidence rising above
control only at 4 and 6 Gy. Single doses were more
effective at 4 than at 6 Gy.
246. Other data on thymic lymphoma induction by
x rays in neonatal (e57Bl/6 JNrs X WHT/HC) F I mice
were reported [S48]. Even though the incidence infemales and males at three exposure points (200. 400 and
600 R) could be fitted to a linear-quadratic equation
with a negative linear term (P > 0.80), the data
adequately fit a threshold-type response such as that
presented in Figure XVII for the e57Bl mice.
247. Fast neutrons (acutely delivered doses at 0.05
and 0.25 Gy rnin-I and chronic doses at 0.01 Gy perday, with total doses between 0.1 and 3 Gy) induced
thymic lymphoma in female RFM mice [U5]. In therange 0.25-0.5 Gy, the RBE with respect to high-doserate 137 es gamma rays was between 3 and 4. For acuteneutron exposures. the dose-response curve was concave
downward. In the range 0-0.94 Gy, linearity could be
rejected (P > 0.001) and a good fit was obtained withthe square root of the dose (P > 0.8). Up to 0.47 Gy, alinear fit was satisfactory (P > 0.75). For chronic
neutron exposure, a linear fit adequately described thecurve over the 0-0.94 Gy range (P > 0.8); and the lossof effectiveness over the acute exposures amounted toabout 30%. However. there was a decrease of susceptibility to thymic lymphoma upon acute exposure
with increasing age, so that the lower efficiency of the
low-dose-rate exposure may in part be due to thislatter factor alone. The RBE of acute neutron exposure
relative to gamma rays varied proportionally to theinverse square root of neutron dose.
248. Induction of thymic lymphoma was also studiedin male BALB/c mice irradiated at the age of 12 weeks
with d(50)Be neutrons (modal energy about 23 MeV)
[M63] at doses from 0.02 to 3 Gy. The actuarial
incidence of thymic lymphoma fitted the same sigmoidal
threshold-type curve found for 137es gamma rays [M62].

80

70
>-

z

w

u

C57Bl[

Number oftreatments

Interval
betweentreatments(days)

1

0

2
4
8

1

~

60

•

w

•

Q.

w

•

0

0

C:

•

5

u

z

w

0

u

z

40

w

0
::,
C:

u

30

•

0

20
10
_

100

200

300

Spontaneous frequency

400

500

600

700

800

900

1000

EXPOSURE (R)
Figure XVII. Crude incidence of thymic lymphoma in C57BI mice given single and fractionatedx-ray doses at 1 day interval [K33). Rhombard symbols represent the crude incidence of thymic
lymphoma in neo-natal (C5781/6 JNrs x WHT/Ht) F1 mice [S48].

3.

Other reticular tumours

249. The so-called mouse reticulum cell sarcoma is agroup of neoplasms showing a decline of the incidencewith dose after whole-body x irradiation (CJ9, K25,
U3, U5. U20]. Ullrich and Storer [U3, U5, U20]
studied the age-corrected incidence of reticulum cellsarcoma among SPF RFM/Un male and female mice
irradiated with gamma rays (0.45 Gy min- 1 or 0.083 Gy
per day) and in RFM/Un female and BALB/c mice
irradiated with fast neutrons (0.05. 0.25 Gy min- 1 and0.01 Gy per day). All treatments produced a decreaseof reticulum cell sarcoma with dose, neutrons being
more effective than gamma rays, and chronic exposuresless effective than acute ones. The difference between
acutely and chronically delivered gamma rays was more
pronounced than that for neutrons. There was a clear,inverse relationship between the increase of thymic
lymphoma and the decrease of reticulum cell sarcoma.
suggesting some link between various radiation-induced
reticular neoplasms which could greatly affect theobserved dose-response curves.
250. Male mice (C578L/Cne x C3H/Cne)F 1 hybrids
received lethal whole-body irradiation (9 Gy) andwere rescued from early death due to haematological
failure by a homologous bone-marrow graft [C 18]. In
these mice. the spontaneous incidence of reticulum cellsarcoma of about 50% is reduced in irradiatedsurvivors to a few per cent. Shielding of a part of themarrow during exposure affords a similar protection
against early post-irradiation death and effectively

depresses the incidence of the tumour. It was suggested
that whole-body irradiation sterilizes cells from whichthese neoplasms originate [Cl8. CJ9] and that the 0 0
for these cells is similar to that for the bone-marrowstem cells [M20].
251. Further studies [M20] showed that in vivo
irradiation of the bone-marrow graft with doses of
2 and 4 Gy of x rays before transplantation into hosts
given whole-body irradiation (9 Gy) provides the same
protection against early death, but leads to a significantly elevated incidence of reticulum cell sarcoma
in animals given irradiated marrow. The incidence
expressed per number of injected marrow cells rises
with dose, amounting to 1.65 10- 8, J.90 10- 8 and 2.38
10-s tumours per cell irradiated with 0, 2 and 4 Gy.
When related to the number of injected surviving stem
cells, the incidence rose steeply from 4.3 10- 5 through9. 7 10- 4 and 6.4 10- 3 at 0, 2 and 4 Gy. respectively. It
is an unproved assumption that the tumours originatedfrom these cells. If this hypothesis could be accepted,
the dose-response would display a pronounced curvilinearity (concave upwards). the effect rising with apower of dose appreciably greater than l. and eventhe presence of a threshold dose could not be rejected.
252. In the same animal model, studies [M 19] weremade on whole-body irradiated mice with shielding of
one or two hind legs, from which shielding wasremoved for a variable fraction of irradiation time.
thus exposing some of the protected marrow in situ 10
graded doses of x rays up to 8 Gy. The observed
207incidence of reticulum cell sarcomas increased in thesemice to a maximum at about 5 Gy and then declinedwith further increase of the dose. The final incidenceof these neoplasms in all experiments with exogenousand endogenous bone-marrow protection is plotted in
Figure XVIII, showing in all instances a curvilinear(upward conca,·e) rise with x-ray dose. The form of
these relationships is similar to that observed formany other radiation-induced tumours in animals
irradiated in vivo.
60.~

•

-

50

ex
w

40

•

I-

z
.....
u
0..

•

• wb1 sh

A
V

2 sh

a exo

results were given as incidence corrected for theslightly enhanced mortality of irradiated versus control
rats. Data on tumour multiplicity and on tumours per
animal were not presented.
255. A least square fit yielded the following functions describing the dose-response relationships(Figure XIX):
1(0) = 7.47 I0- 4 (0 + 10)°- 68 38 for x rays
I(O) = 1.78

where O is the dose given in rad (0.01 Gy). The exponents were significantly lower than unity (p < 0.001).
indicating that the incidence of thyroid carcinomas inthese rats rose with approximately the square root of
the low-LET dose. Thus. there was no difference inthe effectiveness of the two radiations over theobserved range of doses, but a lower effectiveness of
131 1 per unit dose (up to a factor= 3) could not be
excluded on statistical grounds [N 10).

~

24

u

ex
~

w-3 (O + IO)D-5348 for 131 1

...J

g
z

u

a:

30

....I

.....

w

u

• --O --

20

x raysiodine-131

""u:c

3 20

- 16

-a

I-

3:

I-

'-'
er:

Ill
....I

""-

::::
z

""
.....
0

12

---

8

....z
0

2

1

3

4
5
DOSE (Gy)

6

7

8

9

I.I

u

4

IX

I.I

Q..

Figure XVIII. Final Incidence of reticulum cell sarcoma as afunction of dose under three different experimental conditions:(a) whole-body Irradiation (wb); (b) shleldlng of one (1 sh) or two(2 sh) hind legs; (c) syngenlc bone marrow transplantation (exo).
[M19]

4.

Tumours of the thyroid

0
0

2

4

6

8

10

12

DOSE (Gy)Figure XIX. Incidence of thyroid carcinoma as a function ofmean thyroid dose from Injected lodlne-131 and localized
x Irradiation, Error bars are estimates of the 950/o confidence
llmlts.
[L29)

253. An extensive study of thyroid tumour induction
by 250-kVp x rays and 131 I in about 3000 6-week-old
female Long-Evans rats was reported by Lee et al.
[L29]. The study aimed at comparing the effectivenessof the two radiations delivered at different dose rates(2.8 Gy min- 1 for x rays; the maximum dose rates for
131 1 in individual groups were estimated at 0.17, 0.69
and 1.6 mGy min- 1). Local doses of x rays to thethyroid were 0.94, 4.1 and 10.6 Gy. Total dosesdelivered by 13IJ were estimated at 0-8. 3.3 and 8.5 Gy.
The role of pituitary irradiation in the induction of
thyroid cancer was also explored by delivering dosesof 4.1 Gy of x rays to the pituitary alone. or to thethyroid and the pituitary together: findings were
negative in this respect.

where Dis the dose in rad (0.01 Gy). At no dose point
was there a significant difference between the effect of
the two radiations. However, due to the large variabilityof the observations. some difference in the effectivenesscould not be excluded. Control incidence of medullary
tumours was not affected by either radiation.

254. Tumours included were those that appeared
later than 6 months in rats dying before the age of
26 months and in animals sacrificed at 24 months. The

257. The downward concavity of the dose-incidence
curve for carcinomas was attributed to killing of
initiated cells. If an in vivo survival curve of thyroid

208

256. For adenomas. the two dose-response relationships were slightly different (p < 0.01) and when fitted
by exponential equations they assumed the following
forms:
1(0) = 0.0245 exp (0.00207 0) for x rays
1(0) = 0.0240 exp (0.00123 D) for 13 1J,

follicular cells with Dq = 4.9 Gy and 0 0 = 4.5 Gy is
assumed [D 15. M5 l), then the dose-response curve for
initiation of carcinomas or adenomas in this experiment may be expected to rise with a power of dose
either close to or greater than unity. The slope of theinitial portion of the dose-incidence curve for carcinomas was estimated at 1.9 10- 2 Gy- 1, which is
close to the estimate for humans [S60).
258. The presence of a strong linear component in
the relationships is suggested by the absence of a clear
dose-rate effect, at least in young animals. Thisobservation contradicts previous findings (reviewed in[D 16. W 12]) that. per unit dose, x rays are more
efficient for thyroid tumour induction than 13 11. The
study reviewed here [L29] differs from the older ones
in two important aspects: first, the range of doses isbelow lO Gy. and thus cell killing and other nonstochastic effects would not be expected to prevail:second, the number of animals used is large and gives
the study good statistical credibility. Nevertheless. thefindings refer only to one sex of one particular strainof rats. These experiments do not support the suggestion [R29] that irradiation of the pituitary gland may
give rise to increased incidence of thyroid cancers inchildren irradiated for treatment of tinea capitis.

5.

Mammary tumours

259. The age-corrected incidence of mammary adenocarcinomas was studied in SPF female BALB/cmice after high- and low-dose-rate exposure to gamma
rays [U3. U25) as well as to high-dose-rate. Jow-doserate and fractionated exposures to fission neutrons[U4. U25. U26]. After acute gamma-ray exposure(doses 0.1-2 Gy) the incidence increased rapidly over
the range 0-0.25 Gy. with a rather irregular plateau
appearing at higher doses. The irregular response wasconsistent with the models l(D) = 7.7 + 35 D + 150 D 2(P > 0.4) for the high dose rate and with
I(D) = 7.7 + 35 D (P > 0.4) for the low dose rate, in
accordance with the linear-quadratic model. Ramzaev
et al. [Rl] described a "supra-linear" response forinduction of mammary adenocarcinoma in mice irradiated over ten generations through constant feedingof 137Cs and 90Sr.
260. Acute irradiation of BALB/c mice with fission
neutrons (0.05-0.25 Gy min- 1) [U25] yielded a doseresponse that was downward concave over the range
0-0.5 Gy (the lowest dose being 0.025 Gy) and would
be poorly described by a linear model. A good fit was
obtained by a model 1(0) = 7.9 + 27 l/0 (P > 0.85).
In the range 0-0. l Gy. the response could be wellfitted by a linear model I(D) = 7.9 + 114 D.
261. When fission neutron exposures were split into
two equal fractions delivered 24 hours and 30 days
apart [U26], there was no difference with respect tothe single dose-response for the 24-hour interval. but
for the 30-day interval there was an increase of about
30-40% only for the highest dose tested (0.5 Gy). In
the latter case. the curve was still bending over in therange 0-0.2 Gy. Protracted irradiation (0.01-0.1 Gy
per day) Jed to a significant enhancement of the effectrelative to the acute exposure. and over the whole
range of doses. This was interpreted either as apromoting effect or as stimulation of progression of
the growth of malignant clones. The maximum RBEof neutrons was 33; this was calculated as a ratio of
the linear slope for the gamma and neutron curves(for single irradiation at low dose rates).
262. Two-month-old female. Sprague-Dawley rats
were followed by Shellabarger et al. [S37] for their
entire life span after single exposures to 250-kVp
x rays (0.28, 0.56 and 0.85 Gy) and 430-keV neutrons(0.001. 0.004. 0.016 and 0.064 Gy). The animals wereobserved for appearance of adenocarcinomas andfibroadenomas. In all irradiated groups the tumour
rate increased steeply with age and the effect ofirradiation could be described as a forward shift intime of the spontaneous age-specific tumour rate.
263. The response was expressed separately for
carcinomas and adenomas as mortality-corrected prevalence and cumulative tumour rate [R(t.D)]. The
fibroadenoma and total mammary tumour responses
were approximately proportional to x-ray dose over
all times, while neutrons produced a downward
concave relationship. rising with a power of neutron
dose less than unitv. The increase in R(t,D) was
significant even at I ~Gy of neutrons and the forward
shift of the prevalence. corrected for age-specificmortality, caused by this dose was equivalent to
35 days. The R(t.D) for fibroadenomas at 800 days
was less curvilinear than at I year after exposure. The
distribution of tumours was non-random among theanimals (over-dispersion was noted relative to Poisson
distribution). The response for adenocarcinomas was
statistically uncertain. owing to the small number oftumours involved, but linearity is the best approximation to the dose-response relationship.
264. In this study [S37]. the RBE varied roughlywith the inverse square root of the neutron dose. At
the highest doses studied it exceeded 10: at the lower
end of the dose scale. it approached a value of 100.
The implications of these observations were alreadydiscussed in chapter II.
265. In other experiments [V9]. female SpragueDawley rats were acutely exposed whole-body tofission neutrons. or to protracted doses of 0.02. 0.06
and 0.5 Gy (over 242 hours in one month). The
prevalence of mammary tumours at JO months after
exposure increased. relative to single irradiation. at all
doses tested. Protraction of gamma-ray exposures(150, 300. 450 R) in a similar pattern reduced
significantly the prevalence seen after corresponding
single exposures. The RBE values for neutrons,
measured at 20% prevalence, were 16 and 68 for acuteand chronic irradiation. respectively.
266. Breast tumours (histology not specified) inyoung female Sprague-Dawley rats were studied [G35]after acute (over one hour) and chronic (over 10 days)
x irradiation, as well as after internal irradiation bytritium, administered as tritiated water (75 and 90% of
total dose delivered over lO and 20 days, respectively).
The doses of 200-kVp x rays varied from 0.29 to 2 Gy,
209

and those of tritium from 0.5 to 4 Gy. The competitiverisk-corrected tumour rate was calculated up to 450 days
after the start of exposure and the integral values werelinearly related to dose for all three irradiation modes.
The effectiveness of tritium per unit dose did not
differ from that for the chronic x-ray exposure. The
latter produced effects similar to those of acuteexposure at 0.6 Gy, but was 25-30% less effective at
about 1.8 Gy.
267. X-ray-induced and neutron-induced (0.43 MeV)
mammary tumours were studied in weanling, virgin
female ACI rats [S52], irradiated at 88-89 days. The
doses for x rays ranged from 0.17 to 3 Gy and forneutrons from 0.01 to 0.36 Gy. The animals were
irradiated either 2 days after implantation of a pellet
containing 5 mg of diethylstilbestrol (DES) or without
prior hormonal treatment. Fibroadenomas and adenocarcinomas were diagnosed histologically and recorded
separately. DES greatly increased the incidence of
spontaneous and radiation-induced adenocarcinomas
in this strain, which has a low spontaneous incidenceof mammary neoplasms. Significant excess prevalence
was detected in DES-treated rats even at the lowest
neutron dose; for x rays. the significance occurred at
0.17 Gy. The RBE varied inversely with the squareroot of the dose and approached a value of 100 at thelowest end of the range.
268. Appearance of tumours in rats not treated with
DES was followed, on the average, to about 750 days
after irradiation. For x rays, the cumulative tumour
rate at 600 days (for the sum or for each type oftumour separately) rose almost linearly with the dose.
The same applied to adenocarcinomas after neutron
irradiation, but for fibroadenomas a downward concave relationship could not be excluded. The RBE ofneutrons for the sum of tumours tended to decrease
with dose over the range of doses tested, but did notvary much from an average value of 10. The length oftumour-free life lost due to the sum of benign andmalignant tumours was a linear function of dose, forboth x rays and neutrons, and for the whole range ofdoses tested.
269. When non-inbred female rats were irradiatedexternally, with single. increasing doses of fJ rays froma 90 Sr + 90 Y source, the rise of the crude incidence of
mammary carcinoma was linear with dose, up to 4 Gy
[M68, M7 l]. These animals were also irradiated,starting at the age of 8 weeks. singly. with dosesof 16 Gy (from the published text it appears likely thatthe doses refer to the surface of the body): daily(5 days a week) at 0.8 Gy per day for 4 weeks; or once
every two weeks with 0.8 Gy over a period of
39 weeks. The observed life shortening differed significantly from the control value. but not between
groups with various irradiation schemes. There was an
obvious acceleration of the appearance of mammary
tumours after irradiation. and the fractionated schemes
were slightly less effective, although this difference
could be accounted for by the fact that, on average,
the fractionated exposures were delivered somewhat
later in life. The crude incidence over lifetime waselevated in all irradiated groups to 100% from 40% in
controls. This experiment [M7 l] supports the notion
210

that fractionation of low-LET radiation has little
effect upon the incidence of mammary tumours in
rats.
270. Other authors reported that mammary tumours
were also induced in female Sprague-Dawley and in
W AG/Rij rats by x rays. and by monoenergetic 0.5Me V and 15-MeV neutrons [B86, B92]. There was noevidence that a virus played any role in mammary
carcinogenesis in these animals. The rats were 8 weeks
old when irradiation was started with fractionateddoses or given as single doses (absorbed doses in theglands). They were kept until their death. and thefrequency of fibroadenomas and carcinomas was
based on histological examination.
271. The probability of animals surviving without
evidence of a tumour was calculated according to the
Kaplan and Meier life-table analysis. Weibull functions were fitted to these data and showed that
irradiation caused an acceleration in the appearanceof fibroadenomas and carcinomas in both strains ofrats. X-ray fractionation (10 x 0.2 Gy at one-monthintervals) in WAG/Rij rats was marginally less effective. in respect of the appearance time of mammary
carcinomas. than a single dose of 2 Gy. Fractionationof 0.25 Gy of neutron into 10 equal fractions at onemonth intervals was also without a significant effectrelative to I X 0.25 Gy.
272. When dose-response relationships were calculated from actuarial incidence data at 95 weeks of age,
the results for carcinomas in W AG/Rij rats for x rays
and 0.5 MeV neutrons showed such a wide scatter as
to preclude unequivocal inferences about the characterof dose-response relationship. For fibroadenomas(Figure XX) the response for x rays (0.25-4 Gy) was
proportional to dose. The response for 0.5 and
15 MeV neutrons (0.025-0.8 or 1.6 Gy. respectively)
showed a saturation effect. In Sprague Dawley rats,
the actuarial incidence of fibroadenomas showed
100•0 0.5raysHeV neutrons
x

~

.....
z
.....
C

80

A

15 HeV neutrons

u
u

z

60

_,

:::
0:

~

40

•

~
Ill
Ill

.....

... 20
u

><

0
0

0.8

2.4
1.6
ABSORBED DOSE (Gy)

3.2

4.0

Figure XX. Actuarial Incidence at 92 weeks of age of mammary
adenomas In WAG/RIJ rats as a function of dose for various
types of radiation.
[B92]

saturation effects at high doses of all radiations. The
RBE of neutrons was much lower than that observedin other studies on the same strain [S37, S52].
Carcinomas were so rare that no dose-response
relationship could be established.
273. When the prevalence of mammary adenocarcinomas was studied at 10 months after x-ray exposure{200 R) in female Sprague-Dawley rats irradiated as.
young virgins or as pregnant, lactating or postlactating animals [H23], no effect of the physiologicalstate upon the incidence could be found. This result is
at variance with the age-effect seen in women (seechapter V).
274. Numerous studies show that several factors may
influence the development of radiation-induced
mammary tumours in various strains of rats. Some ofthese studies were considered in annex L of the 1982UNSCEAR report [U24]. A strong influence ofgenetic factors on neutron-induced mammary carcinogenesis was reported by Vogel et al. [VIO]. After asingle dose of 0.5 Gy from fission neutrons. thehighest (56%) prevalence at I year after exposure wasseen in Sprague-Dawley and Long-Evans females; thelowest (5%) was observed in Wistar, and an intermediate one (25-29%) in Buffalo and Fischer-344 rats.
Wide variation in susceptibility to mammary tumour
induction was also found by Broerse et al. [B86, B92]
for Sprague-Dawley. WAG/Rij and BN/BiRij rats.
6.

Lung cancer

275. Lung adenocarcinomas were induced in BALB/cfemale mice by gamma irradiation at 0.45 Gy min- 1
and at 0.083 Gy per day in the dose range 0.1-t Gy[U2, U3, U25]. After acute exposure. the age-corrected
incidence could be related to dose by a linear[l(D) = 10.9 + 11 D: (P > 0. 7)] or a linear-quadraticmodel [l(D) = 11.9 + 4.1 D + 4.3 D 2 (P > 0. 7)]. At
low dose rate, the dose-response relationship was
linear with the same slope [l(D) = 12.5 + 4.3 D(P > 8)] as at high dose rate in the linear-quadraticmodel. This model, therefore, seems to describe
adequately the response in question.
276. After single acute exposure to fission neutrons(doses 0.025-2 Gy; 0.05-0.25 Gy min- 1). the relationship was downward concave with a maximum at
0.5 Gy [U25]. Over the range 0-0.5 Gy the data wereconsistent with a square-root model [(D) = 13.6 + 29
VD (P > 0. 7)]. A linear model could not be rejected
but was obviously unlikely. ln the ranges 0-0.2 Gy, thedata were fitted by a linear model [I(D) = 14.7 + 76 D
(P > 0. 7)]. When the doses were split into two equal
fractions. no difference was seen for 24-hour fractionation [U26]. A slight increase of the incidences
was noted for 30-day fractionation. but only at thehighest dose of 0.5 Gy. For this irradiation mode thedose-response became practically linear up to 0.5 Gy.
277. Protracted neutron irradiation (8.3 10- 5 Gy per
day and 8.3 10- 6 Gy per day) was more effective thanthe high-dose-rate exposure and, as in the case of
30-day fractionation more nearly linear over theentire dose range [U26]. Higher effectiveness for
0.5 Gy at chronic and at 30-day fractionated exposureis unlikely to result from repair of sub-transformation
damage, as no repair was seen for fractionation over
24 hours. The effect was attributed to repopulation ofalveolar target cells. The maximum RBE of neutrons
from the ratio of the linear slopes at low doses was
18.5. When derived from the square root of the dosemodel, it equalled 70.7/J/D 0 •278. Chmelevsky et al. [C34] analysed the inductionof lung carcinoma in male Sprague-Dawley rats whichwere 90-clays old at the start of an exposure to radonin equilibrium with its short-lived daughter products.
The radon concentrations and the duration of daily or
weekly exposure were varied. The total duration of theinhalation period was kept within one to six months.
The dose was defined as a product of potential alphaenergy concentration and exposure time, and expressedin working level months (WLMc): the range of dosecovered zero to 14,000 WLM delivered at various
rates.
279. Animals were studied at death for the presence
and histology of lung neoplasms. In this species, lungcancer is almost never a cause of death: therefore
independence between disease and death could beassumed and the data could be treated as fully
censored. The prevalence of neoplasms as a functionof time was estimated for each exposure group by
non-parametric methods in the form ofa monotonicallyincreasing function (by a most-likelihood fit). Threemodels were selected for fitting prevalence to dose: atime shift, an acceleration, and a proportional hazard
model. The fit of the data to all three models wasequally good: none could be discarded on statisticalgrounds.
280. The crude and mortality-corrected incidence oflung carcinomas was calculated from the prevalence
function up to 900 days. The results of the actuarial
incidence are shown in Figure XXI. The initial slope(below 1000 WLM) is practically linear in both cases.
When the incidence was fitted to a function of cumulative exposure E of the type I(t:E) = K EP, the parameters obtained at t = 850 days were: K =(3.4 ± 1.4)
10- 4 and p = 0.92 ± 0.07. When linearity was assumed
to apply over this range of exposures. the proportionality coefficient was (2 ± 0.5) 10- 4 per WLM. Perhaps
by accident, these values are very similar to those foundfor man (chapter V). At doses above 3 10 3 WLM, theresponse flattens off. At doses above 4 10 3 WLM, theexposures at high dose rate(> 1600 WLM per month)
are less effective in inducing tumours than thosedelivered at lower rates. Toe data do not suggest athreshold, which. if present. would have to be much
lower than 65 WLM. The character of the doseresponse relationship is basically similar to that seen
'The concentration of potential alpha energy of short-lived
radon-222 daughters is sometimes expressed in units of Working
Level (WL). This level corresponds to any mixture of thesedaughters which, upon complete decay, will emit alpha particles\\ith total energy of L3 10s MeV per litre of air (2.08 10-s J m-3).
The Working Level Month (WLM) corresponds 10 exposure to amean concentration of I WL for the reference period of 170 hours.
I WLM = 170 WL hours= 2.2 104 MeV h m-3 = 3.5 10-J J h m-3.

211

0

...z
...

C •

ST

.t::. ...

AT

o+

PH

••

u

C

uz

... 0.1
C

,-

"'

::,
~

~

0.01

......
104-,...~~~~~~~~-,-~~~~~~~~.,...~~~~~~~~

102

10

103

~~

OJMULATIVE EXPOSURE (WLM)
Figure XXI. Adjusted Incidence of lung carcinoma In rats as a function of the cumulative
exposure (WLM), calculated on the basis of three models: ST, time shift model; AT, accelerated
time model; PH, proportional hazard model. Open symbols: exposure rate< 1600 WLM permonth; Solid symbols: exposure rate> 1600 WLM per month.
[C34]

in uranium miners (chapter V). The loss of tumourfree life (the so-called "effect period" [U6)) was alsostudied in these rats as a function of cumulative
exposure. Agreement between the models is less close
than for the mortality-corrected incidence: however,linearity seems to prevail up to 1-2 103 WLM.
281. The actuarial incidence of lung carcinomas wasstudied [C38] in Sprague-Dawley rats. after wholebody irradiation with fission neutrons. and evaluatedby methods of analysis similar to those described forradon-induced cancers [C34]. The neutron doses
ranged from 0.012 to 8 Gy. The doses up to 2.3 Gy
were delivered within I day and the higher doses were
protracted over periods from 14 to 42 days to secure
early survival of the animals. The time-related prevalence of pulmonary cancers was fitted to shiftedtime and accelerated-time models and an actuarial
incidence was calculated which did not depend upon
the model chosen (Figure XXII). The dose-response...."'u
....z

!=

u
~

...

ei

e

e

relationship could be linear up to about 0.5 Gy. At
higher doses, the curve does flatten, but does notdecrease (actually, the absence of a decrease is due tocorrection for life shortening). In the low-dose range,the. efficiency of neutrons versus radon in inducing
pulmonary carcinomas exceeded 3 WLM/mGy. At
higher doses, it was lower. Recalculation of this ratio
in terms of lung doses, rather than exposures, indicatesthat the efficiency of neutrons, relative to alphaparticles, is about 14 when expressed in terms of thebronchial dose and about 2 in terms of dose to thepulmonary parenchima [T3].
282. An exhaustive review of lung cancer induction
by inhalation of various radionuclides in differem
animal species was compiled by an ICRP Task Groupand published as ICRP Publication 31 [13]. When thedata from various experimental series were combined
for an analysis of dose-response relationships a very
wide scatter was apparent. Whereas for various alphaemitting transuranic nuclides a linear fit to the data
did not appear unreasonable, a linear dose-response
relationship did not adequately describe the experimental points obtained for beta and gamma emitters.
For these an upward concave dose-response relationship was typical.

i

10- 1

7.

0

I-

•

0

:::,
"'
..,

o

•

0
cC

accelerated time model

0

• •

0
10- 2
10-2

10- 1

1

10

NEUTRON ABSORBED DOSE (Gy)
Agure XXII.

212

Lung adenomas

shifted time model

Adjusted Incidence of lung carcinomas In neutron•
irradiated male Sprague-Dawley rats.
[C38)

283. Induction of benign Jung adenomas in RF mice
was studied [YI] by locally-delivered, acute doses of
x rays of between 2.5 and 15 Gy. The dose-response
curve for tumours recorded 12 months thereafter,
when plotted on a log-log scale. had a slope of I
below 7.5 Gy and a steeper increase of the tumour
yield at higher doses. In terms of a linear-quadraticmodel, this would imply induction of tumours bysingle-track kinetics in the lower portion of the curveand two-track kinetics in the steeper region of therelationship. A split-dose experiment with fractionation inter.-als of 24 hours confirmed that the numberof adenomas per animal was lowered by fractionation,but only above 7.5 Gy, where repair of interacting
lesions would. theoretically, be expected.
284. Induction of lung adenomas by localized irradiation of the thorax with 300-kVp x rays and fastneutrons was also studied in I 0-12-week-old female
SPF RFM/Un mice [U21). After 0.5 Gy of neutrons,
the number of tumours per mouse at 6 months did notincrease further and it was assumed that by 9 months
it should have been complete. The doses of x rays
ranged from I to 9 Gy and of neutrons from 0.05 to
1.5 Gy. The level of mortality did not influence theresults substantially. For acute x irradiation, linearity
could be excluded and the dose-response curve could
be described by: (a) a linear-quadratic model with an
initial negative linear slope (P > 0.90); and (b) athreshold model of the form P(t:D) = c + a (D - D*) 2(P > 0.99). where D* is the threshold dose. estimatedto be 2.47 Gy. For neutrons, the average number of
adenomas per mouse rose about linearly to 0.25 Gy.
peaked at I Gy. and then declined by a factor of
about 2 toward 1.5 Gy. Over the range 0-0.25 Gy. therise was appr~imately linear (P > 0.50). A yroportionality to \/ D could be rejected over this range(P< 0.05). Also a linear threshold model with thresholddose at about 0.07 Gy described the response within
the range 0-0.25 Gy very well (P > 0.99). For the
linear model, the RBE of neutrons increased from avalue of 25 at 0.15 Gy neutrons to one of 40 at
0.01 Gy.
285. Splitting of the dose of either radiation into two
equal fractions separated by 24 hours or 30 days was
also tested [U22]. Under these conditions. there was a
reduction in tumour yield for x-ray doses above
4.0 Gy. and the response tended to become morenearlv linear. There was no difference between responses
with doses split by 24 hours or 30 days. Recovery wascomplete by 24 hours, and amounted to 50% of theinitial effect. After split neutron irradiation. no recovery
could be seen. Linearity for all data combined over
the range 0-0.25 Gy could not be rejected (P > 0.8),
but better fits were obtained with a dose-squaredmodel (P > 0.99) or with a model using a thre~holddose at about 0.054 Gy. If it is accepted that decline of
the tumour yield at high doses reflects killing ofpotentially transformed cells. then linearity over therange 0-0.25 Gy becomes rather improbable. as alre~dy
discussed in chapter ll. However. an al~~rnau_ve
explanation of the slight upwards concave curv1lmearttyin the 0-0.25 Gy range could be a possible inverse
relationship between latency and dose.
8.

Ornrian tumours

286. Induction of ovarian tumours by x rays andneutrons was studied by Ullrich et al. [U2] using SPF
RFM mice. An acute gamma-ray exposure (0.4 Gymin- 1) induced various types of ovarian tumours, andtheir age-corrected incidence increased rapidly overthe dose range 0-0.5 Gy. At higher doses, there was aplateau of the response with a marginal rise of tumour

incidence with increasing doses. Over the range 0-0.5 Gylinear and dose-squared non-threshold models could
be rejected (P < 0.01) while a linear-quadratic modelwith a negative linear component adequately described
the relationship (P > 0.25). Since. according to theauthors, no biological meaning could be attributed tosuch a model, threshold models were tested and alinear one was again rejected (P< 0.01). However, athreshold dose-squared model (threshold estimated tobe 0.12 Gy) provided a satisfactory fit (P > 0. 75) overthe dose range up to 0.5 Gy. At 0.08 Gy per day, asignificant incidence was seen at l Gy. where it
corresponded to that seen after 0.25 Gy acute exposure.
Again, non-threshold linear and dose-squared models
could be rejected (P < 0.0 l} as well as the thresholddose-squared one. An adequate fit was obtained for a
threshold linear model with a threshold dose of 0. 7 Gy
and a linear-quadratic model with an initial negative
linear slope (significantly negative at the 5% level).
287. After neutron irradiation (U5]. the ovarian
tumour incidence in RFM mice was lower at 0.0 I Gy
per day than at 0.05 and 0.25 Gy min- 1 for all doselevels. The decline was attributed partly to the
reduction of the dose rate and partly to an age-related
decrease of susceptibility. This suggests that a true
dose-rate effect was perhaps observed in this tumour
system after high-LET irradiation.
288. Ullrich [U23, U25, U26] studied the age-corrected incidence of all ovarian tumours (granulosa celltumours. luteomas, tubular adenomas) in BALB/cfemale mice, induced by gamma radiation and fission
neutrons. High-dose-rate gamma irradiation (in therange 0.1-2 Gy} increased the incidence steeply fromcontrol levels (about 2.5%) at 0.1 Gy to 77% at
0.5 Gy. with a plateau at higher doses. As previously
observed for RFM mice, the dose-response relationship was consistent with a threshold model, and thelinear. dose-squared and linear-quadratic models co~ld
be rejected (P< 0.01). Irradiation of BALB/c micewith fission neutrons (0.025-2 Gy) led to a steep
increase in the incidence of ovarian tumours fromcontrol level at 0.025 up to 76% at 0.5 Gy. with aslight decline towards 2 Gy. Over the dose range
0-0.5 Gy, a variety of dose-response models could
describe the data, including the non-threshold models(linear-quadratic, dose-squared) and a threshold-typemodel. The linear non-threshold model could. however, be rejected (P < 0.01). A threshold model would
be consistent with both the postulated role of nonstochastic mechanisms involved and the data for
gamma radiation. Because of the app~rent thr~shold.
at low doses any estimate of RBE 1s meanmgless.
From 0.2 Gy upwards the RBE is close to unity [U25].
Splitting the neutron dose at 24-hour and 30-day
intervals was ineffective. the data being practicallyindistinguishable from the single-dose series. At protracted exposures, the neutrons were Jess effective thanwhen delivered acutely but, for instance, 0.4 Gyyielded the same result whether delivered ?ver 4 or
40 days. This indicates that the difference with regard
to acute exposure is a true dose-rate effect and not achange of susceptibility to tumour induction with age.
The observation is similar to that for the RFM mouse,
but no explanation is available.
213289. In other experiments [Y2], mice received a seriesof x-rav doses over a variable time T and the animals
were f~llowed for incidence of ovarian tumours. The
results were later re-analysed [KS] on the assumptionthat the cumulative net incidence (prevalence) is
described by the equation(4.1)
F{t) = f [a 1D + q(T)D2]
where the form of the function is left undecided andq(T) is a reduction factor for recovery of the damage
with protraction of irradiation. The optimal fit to thedata was obtained for an assumed exponential decayof the sublesions T = 15 h. The optimum value for a1
for the linear term was zero, and a 1/a 2 quotients
greater than 0.04 Gy in terms of the linear-quadraticmodel could be excluded when data were corrected fortime-dependent repair using non-linear optimization.
In essence, no linear component could be found, andincidence was proportional to the square of the doseover a wide dose range.
9.

Pituitary gland tumours

290. In female RFM mice, pituitary tumours increased irregularly with gamma-ray dose over therange 0.05 to 3 Gy (0.45 Gy min- 1) and the agecorrected incidence was not significantly different
from control. A linear-quadratic response adequately
described the data (P > 0.6), but a linear response
could not be excluded (P > 0.2) [U2]. In male mice.
the effect was so slight that the dose-response could
not be investigated. Lowering the dose rate (0.083 Gy
per day) caused a less efficient induction of pituitary
tumours in the same mice [U3]. If a linear-quadratic
response was assumed at high dose rate, the linear
component was very similar under both conditions
and the lower dose rate eliminated the contribution of
the dose-squared component. Neutrons induced alarge number of pituitary tumours with an RBE
greater than 5. A dose rate of 0.0 I Gy per day
appeared as effective as 0.05 and 0.25 Gy min- 1 up to
0.2 Gy, but rather less effective at 0.47 and 2 Gy.

10.

Harderian gland tumours

291. These tumours were induced by gamma rays inboth male and female RFM mice, and the response in
the two sexes was very similar. The data on ageadjusted incidence appeared to fit best a linearquadratic model (P > 0.25 and> 0.99 for females andmales, respectively), but linearity could be excluded
only for females (P > 0.05). The low-dose-rate gamma
irradiation substantially reduced the incidence oftumours, and a good fit (P > 0.90) to the equation
was obtained with the same linear coefficient as forhigh dose rate but without a dose-squared term [U2,U3]. The same rumours showed a marked sensitivity
to induction by neutrons, with an approximately
linear increase in age-adjusted incidence as a functionof dose up to about 0.5 Gy. with a plateau at I Gy
and a decline at 2 Gy. No significant effect of the dose
rate was observed [U5]. When the age-adjusted
incidence of harderian gland tumours was studied inwhole-body x-irradiated CBA mice [03) it was found
214

that the dose-response curve rose as a function of dose
up to 3 Gy (there were, however. only 3 points) andthen became flat. Correction of these data for cellkilling (a survival curve was determined independently)
resulted in a dose-response curve per surviving cellwhich rose with the square of the dose between I and
7Gy.
11.

Skin tumours

292. Skin cancer can be induced in experimental
animals. mostly CBA mice and CD rats, by bothdensely- and sparsely-ionizing radiation, and relevant
experiments were reviewed in the 1972 and 1977
UNSCEAR reports [U6, U7]. For both species. highly
curvilinear dose-response relationships were reported
for p particles and high-energy electrons [B59, Hl2,
H 13) as well as for accelerated (40 MeV) helium
nuclei. which also produced a curvilinear response in
CD rats [B59]. From detailed considerations of depthdose distribution versus efficiency of cancer induction.
and from the association of the latter with damage tothe hair follicles, it was concluded that radiationinduced skin cancer in this latter strain is likely tooriginate from cells located in the follicles.
293. The induction of epidermal and dermal skintumours was again studied in 3-month-old female
CBA/CaH mice (3125 exposed. 612controls), irradiatedlocally over one-third of their skin surface (mid-torso)
by P particles emitted from a 2~TI source [H33]. The
radiation neither penetrated the abdominal wall nor
reached the bone marrow. Tumorigenic doses weretaken to be 75% of the nominal dose at the bodysurface for epidermal tumours. and 65% for dermal
ones. The nominal doses ranged from 5.4 to 260 Gy,
and the dose rate varied from 2 to 0.017 Gy min- 1•
Most tumours arose well within the irradiated area
and only a few at the edge. Over 70% of all tumours
were dermal (fibromas and fibrosarcomas). and about
60% of the dermal and epidermal ones were malignant.
It was confirmed histologically that fibromas could
become malignant. and multiple tumours were noted
in 12-15% of tumour-bearing mice irradiated at thehighest rates. The incidence of tumours was expressed
per unit area of skin. Reduction of dose rate from 1-2
to 0.11-0.22 Gy min- 1 did not alter the incidence
appreciably; at 0.05-0.08 Gy min- 1• the incidence of
epidermal tumours was reduced at all except thehighest doses ( 120 Gy).
294. The incidence of dermal tumours began toincrease significantly with doses to the dermis ofabout 16 Gy and rose steeply into a plateau above
60 Gy. The incidence of epidermal tumours increased
significantly and then rose steeply when the dose in
the epidermis exceeded 21 Gy. The peak incidence wasreached at 60 or 100-120 Gy and fell at still higher
doses. At exposure rates of 0.017-0.024 Gy min- 1• noepidermal tumours occurred and the incidence ofdermal tumours was very much reduced. At lower
rates, therefore. a range of high doses was ineffective
in producing skin tumours. The dose-response curve
resembled those typical of non-stochastic effects. with
an apparent threshold at about JO Gy.

295. The series irradiated at the highest dose rate
( 1.1-2.2 Gy min- 1) had sufficient statistical power todistinguish between various dose-response models.
The observed incidence was fitted to a series of models
incorporating both initiation and cell-killing terms atvarious powers of dose, as well as threshold doses[P21]. From a rather elaborate analysis it was concluded that only one non-threshold model could not
be discarded, and this was for induction of epidermal
tumours with a very high exponent of dose (about 4)
in the induction term. The incidence above apparent
thresholds usually rose very steeply with dose. The
authors suggested that the apparent thresholds may be
due to some relatively radioresistant factor in the skinthat restrains potential tumour cells, and that thisfactor can be overcome by very high doses. and also
perhaps by aging.
296. In CD rats. the incidence of tumours over the
ascending part of the curve rose roughly with thefourth power of the electron dose [B59. H12, Hl3]
and with the square of the dose of alpha particles[B59]. However, these conclusions are only approximate, because the data were insufficient for moredetailed analysis. The value of the RBE of alphaparticles at about 1 tumour per animal, relative tohigh energy electrons. was roughly 3. The peak
incidence of skin tumours always occurred at several
tens of Gy of sparsely-ionizing radiation.
297. Fractionation of the electron dose [B57, B58]
showed that suboncogenic damage was repaired witha half-time of about 4 hours. This observationsuggested that the repair process was operating at thecellular level, as for sublethal damage. Experiments on
the influence of dose fractionation were also madewith 10-MeV protons [B56): when fractions wereseparated by 24 hours. a reduction of the effect wasinterpreted as showing complete repair of recoverable
damage. It was concluded. therefore. that for skintumour in CD rats 10-MeV protons have the usual
characteristics of both high- and low-LET radiation:an RBE of about 3. typical for the former, but
recovery at fractionation and yield of the effectproportional to a power of dose greater than one,typical for sparsely-ionizing radiation.
298. It is difficult to say to what extent skin cancer
induction in rats is an adequate model-qualitatively
or quantitatively-for man. A relatively low sensitivityof human skin to cancer induction by radiation wasnoted in annex G of the 1977 UNSCEAR report [U6]and in the BEIR III Report [C29). On the other hand,
histogenesis of most skin cancers in rodents isdifferent from those of the human skin [LS). Albert.
Burns and Shore [A4) suggested that radiationinduced cancers in CD rats, and in children irradiatedfor tinea capitis. show similarities in the distributionof the latent periods when time is normalized for both
species to their mean life spans. However, the fractionsof total skin surface irradiated were different inanimals and in children, so that any similarity could
be fortuitous.
299. On the basis of data in CD rats, Vanderlaan etal. [VI) proposed a mathematical model of skincancer induction by ionizing radiation. The model isbased on the hypothesis that radiation can initiate acancer by converting normal cells (S 1) to potentiallymalignant cells by one of two routes: a reversible routeinvolving two steps (S 1 - S2 - S 3, the reversible stage
being S 2) and an irreversible single-step process(S 1 - S3). It was assumed that the initiation process
takes place in single cells but its nature was not
specified. Cells in the intermediate stage S2 can revert
to the normal state S I at a rate ;. assumed to beconstant and independent of dose. The probability ofdeveloping carcinoma of the skin was assumed to be
proportional to the number of irreversibly transformed cells S3. Expression of the latter as a functionof time after irradiation was obtained from solution ofa pair of differential equations. The solution showedthat the relationship of cumulative incidence versus
dose was dominated by the dose-squared component.
In this model, the relative values of the linear andsquared components are not predicted by LET or any
other microdosimetric consideration. From experimental observations. Vanderlaan et al. [VI] concluded
that, after a dose-independent tumour-free inten:al,throughout the remaining life span the tumours
appear at an approximately constant rate. directly
proportional to the dose. However. the experimental
data show a considerable scatter for all radiations
used.
300. From fractionation experiments. a decrease of
unrepaired damage with time was deduced, with ahalf-life of about 4 hours. For estimation of the doserate effect on the yield of tumours. a dose-rate factor
DRF (the ratio of acute to protracted dose for thesame yield of S3 cells) was calculated, and it waspredicted that the reduction of the carcinogenic
response at low dose rate would be very pronounced.
This was confirmed in fractionation experiments with
0.8-Me V electrons [A 18), showing that weekly exposure
to fractions of 2 Gy per week (130 Gy in 65 weeks)yielded the same incidence as a single exposure to
15 Gy.
30 I. In conclusion, all the data discussed above
suggest that linear extrapolation of skin cancer risk
from the rates observed at high acute doses to the lowdose range would greatly over-estimate the risk. To
what extent these conclusions might apply to man isstill. however, an open question.
12.

Bone tumours (internal irradiation)

302. Although the data discussed in the following
paragraphs are often referred to in terms of theaverage skeletal dose, it should be borne in mind thatthe relevant dose for the effects in question is thatdelivered to the bone-lining cells. The crude incidenceof bone sarcoma induced by 239Pu. 249Cf, 252 Cf. 24 'Am,
and 226 Ra was compared in C57BI/Do mice andalbino mice [T22); the data seemed compatible withlinearity of the dose-response relationships for all
radionuclides. However, the scarcity of data points foreach series makes this conclusion at best tentative. It
will be recalled that linearity of the dose-response wasalso seen earlier for bone sarcoma induction by 226Ra
in CFI mice [M69].
215

303. The question of a practical threshold in bonesarcoma induction following internal irradiation bybone-seeking radionuclides was raised originally byEvans [E4]. This issue was addressed again by a studyof Raabe et al. [R32, R40] who tested the hypothesison the basis of results on beagle dogs. Two groups ofanimals were given: (a) 226 Ra in 8 fortnightly injectionsof graded activities, the median age during theinjection period being about 14.5 months, to simulate
the human experience with radium: and (b) 90Sr bycontinuous feeding at various levels of 90Sr/Ca ratio
from mid-gestation through 540 days of extra-uterine
life, to simulate the human contamination from theenvironment.
304. On inspection, the mortality data showed thatat higher dose levels survival declined as the dose rate
to the skeleton increased. The mean latent period of
osteosarcomas varied inversely with the time-averaged
dose rate calculated for individual animals fromperiodic measurements of whole-body activity (Figure
XXIII). When the survival period t was plottedagainst the mean dose rate to the skeleton, the data
could be fitted to the relationship t = K o-s. where K
and S were parameters determined by a least-squares
procedure. When a log-normal distribution of times todeath from osteosarcoma for a given dose rate ,vasassumed (on the basis of empirically tested distributions), K and its geometric deviation {± ag) for
radium and strontium-90 were 2500 (± 1.24) and 8400(± 1.72). respectively. The corresponding values for
S ± S.E. were 0.29 ± 0.0 I and 0. 77 ± 0.05. For 116 and
27 dogs dying with malignant bone tumours in groups
given radium-226 and strontium-90, respectively. the fit
to the function was good, with correlation coefficientsof 0.92 and 0.95.
305. From inspection of the regression lines. it
appeared that, if the relationship held down to thelowest dose rates, there must be latent periods in the
low-dose range exceeding the normal life span. A

practical threshold was therefore defined as the dose
rate corresponding to the intersection of the regression
line log(t) versus Iog(D) (Figure XXIII) minus threegeometric standard deviations of the mean survival
time t for control dogs. For dogs injected with 22"Ra.
the threshold dose rate so defined was 0.11 mGy perday, corresponding to a lifetime dose of 0.5 Gy and aprobability of about 0.7% of incurring a sarcoma
towards the end of life. Corresponding values were
not given for 90Sr-contaminated animals but theywould be expected to exceed the values for radium by
one or two orders of magnitude.
306. The S values derived from dogs injected withradium were used to fit the data on latency andskeletal dose rate in women dial painters and in RFM
mice. There was a high degree of correlation between
the species' average life span L (years) and K values
calculated for each species according to the relationship
Km= [655 ± 57 (S.E.)] + [119 + I (S.E.)] L (4.2)

It could be concluded that a practical threshold for
2 26Ra in man is 0.039 mGy per day and a total dose of

0.8 Gy. The relative effectiveness of 90Sr and radium,in terms of doses inducing equal effects in dogs. wasalso estimated: it varied in some proportion to theaverage dose from 90Sr to the skeleton. If this relation
holds down to the lowest doses. a practical thresholdof dose rate and cumulative dose for 90Sr would be atleast one or two orders of magnitude greater thanthose for 226 Ra.
307. The same methodology was applied [R40] to a
study of relative effectiveness for the induction ofbone sarcoma in young beagles injected with nine aemitting bone-seeking nuclides. All nine studies showed,
with relatively good precision, a three-dimensional,
log-normal, response relationship represented in two
dimensions by the equation t = Ko-s. S was found tobe, on average. 0.29 (± 0.0 l S.E.) for all radionuclides.

10000.,, 3000
>,
"'
-0
2000

....<:c....

t Ra =2500(0 Ra ,- 0 · 29

1000

C

....

0

....
....

• Bone tumour from radium-226
o Bone tumour from strontium-90
1 Time to death (days) after beginning exposure
0 Average dose rate (rad/day)

500

:!:

300

0

... ...

•,

...

''

' ...

' ...

200
100

10- 2

10
AVERAGE OOSE R~TE TO SKELETON, D (rad/day)100

Figure XXIII. Comparison of the dose-response relationships for radlum-226 and strontlum-90 In
beagle dogs that died of primary bone cancer. The dala show the median time, tL, of spontaneous
deaths among unexposed control• and the fitted functions In irradiated animals.

[R32]

216

A practical threshold dose or dose rate, below whichbone sarcoma deaths are very unlikely. is suggested at
low dose rates for all these radionuclides. just as it wasreported for 226 Ra [R32]. Mean skeletal doses at which
the defined practical threshold was reached were lower
than for 226 Ra (0.5 Gy) by the following factors: 228 Ra,
3.0; 241 Am, 6.4; 249 Cf. mcf. 253Es, 6.6: 239Pu. 9.0;228
Th. I 0. 7; 2J8Pu, 15.5. If these factors were expressedin terms of the doses 10 the bone-lining cells, theirspread would be considerably reduced.
308. The reasoning of Raabe et al. [R32] is based onan empirical linear regression of survival times versus
mean skeletal dose rate in animals dying with, or due
to, malignant bone tumour. However. in the low-doserate groups and among the controls a majority ofanimals were still alive at the time when the experiments were evaluated. There is some uncertainty inthe data as to the mean survival values and theirdistribution among control animals. The data could
also change somewhat as a result of further follow-up.
The derived practical thresholds must therefore betreated as tentative at best and any final assessment
must be deferred. Moreover. any hypothesis regarding
species-related interpolation of the risk neglects differences in susceptibility to the induction of bonesarcoma among various strains of mice and breeds ofdogs. Alternative interpretations of the data were
presented by Mays [M69]. However. the concept of apractical threshold for bone sarcoma is important forrisk assessment. because. if extrapolation of the basic
relationships is correct. there must be values of thedose and activity at which no radiation-induced life
shortening occurs, and therefore the somatic component of the index of harm [I 6] can be taken to be zero.
309. Osteosarcoma induced by 239 Pu in 294 beagle
dogs of both sexes was studied following single
injections at ages between 400 and 800 days [W 14].
The activity injected ranged up to about 0.11 MBq/kg
body weight. in 7 groups of animals [M 11]. Times atdeath due to osteosarcomas were fitted to the Weibull
distribution function and described in terms of cumulative hazard or hazard rate. in both cases as afunction of time after injection. The power functionsof time for cumulative hazard or hazard rate corresponding to R(t,D) and r{t.D) for tumours detected
at death in individual injection groups were fitted tothe data by a most likelihood method. The plots on alog-log scale were virtually parallel for all groups, andtherefore the proportionality constants of the lines
could be analysed as a function of the injected activityof 239Pu. Below 37 kBq/kg. there was a strong inverse
relationship between the injected activity of plutonium
and the time at which a given value of R(t.D) was
reached. At the highest injection level the hazard was
lower than in the preceding group, probably due tocell killing or some other non-stochastic effect. Whenthe highest activity level (0.095 MBq/kg) was discarded. the data for R(t.D) (below 37 kBq/kg) gave an
acceptable fit to a pure quadratic model (P = 0.19)
and linearity could be rejected (P < 0.00 I). A model
containing both a linear and a quadratic component
did not fit the data better than the quadratic one,
where R(t,D) depended also on time after injection to
the power of 5.9.

310. The same data were studied in parallel [Wl4]by the generalized Marshall-Groer model for bonesarcoma induction [M4) (see V.E.2 for details). The
solution of the model showed lack of a linear
component in the relationship between effect andcumulative dose. The best fit was obtained for aquadratic relationship between dose and R(t,D) for
osteosarcoma. Since many animals injected with thelower activities are still alive. a linear contribution to
the dose-incidence relationship might still appear after
further follow-up. When the same data [PI 7) weretreated in terms of a non-parametric proportional
hazard relative risk model. both a linear and aquadratic function could be fitted to the data andneither could be excluded. However. if-as waslegitimately done by Whittemore [WI4]-the data forthe highest injection level are omitted. the results
again support a roughly quadratic rise of the relativerisk with injection level.
311. An experiment has been completed [Wl9] on
160 young beagle dogs. injected at the age of
17 ± 2 months with saline (controls. 44 dogs) or withincreasing amounts of 226Ra (8 levels from about 260
Bq to 370 kBq/kg). The average a-particle dose to theskeleton varied from 0.35 to 190 Gy. Most of the
primary bone tumours were osteosarcomas. Bonesarcoma incidence was a monotonically increasing
function of the dose up to 70 Gy. The dose-responsefits well a linear non-threshold model over the six
lowest dose ranges with a slope of 3.3% per Gy. No
tumours were found in the controls or in the 0.35 Gy
group, but I tumour over 25 dogs was found in thenext group with a mean skeletal dose of 0.85 Gy. No
significant change in bone tumour incidence was seenamong the three highest dose levels at which theincidence exceeded 90%. and the life span wasconsiderably shortened. There was very little. if any,
life shortening at the five lowest levels up to 9.5 Gy.

312. Liver tumours were induced in Chinese hamsters
by 239 Pu citrate injection. and the crude incidence forthe few dose points available suggested an initialapproximately linear rise up to 2.7 Gy at the timeof 50% survival. At the highest dose of 14 Gy. theeffectiveness per unit dose was much lower [B87].
313. The dose-response relationship of injected
thorotrast was studied in female Wistar rats for thesum of liver and spleen tumours [Wl5]. In some of theexperimental groups. the preparation was enrichedwith 23°Th in order to study the influence of the massof injected colloidal thorium dioxide. For a constantdose rate (activity). an increase in mass by a factor of
10 proved more effective in respect of life shortening.
When the crude percent incidence (I) of all benign andmalignant liver tumours was plotted against therelative dose rate (D), a linear dose-response relationship was observed: I{D) = 3.3 ± 0.79 D with a correlation coefficient of 0.97. The I value at D = 0 does
not differ essentially from the observed control incidence of 2. 7%.
217

1-t

Combined tumour data and indirect inferences

314. Life shortening by radiation was reviewed in
depth in the 1982 UN SC EAR report [ U24]. It was
concluded that, in the incermediate- and low-dose
region, life shortening is due essentially to a higher
tumour mortality. This does not mean, of course, that
dose-response relationships for both endpoints are
directly comparable, because, even for the sameradiation, the mean latent period of some tumours
varies with dose, dose rate, age at exposure, etc.
However, if life shortening is the major consideration,then comparison of results from \'arious dosage
schedules for the same radiation and in the samestrain of animals could provide some indication as towhat the comparative incidences and/or latent periods
might be. This seems particularly interesting forneutrons. for which no human data are available.
315. Life shortening and incidence of various diseases.
including Jeukaemias and malignant tumours. werestudied in male BALB/c mice [M62] after single andfractionated doses of gamma rays split into 10 equal
fractions delivered at intervals of I day. The doses
ranged from 0.25 to 6 Gy. The causes of death wereascertained by autopsy and histological examination,
and actuarial incidences were calculated, with correction for competing risks. In general. single exposures
were more effective than fractionated ones with regardtO life shortening. Over the whole range of doses, theincidence of all leukaemias and cancers combined
appeared significantly higher after fractionation. However, the dose-responses were very flat and included
more than 70% of spontaneous cancers. For all
carcinomas and sarcomas, except lung carcinomas (forwhich the spontaneous incidence in BALB/c males isvery high). a higher effectiveness of fractionated doses
was seen only after doses above I Gy.
316. These observations must be taken with somecaution, due to the very high spontaneous tumour
incidence; to the Jack of statistically significant differences between incidences of individual tumours after
two modes of irradiation; to the generally flat doseresponse relationships; and to the fact that. as shownby Storer [S53]. this strain has a number of significant
associations between various tumours. Finally. theeffect of single and fractionated gamma-ray doses
upon life span was opposite to that seen for combinedcancer incidence, showing. perhaps. that in this case a
specific combination of induction and acceleration ofsome tumours could have played a significant role.
317. Whereas incidence of all carcinomas and sarcomas combined (except lung carcinomas) showed anegative trend after single doses of gamma rays on thesame strain [M63]. an almost linear increase was seen
after single doses of d(50)-Be neutrons in the range
from 0.02 through 3 Gy.
318. Life shortening of B6CFI mice was studied bysingle, fractionated (short- and long-term), and lifelong exposures to gamma rays and fission (0 . 85 MeV)
neutrons [T20. T21. T25]. When survival data werecompared for doses given in 24 weekly fractions or as
single exposures. the effectiveness of gamma radiation218

was consistently decreased by fractionation. However,for neutrons the same fractionation scheme increased
the effect throughout the whole range of doses. down
to 0.05 Gy. It was argued. therefore. that neutron
fractionation in the intermediate- and high-dose range
led to an increased incidence of tumours, or theirearlier appearance, or both.
319. Thompson et al. [T26] recently published new
additional data on life shortening induced by single
exposures of 86CF I female mice to fission neutrons indoses down to 0.01 Gy. They concluded that theassumption of a response proportional to og.s grossly
overestimated the life shortening induced by 0.010.03 Gy of neutrons and that the data up to 0 . 1 Gy ofneutrons were best fitted by a linear dose-response
relationship. The limiting value for the RBE fission
neutrons compared with gamma rays was in theregion of 12 to 16. depending upon the method used
to analyse the data. No consideration was given in anyof these publications to RBE values at low doses forfast neutrons as compared with the standard reference
radiation. i.e .. x rays of about 200 kVp.
320. In another experiment [S57], life shortening wasstudied in female BALB/c mice exposed to single
doses of fission neutrons (mean energy 1.3 MeV) or
given into two equal fractions at either J- or 30-day
intervals (whole-body doses from 0.02 to 2 Gy).
Protracted exposures from a 252Cf source were also
used at rates from J to 100 mGy per day (total 0.025
to 0.4 Gy). Life span was considerably shortened
between zero and 0.5 Gy for both single and fractionated exposures. and then a plateau ensued. The
data were fitted by a linear and a square-root model.
Both models adequately described the results below
0.4-0.5 Gy for single. fractionated and protracted
exposures. with the exception of a 30-day protraction
scheme where the square-root model could be rejected
and the linear one still provided a good fit. In contrast
with the observations in B6CF 1 mice, no increase ineffectiveness on life shortening was observed for
fractionation and protracted exposures to neutrons
below 0.5 Gy. Only at 0.5 and 2.0 Gy was a significantly
increased effect of fractionated doses observed.
321. Storer and Mitchell [S62] analysed publisheddata from the Oak Ridge and Argonne laboratories on
the shape of the dose-response curves for life shortening induced by single exposures to fission neutrons atdoses from 0.025 to 0.2 Gy and by fractionatedexposures resulting in total doses up to 0.8 Gy. The
response was found to be proportional to 0~·9 to DJ·0,
and not to the function 0~· 5• which does provide a
reasonable description of the dose-response curve at
higher neutron doses. The limiting RBE of fission
neutrons compared to gamma rays was found to be
18-29 if the response were proportional to 0~· 9 and to
be 13-22 in the equally likely event that the response
were proportional to 0~· 0• The range of RBE in bothcases was determined by the strain and sex of themice. Thus. the most recent publications [S62. T26]
suggest that a linear dose-response model rather thana square-root model is appropriate at low neutron
doses.

C.

SUMMARY AND CONCLUSIONS

322. On the assumption that cancer is initiated bylesions in the genome of a single and relatively
autonomous cell. the kinetics of induction of point
mutations and chromosomal aberrations. mostly symmetrical translocations, could perhaps throw somelight on the form of the dose-response relationship forcancer initiation. Studies of cell transformation invitro could also provide some information in thisrespect. These end-points cannot, however. provide
insight into other factors affecting tumour development at the tissue and systemic level: thus, therelevant conclusions must be regarded as over-simplifications of the real situation.
323. The dose-response relationship for point mutations induced by low-LET radiation in mouse maleand female mouse germ cells appears to be curvilinear(upward concave). It also appears to be greatly
dependent on dose fractionation and protraction as aresult, at least in part. of repair of primary damage at
the cellular level. At very low dose rates. linearity andindependence of dose rate have been observed. For
high-LET radiation the usual form of the curve islinear for all dose rates; fractionation and protraction
effects are marginal or absent. Under these conditions,linear extrapolation from high and intermediate dosesdelivered at high dose rates. down to low doses anddose rates, \vould over-estimate the mutation rate bysparsely-ionizing radiation. For high-LET radiation, alinear extrapolation provides an adequate estimate of
the risk.
324. The induction of somatic mutations in thestamen hair of the plant Tradescantia was studied
over a wide range of doses, dose rates and radiation
qualities. This system provides direct and extensive
information at very low doses of x and gamma rays
and of neutrons. The relevant dose-response relationships fit very well a linear-quadratic model for lowLET radiation and a linear model for neutrons.
325. Data on various other types of somatic mutations are also available in several established andearly-passage mammalian cell lines. For x- or gammaray doses delivered acutely, the observed dose-response
relationships are mostly curvilinear. with pronounced
fractionation effects in the few instances tested.
Exceptions showing linear responses (e.g.. humanfibroblasts) are also found, showing that the shape ofthe curves depends on the biological characteristics ofthe cells. High-LET particles induce mutations in a
linear proportion to dose. Sub-mutational damage isreadily reparable after low-LET radiation but not
after high-LET particles. Studies in several cell lines
show a simple inverse relationship between the induction of somatic mutations by low-LET radiation andthe logarithm of cell survival. This must imply thatlinearity of the observed response is accompanied bysimple exponential cell survival. Since for low-LET
radiation this is an exceptional finding in mammaliancells, the inverse relationship between survival andmutation must, as a rule, imply an upward concave
dose-response for induction of somatic mutations.
similar to that described for Tradescantia.

326. For low-LET radiation. data on chromosomal
exchanges in germinal and somatic cells are, almost
without exception, in agreement with a linear-quadraticmodel, both in respect of dose and of time-dose
relationships. For terminal deletions. linearity would,
in theory. be expected for all types and dose rates ofradiation. but curvilinearity is often seen in some cells(e.g., lymphocytes). This is attributed to the difficultyin distinguishing between terminal and interstitialdeletions that have linear and quadratic relationships,
respectively. with resulting curvilinearity of the response
for both types combined. For high-LET radiation the
response is linear and practically unaffected by dose
protraction or fractionation.
327. Much work has been done over the last few
years on radiation-induced oncogenic transformationin vitro of several established and some early-passage
mammalian cells. Numerous factors affect the observed
transformation frequency. These include: cell density
at irradiation and post-irradiation: cell-cycle stage;
time between seeding and exposure: phase of growth
at exposure; mitotic delay; and promoting and inhibiting agents. The experimental model appears to bemuch more complex than originally envisaged for cells
in culture, and cell-to-cell influences are found to bepresent.
328. Cells irradiated with a wide range of doses andtypes of radiation show dose-response curves thathave some features in common with those reported fortumour induction in animals. These are: an initial riseof the transformation frequency with dose up to a
maximum and an ensuing decline or plateau: a higher
transformation efficiency by high-LET radiation: anda decline of the transformation yield by low. as
opposed to high, dose rate of gamma rays in cells
irradiated in culture 40 hours or later after seeding.
An enhancement of the oncogenic transformation invitro by a reduction of dose rate of fission neutrons at
low and intermediate doses is similar to that which
has been described in some, but not all, experiments
on tumour induction (or life shortening) in animals.
329. However, several features of the single-cellstudies are at variance with animal studies. These aremostly for cells irradiated shortly after seeding: ashallow rise of the transformation rate over the range
of intermediate doses. with a power of dose less thanunity: an enhancing effect of low dose rate and dose
fractionation for low-LET radiation for a fractionation interval of about 5 hours at doses below 1.5 to
2.0 Gy, with reduced transformation at higher total
doses. These results most probably indicate a nonhomogeneous sensitivity to transformation of theirradiated cells. due to the non-random distribution ofcell-cycle stages in freshly seeded cells. If so. theywould not be representative of most situations in vivo.
330. The above results were sometimes interpreted to
imply that linear extrapolation to zero dose from thetransformation frequency at high doses could lead toan under-estimation of the effect at doses below
0.5 Gy, particularly for fractionated and protracted
exposures. For the time being, however. while taking
note of the complexities referred to above and of the219enhancing effect of fractionation, UN SC EAR does notencourage a direct projection of the in vitro data to
the situation in vivo. particularly when irradiation is
performed early after seeding. Further analysis ofvarious culture conditions, and a better understandingof the mechanisms of initiation, oncogenic transformation and progression in vitro, is required formeaningful extrapolations to tumour induction in
vivo. It appears likely that results obtained fromasynchronous cell cultures (i.e., those irradiated later
than about 40 hours after seeding) and those irradiatedin density-inhibited state may more adequately represent the situation in vivo.

331. New dose-response relationships for a variety oftumours generally support the conclusions reached in
the 1977 UNSCEAR report. the most important being
the specificity of the response for each tumour-hostsystem. The new experiments enlarge the data base,particularly at the lower end of the dose scale, down
to 150 mGy of gamma rays and to a few tens of mGy
for neutrons. They justify more specific statements
than hitherto possible about the form of some doseinduction relationships.
332. For sparsely-ionizing radiation, most curves are
upward concave and may be fitted by linear-quadraticor quadratic (leukaemia in CBA/H mice) models, but
in some cases approximate linearity may apply. This is
so with mammary fibroadenoma and carcinoma inSprague-Dawley, adenomas in WAG/Rij and carcinomas in AC rats. thymic lymphoma in RFM mice,and lung adenocarcinoma in BALB/c mice. Thymic
lymphomas in most mouse strains and tumours witha pronounced hormonal dependence (e.g., ovarian
tumours), show curves with pronounced thresholds.
They may reflect the role of non-stochastic mechanisms
in the development of these tumours, such as the needto inactivate a large proportion of hormonally-active
cells in the ovary. or to kill a large proportion of cells
in the thymus.

333. The incidence of the so-called reticulum cellsarcoma after whole-body irradiation usually declines·with increasing dose in several mouse strains. Animals
protected from early radiation death. by either bonemarrow transplantation or partial marrow shielding,show a very low incidence of this neoplasia. It has
been suggested that by relating the number of induced
tumours in these animals to the number of irradiatedmarrow stem cells at risk (assumed to be the targets
for tumour induction) it may be possible to estimate invivo the incidence of tumours per cell at risk. The x-ray
dose-response curves obtained under these assumptions
are curvilinear (upward concave).
334. Induction of skin cancer in rats and mice by
local low-LET irradiation requires high doses. The
dose-response relationships are therefore grossly
curvilinear (upwards concave) and apparent or real
thresholds cannot be excluded. Fractionation andprotraction of doses greatly reduces the carcinogenic
action of radiation in the skin of rodents.

335. Dose-rate studies with sparsely-ionizing radiation almost invariably show a decreased incidence220with decreasing dose rate. In some instances (lungadenoma in RFM and BALB/c mice and harderian or
pituitary tumours in RFM female mice), lowering thedose rate results in a more nearly linear dose-response
relationship in which the dose-squared component issubstantially reduced or abolished.

336. For neutrons. the ascending slopes of the doseresponse curves are closer to linearity than for gamma
rays. However, in some cases (lung adenoma in RFMmice). curvilinearity is suggested at low doses, eventhough linearity cannot be excluded. Factors such as adose-related latency may perhaps contribute to thiscurvilinearity. In other cases, neutron-induced tumours
rising with a power of dose Jess than unity have been
confirmed at low doses. The downward concave shape
may be accounted for by killing of potentially neoplastic
cells.
337. For most tumours, either no effect, or anenhancement of the tumour yield by a lower neutron
dose-rate or fractionation, has been documented. At
low and intermediate neutron doses, such effects are
Jess pronounced than for x rays. At high doses. anenhancement of tumour incidence bv fractionation or
protraction is often observed. but th~ overall picture is
not as simple as cellular data might imply. Factors
operating at the tissue level, or perhaps systemic
influences, could modify the final tumour appearance
to some extent.

338. Pulmonary carcinomas induced by low doses of
inhaled radon and of neutron irradiation show anessentially linear non-threshold relationship withcumulative exposure or dose. respectively. Highexposure rates of radon daughters at high total
exposures are, however, Jess efficient than low rates.
For neutrons also, the effectiveness per unit dose
decreases at high doses. These observations are in linewith results of epidemiological studies in miners
exposed to radon daughter products.
339. Analyses of the latent period of bone sarcoma
after incorporation of 226Ra and 90Sr in dogs and miceshow an inverse relationship between mean latent
period and mean dose rate to the skeleton. According
to these observations, there may be a practicalthreshold for these tumours. Under these circumstances
a linear extrapolation of the incidence race and of thelength of life lost per induced bone sarcoma down tozero, from values recorded at high doses. would surely
overestimate the risk at low doses. This also applies totumours induced by P-emitting bone seekers.
340. Studies of bone sarcoma induced by alphaemitting bone-seeking radionuclides. particularly 226 Ra.
support a linear activity-response relationship for
crude incidence. However. for 239pu, more refined
statistical analyses of data from dogs injected with thisnuclide, and observed for longer times, have shownthat a purely linear dose-response relationship between
integral tumour rate (cumulative hazard) and administered activity is highly unlikely. The same seems toapply to the relationship between dose rate to cells at
risk and tumour rate (hazard rate). The appearance ofa linear component in the curves cannot be excluded

in the follow-up of animals that are still alive but atpresent the dose-squared component is dominating.
341. The most recent data on radiation-induced life
shortening in mice suggest that a linear dose-responsemodel applies at low neutron doses, while at intermediate and high doses the response follows a squareroot function of the dose. Fractionation and protraction of the neutron dose increases the effect of life
shortening in some experiments. but not in others;
fractionation of low-LET radiation reduces the effect.
To the extent that life span shortening in irradiatedmice can be attributed to the induction of new
tumours, these conclusions may also be applicable toradiation carcinogenesis.

V.

DOSE-RESPO:'\SE RELATIONSHIPSFOR TUMOURS IN MAN

R4, R6] and a new dosimetry system (DS86) is being
installed at the Radiation Effects Research Foundationin Hiroshima as of March I 986. Preliminary estimates
based on somewhat more detailed analvs~s and thecurrent state of knowledge (for a prelim°inary review
see [877)) differ substantiallv from those of T65
dosimetry. It appears now tha"t the gamma-ray component had been under-estimated in Hiroshima bv afactor of 1.5 to more than 2. and the neut;oncomponent had been over-estimated bv a factor of
about 10 in Hiroshima and of about 2.5 in Nagasaki.
As a result, much of the information based on T65
dosimetry will have to be re-assessed upon completionof the ongoing dosimetric revision and will be
reviewed by UNSCEAR in the future. However. there
is no question as to the qualitative validity of thepreviously accumulated information about the effects
of age and sex upon the incidence of various neoplasms in atomic bomb survivors. The same applies tothe clinical and pathological forms of diseases and to
the distribution of their latent periods, which are
discussed here.

342. Data on the incidence of radiation-induced
human cancer, at different levels of dose, may be tested
for consistency with various models in two ways:
directly or indirectly.
343. Indirect inferences may be drawn from limited
comparisons in the few instances where risk coefficents(FT,\ or FTA) are available at two ends of the scale:high and low doses (total or per fraction). Risk
coefficient which are not substantially different undersuch circumstances will be taken to be consistent witha linear-quadratic or a linear model, because in mostcases the variability of data precludes a clear distinction between the two models. Theoretically, for adose-squared model, an appreciable difference would
be expected between Fn, or FTA at low and intermediate doses, but examples of this kind ha\'e notbeen found for the types of cancers re\'iewcd.
344. In direct studies, attempts may be made to fit
various models to the epidemiological data O\'er awide range of doses. There are often shortcomings tothese data (dosimetric uncertainties, a narrow range ofdoses, pre-selection of groups. ill-defined controls,possible influence of confounding variables. errors ofsampling) and consistency with a model rarely, if ever,excludes a fit to alternative models. Thus. consistencyof a set of data with a gi\'en model should not betaken as evidence that only that model provides anadequate description.
345. Much information on dose-response relationships for radiation-induced malignancies (e.g., leukaemia, cancer of the breast) has been derived in thepast from the follow-up of atomic bomb survivors at
Hiroshima and Nagasaki. These cohorts represent thestatistically most powerful set of data available fordose-response studies, because of the great number of
person-years at risk. the wide range of doses, and therelative lack of selection of the samples.
346. The dose-response data in these groups werebased on the so-called T65 dosimetry. Since 1980 thisdosimetry has been under revision [K34, L27, L30,

(a)

A.

LEUKAEMIA

I.

Direct studies

Leukaemia in aromic bomb sun>ivors

347. From the information collected in the Life Span
Study Sample it appears that the age at time ofirradiation had a pronounced effect on the magnitudeof the risk when expressed in absolute and relati\'eterms. The effects of sex differences were also discussed in the 1977 UNSCEAR report [U6]. The ageadjusted leukaemia mortality rates reveal that therisk of leukaemia (all types) in males is significantly
higher than in females. For both cities combined. themale : female ratio is 1.36. 2.86 and 1.56 for the TD65
kerma categories of 0-0.09. 0.1-0.99 and> I Gy.
respectively. The distribution of cases in time variedwith the type of leukaemia and with age. as shown
schematically in Figure XXIV [01).

(b)

Leukaemia in x-ray treated spondylitics

348. Smith and Doll [S49) studied mortality through1970 in 14, l l I ankylosing spondilitis patients givena single course of irradiation during the period
1935-1954. Of these patients. 98.5% were traced totheir death, to the date of emigration from the United
Kingdom. to the closing date of follow-up (I January1970) or to the end of a vear after a second treatment.
whichever was the eariiest. The average period of
follow-up of those with one course of treatment was
16.2 years. Causes of death were obtained from deathcertificates.
349. The number of expected deaths in the cohorts
were calculated from age- and sex-specific mortality
rates for England and Wales in the respective calendar
five-year intervals. An analysis of mortality revealed
that the number of deaths was 66% more than221

ALL FORMS OF LEUKAEMIA.....

__ ......

--0

ACUTE LEUKAEMIAAGE ATB--- ------- ----

A - < 15
B - 15-29
C - 30-34
D - > 45
E - > 30------0

5

10

20

15

25

CHRONIC GRANULOCYTIC LEUKAEMIA

0

5

10

20

15

25

YEARS AFTER EXPOSURE
Figure XXIV. Schematic model of the Influence of age et the time of the bombing (ATB) end
calender time on the leukeemogenic effect of radiation (heavily exposed survivors).

[01]

expected in the patients ( 1759 versus 1062 expected).
The total excess of leukaemia, as well as that forneoplasms. was highly significant (p < 0.001), and did
not differ among males and females (the latter madeup only one-sixth of the population).
350. The only malignancies for which the doseresponse relationship has been studied were leukaemias.
The excess death rate was high. the overall observed/
expected (0/E) ratio being 4. 79 (3.06 and 5. 10 inwomen and men, respectively). The time trends werecharacteristic. with the death rate rising even at
2 years after the first irradiation, peaking at 3 to
5 years, and declining to the control level more than
20 years after treatment. Chronic lymphatic leukaemia
was apparently not increased by the treatment. The
relative risk of leukaemia (0/E ratios) was equally
increased in all age groups (age at first treatment). The
excess risk coefficient per 10 5 person-years rose from251, in those younger than 25 years, to 1366 inpatients treated at more than 55 years of age. In thisinstance the radiation-induced leukaemia incidence
increased temporarily in proportion to the age-specificspontaneous incidence {at age of exposure). as represented schematically in Figure II. c and d.
222

351. As the distribution of local absorbed and meandoses to the bone marrow among all patients is
unknown, it had to be reconstructed through an
extensive phantom study in all patients who died withleukaemia and in a sample of all followed-up patients.
The doses ranged from 0.5 to 7 Gy, with a rather
uniform distribution of frequency. involving 90% ofcases below 5 Gy. The proportion of cases above
6.5 Gy did not exceed 2%. The mean marrow dosewas 2.49 Gy.
352. The excess leukaemia mortality rate, plottedversus the mean dose to the marrow is very erratic.
and a zero response (independence of mortality rateon dose) may not be excluded on purely statisticalgrounds. However, due to the time characteristics ofthe mortality, and to the fact that no increase ofleukaemia mortality was seen in non-irradiated spondylitics [R33], the non-zero effect at zero dose wasdiscarded as very unlikelv. Three models, a linear. a
linear with cell killing, and a quadratic with cell killingwere fitted to the data by the method of maximum
likelihood. Such a method is not formally correct for
the last model because simple averaging of organ
doses when a large fraction of marrow was unexposed,must lead to erroneous results when a dose-squared
dependence of initiation of the cells is assumed. The
first model could be discarded (P < 0.03). and the fit
obtained for the second was satisfactory (P = 0.28).

UNSCEAR report [U6] new information has become
available [TI 2, T23] and several attempts have been
made to fit cancer induction models to the relevant
epidemiological observations [B24, B25. Ll, L22].

353. The coefficient of the linear slope in the second
model gave a risk coefficient in accordance with mostother estimates of leukaemia risk. However, owing to
the erratic character of the dose-response, this value
must be taken with caution. The cell-killing term
cannot be taken in its usual meaning of mean lethal
dose. because absorbed doses to the irradiated fractionof the marrow were 2.5 times higher than the mean.
Moreover, the fractionated treatment allowed sublethal repair and cellular repopulation to occur.

357. Dosimetric estimates were retrospective in all
studies. The uncertainties were particularly great in
the Nova Scotia Fluoroscopy Study [M39. M40],
where subjective judgement made assessment of thelikely confidence limits unfeasible [B20. B25]. This
study, therefore, should not be used for discussion of
consistency with dose-response models. The Swedish
radiotherapy study [B4] is also limited by the absenceof an appropriate control group and by a possible
association between fibroadenomatosis or chronic
mastitis and increased cancer risk. The following
discussion. therefore. is based principally on studies ofthree series: atomic bomb survivors (tentative). theMassachusetts fluoroscopy study, and the Rochester
mastitis patients.

2.

Indirect evidence

354. The risk of leukaemia was studied in radiologists exposed to x and gamma rays either at low
dose rates or at higher rates. but in small fractions,accumulated over decades [M7. S8]. The risk wassignificantly elevated. The records of mortality of the
1920-1927 cohort followed for 50 years showedexcesses of 390 and 170 deaths per 10 6 person-years at
risk due to leukaemia and to aplastic anaemia,
respectively. Calculation of risk per unit dose to themarrow is affected by great uncertainty about thedoses accumulated. The diagnoses are also very
uncertain. The BEIR Committee [B20] estimated thelikely average value to be about 6 Gy, with a resulting
annual risk coefficient of 70 leukaemia deaths per
10 6 Gy- 1 a-1. This value is not significantly different
from estimates for low dose and dose rate derived by
UNSCEAR in annex G of its 1977 report [U6] fromstudies on other acutely-irradiated groups (spondylitics, females irradiated for induction of menopause,or other benign conditions) given doses and/or
fractions above I Gy. If the above estimates of dosewere in error in either direction by a factor of 2-3, thederived risk would still appear similar to that deduced
from studies on acute irradiation, and therefore
consistent with the linear or linear-quadratic model of
induction of leukaemia.
355. In conclusion. therefore, it may be assumed, on
the basis of the present fragmentary information, thatthe dose-response relationship for leukaemia after
acute low-LET irradiation is likely to follow a linearquadratic model.
B.

CANCER OF THE BREAST

356. The female breast is one of the most sensitive
organs for cancer induction by ionizing radiation[B20, I I, M28, U6]. The data reviewed in annex G of
the 1977 UNSCEAR report [U6] have been given either
in terms of mortality or morbidity, but the latter
category will preferentially be discussed here. Epidemiological data relate to three categories of exposure:atomic bomb explosions, therapeutic irradiation for
benign conditions (e.g .. mastitis). and tuberculosis
patients undergoing multiple fluoroscopies for pneumothorax or pneumoperitoneum. Since the 1977

358. Several factors could affect the results of suchstudies. if not appropriately accounted for. These
would mostly be age at irradiation, age at manifestation of the effect, length of the latent period, durationof the period at risk, and relationship between latency
and dose.
359. Age at exposure is a major determinant of thebreast cancer risk. The three studies cited provide
strong evidence of cancer induction in females exposed
below age 30, with girls of 10-19 years having thegreatest absolute risk. The coefficient of the relativerisk increment was already highest in the lowest age
bracket (0-9 years) at the time of the bombing, but theabsolute attributable risk coefficient for this age waslower by a factor of 2 when compared with that for
the next age bracket. i.e., 10-19 years. The absoluteand relative risk coefficients for ages 20-39 years
remain approximately constant [T23]. The fluoroscopy
data are scarce for ages 40-49 years. and absent for
older ages at irradiation. The atomic bomb survivors
showed no significantly elevated cancer incidence
when exposed at ages higher than 40. On the otherhand. the Swedish radiotherapy data [B4] imply aradiation risk at all age groups. including 40-49 andgreater than 50 years, but statistically the estimates atolder ages are uncertain. The possibility that concomitant ovary irradiation in atomic bomb survivors at,or close to, menopause might have been responsible
for this protective effect (due to sterilization) was
suggested by Boice et al. [B25] and Kato and Schull[K39], but this explanation must remain hypothetical.
It has more recently been suggested [T23] thatdifferences in the distribution of the risk at ages above
40 parallel the age-specific incidence of mammary
cancer in the various countries (Japan, United Statesof America, Sweden). Taken together. the data showthat the risk is highest when the hormonal action
affecting the gland is most intense [T23]. It should be
mentioned, however. that the follow-up of the younger
age cohorts is still incomplete.
360. The increased incidence becomes manifest in allgroups at ages above 30 and particularly at the ages ofhighest natural incidence rate of the disease. This223

observation calls for the use of age-corrected incidencesin the exposed and control groups. The so-called
minimum latent period can be estimated approximatelyfrom all observations [B25], but pitfalls of such
estimates have been discussed in chapter I. In the
Massachusetts, Nova Scotia and Canadian fluoroscopy
series, no excess of breast cancer could be seen for the
first 10 years after exposure. In atomic bomb survivors, and in the Swedish radiotherapy patients, theincreased risk-particularly in those irradiated at ages
above 30 years-could be seen even at 5-9 years after
irradiation. Thus, it appears that in younger women(under 30 years) the minimum latent period is perhaps
close to 10-15 years, and still longer in irradiatedchildren, whereas in the older women it may be
shorter (about 5 years). This observation is important
for the selection of a period at risk in calculations of
the excess incidence. All studies [B26. Sl6. TI2. T23]
show a continuing excess cancer incidence up tofollow-up times of 30-45 years in women older than
30 years at exposure. There is, as yet. no indication ofa decreasing risk even at the longest follow-up of
45 years. There also appears to be no relationship oflatency to dose [L32].

1.

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DOSE (Gy}Figure XXV.

362. The possible effects of fractionating the dosewere analysed •.vithin a range of total doses below
3.5 Gy. The analysis compared breasts receiving one
or two treatments (mean dose = 1.9 Gy) with three ormore treatments (mostly 3-4. mean dose = 2.86 Gy).

I

(8.5)

a:

Radiotherapy for mastitis

361. The Rochester study on women treated formastitis [S 16] was reviewed in detail in annex G of the
1977 UJ\SCEAR report [U6]. Only those aspects
dealing with the shape of the dose-response relationship are discussed here. By dividing the irradiatedgroup into five dose sub-groups, a dose-response
relationship was obtained which was controlled forage and for interval since entry into the study, bymeans of the Mantel combination 1 2 technique, andby test of linear and quadratic trend. The interval atrisk for the irradiated group was from 10 to 34 years
after exposure. In a first analysis, the average dose toboth breasts was used as the independent variable: thedata are presented in Figure XXV. The difference
between controls and irradiated women was significant(p = 0.0 I) and the linear trend 7. 2 test for association
with dose was highly significant (P = 0.0006). The
incidence increased linearly up to about 4 Gy, andthen dropped al higher doses. No significant quadratic
trend with a coefficient greater than zero occurred.
The second analysis was based on doses to single
breasts. The relative risk for the period I 0-34 years
after irradiation was highly significant (P < 0.0001),
and amounted to 3.3 when controlled for age andinterval since entry into the study. The results in termsof relative risk are presented in Table 1. together withresults of the first analysis. Significance was obtained
for the linear gradient (P < 0.000 I) and for a quadratic effect with a negative coefficient (P = 0.0003).
The latter reflects a decreased carcinogenic effectabove 4 Gy. owing perhaps to cell killing or otherinfluences.

224

(8.0)

Breast cancer Incidence rate as a function of theaverage dose to both breasts in mastitis patients for the Interval
10-34 years after Irradiation. Error bars represent 800/oconfldenceIntervals. Numbers in parentheses are breast cancer cases ineach dose group.

[S16]

Single. non-irradiated breasts served as controls. For arisk interval of 10-34 years post-irradiation, theadjusted coefficient of the absolute (attributable) riskof breast cancer was 910 10-6 Gy- 1 a- 1 per breast in
the 1-2 fraction group, as compared with I 120
10- 6 Gy- 1 a-1 per breast in the 3-4 fraction group.
Thus, fractionation did not appear to reduce the
carcinogenic effect. although the validity of thecomparison is limited by the difference between meandoses in the two subgroups.
363. The annual absolute risk coefficient during theperiod, using the average dose to both breasts, andage- and interval-adjusted incidence rates (irradiatedadjusted to controls), was calculated as 830 10- 6 Gy- 1
a- 1• For irradiation of a single breast, the age- andinterval-adjusted estimate of the coefficient amounted
to 496 10- 6 Gy- 1 a- 1. If this figure is doubled for thetwo breasts. it is consistent with the average for twobreasts given above.

2.

Pneumotherapy patients

364. The Nova Scotia series on breast cancer induction by repeated fluoroscopies [Ml, M39. M40]
showed that repeated low doses of diagnostic x rays,
when delivered to the gland in sufficient amounts, led
to an increased risk of tumours. The doses wereestimated retrospectively, but the margin of uncertainty
was so large [B20. B25] that detailed discussion of thelikely shape of the dose-response relationship isdifficult. However, the fact that the risk estimate wassimilar to that derived from other studies suggests
additivity of the effect and thus approximate linearityof the dose-response relationships.
365. A follow-up study of Boice and Manson [B26]on female tuberculosis patients has been discussed
already in annex G of the l 977 UNSCEAR report[U6]. The methodology of estimating the radiationdose to the breasts was described in detail in a
separate report [B24] and warrants some discussion
because it is critical for the assessment of the doseresponse relationship. The data on the number offluoroscopies were abstracted from the medical records
and checked by interview. It was estimated that 63%of the patients faced the physician during the fluoroscopic examination, 16% faced the x-ray tube, 21 %had variable positions. and 12% reported being
rotated during examination.
366. Out of the 15 former tuberculosis physicians
interviewed. 29% reported that they examined theirpatients with breasts directed to the x ray tube. Sixtynine per cent conducted the fluoroscopy with thebeam-shutters wide open and 81 % always scanned the
opposite lung. The average time of examination wasgiven as 15 s (3 to 60); 70-80 kVp and 5 mA were theusual parameters of x-ray machines employed: andI mm Al filtration was added in 1948.
367. Exposure measurements were made on three
representative types offluoroscopy units. and exposure
rates were determined at the fluoroscope panel. Halfvalue layers for a range of tube voltages and added
filtrations were also checked. The exposure measurements were translated into average conditions before
and after 1948. Based on these data, estimates weremade of absorbed dose in the breast, by means of aMonte Carlo radiation transport method in relation toan anthropomorphic phantom. The shape of the breast
was geometrically simulated, separately for an adult andfor an adolescent breast. A typical elementary composi·tion of the gland was assumed. The absorbed dose in
the breast per I R skin exposure (free in air) was
calculated for selected exposure conditions: 2 beam
qualities, 2 patient orientations. 2 breast sizes and4 field sizes. These calculations were approximately inagreement with TL dosimetry in a phantom.
368. Cumulative breast doses of all fluoroscoped
patients were calculated from all the above information (medical records. physician interviews. patient
contacts, exposure measurements and absorbed dose
calculations). Females under 17 years of age wereassigned doses for the adolescent breasts and the older
ones doses for adult breasts. Individual orientations
could not be determined and it was assumed that 25%of all examinations were performed in the anteroposterior position. and both breasts were assumed to
be in the unshuttered beam 81 % of the time while
fluoroscoping a unilateral lung collapse, and 19% of
exposure time was assigned to the ipsi-lateral breast.
Average doses were computed by adding the dose

received by the directly exposed breast and the scatter
dose received by the opposite breast, and dividing
by 2. In a few cases of bilateral lung collapse, bothbreasts were assumed to be in the beam for 100% of
the time.
369. Uncertainties affecting dose estimates based onso many variables, sometimes estimated from memoryof 20 to 45 years previously. must be affected byconsiderable errors and should therefore be taken withgreat caution. It is very difficult to say whether
average breast doses calculated by Boice et al. [B24,
B26] are representative of the the real situation andwhat might be the systematic errors involved. However, the shape of the dose-response relationshipshould perhaps not be affected by a systematic overor under-estimate of the real dose.
370. For the exposed women, the onset of the periodof risk for breast cancer development was assumed tobe the date of the first fluoroscopic examination, and,for the non-irradiated controls. the date of admission
to the sanatorium. Expected breast cancer cases were
determined with the use of the age- and calendarspecific incidence rate for the neighbouring state ofConnecticut, where a cancer registry has been in
existence since 1935. The number of expected breast
cancers in the exposed group was calculated bymultiplying the age- and calendar-specific womenyears (WY) at risk by the corresponding incidence
rates in Connecticut. Standard morbidity ratios andabsolute risk coefficients were calculated. The end of
the period at risk was regarded as: the date of cancer
diagnosis: or the date of death from another cause: or
I July 1975 for those found alive; or the last date at
which the woman was known to be alive, for those
Jost from the follow-up.
371. The number of breast cancers found among theirradiated women was 41, as against 23.3 expected(excess significant: p = 0.0006). Among the controls.
15 cancers were found, against 14.1 expected. The
observed/expected ratios were. correspondingly. 1.76
and 1.06. The absolute excess risk increased withincreasing numbers of fluoroscopies up to 100-149:
a decrease after a greater number was suggested.
Nevertheless, a linear increase could not be excluded[x 2 (trend) = 4.1. P = 0.04; x2 (departure from linearity)= 6.9. P = 0.14].
372. When the incidence rate was calculated as afunction of the average dose to the breast, the results
were as shown in Figure XXVI. The average dose to
the breast per examination was estimated to be
0.015 Gy, and the mean cumulative dose to the breast
amounted to 1.5 Gy [B24]. No decrease in the excess
incidence per unit dose was apparent at doses above
4 Gy (the highest average was 5.74 Gy) and the doseresponse was consistent with linearity down to thelowest dose group (0.32 Gy average) [x 2 (trend) = 9.4.
P = 0.220: x2 (departure from linearity)= 1.6, P = 0.8].
Some differences between the relationships for doseand for number of fluoroscopies resulted from fluoroscopic examinations in different positions of thepatients. in different periods. at various ages and for
different sizes of the breast.
225

(x 10· 5 )
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BREAST DOSE (Gy)Figure XXVI. Standardized incidence rate ol breast cancer influoroscoped pneumothorax patients per 100,000 women-years(WY) at risk, as a !unction of estimated cumulative breast
doses. Error bars represent 80% confidence limits.
[B24]

373. The breast cancer risk appeared after 15 years.
and the excess risk was present for at least 40 years
after initial exposure. The average age at cancer
diagnosis was 48.4 years (the greatest risk appeared
among women aged 40-49 years at diagnosis) and themean latent period from exposure to diagnosis was
24.4 years. The radiation risk coefficient derived fromsubjects of this study living 10 or more years after the
first exposure was 620 excess cases per 10 6 womenyear and Gy (280- I070 are the 90% Poisson confidence
limits).
374. In 1980 Land et al. [L22] reported a comparative
study fitting the same set of models to mammary
cancer incidence data from 3 main studies: atomic
bomb survivors, Rochester mastitis and Massachusetts
fluoroscopy series. They assumed that the level ofbreast cancer response to irradiation may depend on
age at exposure. To avoid confounding of dose andage. the dose-specific data were age-standardizedusing the overall age distribution of each series as aninternal standard. It was assumed that the shape ofthe dose-response curve was not dependent on age.
Linear, linear-quadratic and quadratic models, with orwithout a cell-killing term. were fitted to the data. The
linear component was omitted from the killing term as
it did not improve the statistical fit. but increased thestatistical uncertainty in other parameters. This procedure is, however, biologically implausible. Anotherconstraint was that no parameters should be negative.
375. The model assumed that the control incidence
rate, a 0 , was equally affected by presumptive cellsterilization. implying that all transformed or potentially transformed cells from which cancers would
later develop were already present at the time of
exposure. This unproved assumption requires that
latent periods for spontaneous and radiation-induced
breast cancers should be the same, or longer for theformer. and is in fact supported by the apparent lackof dependence of the latent period on dose, as shownby Land et al. [L32].
226

376. The results of the above fits are presented inTables 2 and 3. according to the notation in equations(3.6) and (3. 7). For the Massachusetts series, parametric constraints reduced the linear+ killing model
to linear, and the linear-quadratic + killing model tolinear-quadratic. For the Rochester series, the linearquadratic model was reduced to linear. For the mastitis
series, accounting for cell killing improved the fit
significantly (Table 3). Better results were obtained inthis respect when single-breast data were used from themastitis series. where the linear+ killing model gave asubstantially improved fit (P =0.27) over the linear
model (P = 0.012). This suggests that cell killingat 4-14 Gy may be a real effect in unfractionated or
relatively unfractionated exposures. The quadratic
and quadratic+ killing models did not fit the agestandardized data as well as did the models with thelinear term a 1D. The results show that low-dose risk
estimates for breast cancer induction should be basedon models with a pronounced linear term. The values
for the a I term are very close in the series, particularly
when differences in age distribution are considered.
377. When age-standardized percentage incidenceswere plotted in exposed and unexposed women of thethree cohorts against time after irradiation, in nogroup was there evidence of an acceleration of breast
cancer expression with dose. This result emphasizes
two points: that expression of radiation-induced breast
cancer may be influenced by the same physiologicalfactors that affect the normal age-specific incidence
rate of this tumour; and that an inverse relationshipbetween dose and latency is highly unlikely for thisneoplasm (see also [K39 and L32]).

C.

TUMOURS OF THE THYROID
1.

Direct studies

378. In their most recent published report. Shore etal. [S60) updated the follow-up to 1977 and reinvestigated several aspects of thyroid cancer induction by
x rays in a series of subjects irradiated .in childhood
for alleged thymus enlargement [HI 8. HI 9, S38]. The
subjects studied included 2856 irradiated and 5053
controls; 2652 and 4823, respectively, were followed
for five or more years after the treatment (on the
average. for 30 years).
379. Irradiation was performed with x-ray machines
operating at various parameters of voltage and filtrations that were probably not very critical for assessment of the dose to the thyroid (in all cases, the skindose was very close to the absorbed dose in the gland).
The important factor was whether the gland wasinside or outside the primary beam. Individual dose
estimates were made on this basis, with other corrections. For 241 subjects, such estimate proved impossible,
and they were excluded from studies involving analyses
with dose.
380. Siblings of the irradiated subjects were theprimary control, but comparisons were made alsowith cancer rates in upstate New York. The subjects
were located by various means. and a questionnairewas used to identify health problems, including
tumours. Responses were obtained from 88% of thesubjects. Only medically verified neoplasms were usedin further considerations, and pathology reports wereobtained for all cancers and about three-fourths of thenodules (which were benign). From the total personyears, five years were subtracted in each subject as thelikely shortest latent period.
381. There were only small differences in someparameters characterizing the two groups. A large
excess of thyroid cancer (P< 0.0001) was diagnosed in
the irradiated groups (30 cases of various histologicalforms). and only 1 case in the controls ( 1.43 expected).
The relative risk for the carcinomas. adjusted for sex,ethnicity and post-irradiation interval, was 49.1 (90%confidence limits 10.7-225) (p < 0.0001) when related
to controls, or 44.6 (32.1-60.6) when related to the ratein the general population. There was also an excess of
adenomas: 59 among irradiated against 8 among thecontrols (adjusted RR= 15 (90% confidence limits
8.1-27.7) (p < 0.0001). A separate comparison of caseswith matched controls yielded similar odd ratios and pvalues for cancer as given above. but a somewhat
lower estimate of relative risk for adenomas.
382. Doses in the thyroid ranged from 0.05 to 11 Gy.
with a weighted average of 1.38 Gy and 62% of
individual doses below 0.5 Gy. An absolute risk
analysis of the dose-response relation (Figure XXVII)(x 10- 5 )
(368)

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385. In conclusion, these data. derived from a cohort
irradiated in infancy. show a dose-response relationship with a strong contribution of the linear terms,
lack of demonstrable dose-squared terms. and lack of
dose-fractionation effects. A paradox was also noted.
in that irradiation seemed to multiply the sex-specific"spontaneous·· risk. while, at the same time, theresults fitted an absolute, but not a relative, risk
projection model.

u

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383. For adenomas. the risk expressed in absoluteterms yielded a linear dose-response with a coefficientof 5.7 (± 1.2 S.E.) 10- 4 Gy-1 a-1 (7.7 for males and3.6 for females) significant at P < 0.0000 I. In a linearquadratic fit. the linear coefficient was 3.8 (± 1.4)
10- 4 Gy-l a- 1; that for the quadratic term was
negative, -0.04 (± 0.004) 10- 4 Gy- 2 a- 1. and therelationship was downward concave. A strong linear
component (P< 0.00001) and a significant quadraticcomponent (P < 0.0 l) with a negative coefficient. wereobtained for the risk expressed in relative terms. A
simple linear regression yielded a relative increment
coefficient of 0.0044% of the control frequency per Gy.
384. Of 2358 subjects with doses below 6 Gy. 5 I%
were irradiated once, 39% twice and in 10% of cases
the dose was split into 3 to 11 fractions. No influenceof the dose per fraction, number of fractions andinterval between fractions was found for carcinomas
or adenomas. Tumour appearance as a function oftime seemed to decrease slightly beyond 25 years postirradiation. but still after 40 years there were excess
tumours. The data were not a good fit to the relativerisk projection model. but an adequate fit was
obtained to the absolute risk model. The latent
periods of thyroid carcinomas and adenomas did notshow any relationship with the dose.

u.J

u
z

was undertaken with 6 and 12 dose categories,
controlling for sex, ethnicity, and interval since
irradiation. A linear regression (Mantel regression
coefficient) yielded a coefficient of 3.46 (± 0.82 S.E.)
10- 4 Gy- I a- 1 (P < 0.000 I) (5.25 and 2.05 for females
and males. separately). Fitting the data to a linearquadratic model, by iteratively weighted least square
regression analysis, resulted in a highly significant
linear term (P < 0.0001) and a non-significant dosesquared term (P > 0.4). When the so-called ridge
regression analysis was applied, the linear term retained
its predictive power, but the quadratic term waseven farther removed from significance. The Cox
regression analysis used for calculation of RR-model
coefficients yielded for cancer a strong linear component (P < 0.0000 I) and an insignificant quadraticone (P = 0.08). The value of the relative increment
coefficient was 0.0058% of the control frequency
per Gy.

so

0
0

2

4

6

8

THYROID DOSE (Gy)Figure XXVII. Thyroid cancer Incidence per person year (PY)
as a function of the radiation dose In the thyroid. Rates
adjusted for sex, ethnicity and Interval after Irradiation. Error
bars represent 90% confidence limits.
[S60]

2.

Indirect evidence

386. Among the studies on thyroid cancer reviewed
in annex G of the I 977 UNSCEAR report [U6] none
seems to qualify for the derivation of the doseresponse relationship or for testing of various models.
However, when the risk coefficients for irradiated227children are considered (see Table 10 in annex G of
the same report) they seem to fall within a rather close
range, although the average estimates of dose for eachgroup vary from 0.065 to about JO Gy. This would
suggest a dose-response relationship close to linearity,
a suggestion that must be taken with caution owing to
the great uncertainties in retrospective dose estimatesin all studies, and lO the genetic, demographic andgeographic differences between the series.
387. Modan [M25], and later Ron and Modan [R29,R45], followed up children irradiated for tinea capitis
in their childhood. The last paper in the series [R45]summarizes the results for the follow-up period
1950-1978. All individuals were irradiated between 1948
and 1960 at an average age of 7. The majority (96%)
were treated between I and 15 years. and over 50%
between 3 and 8 years. Only 6% were irradiated morethan once.
388. The final cohort study included 10,842 irradiatedpersons (IS) and 10.842 non-irradiated tinea-freesubjects matched for age, sex, country of origin andyear of immigration to Israel (PC). A second control
group was composed of 5400 siblings (SC), nonirradiated and tinea-free. All groups were· equallydivided by sex. By the end of 1978. the threegroups had accumulated 244.909, 245.435 and
121,854 person-years at risk, respectively. The averagefollow-up interval was 22.8 years. The dose to thethyroid was estimated to range from 0.043 to 0.16 Gy.
with a mean of 0.096 Gy.

391. In summary, therefore, a similar value of FTA
for thyroid cancers in a cohort of children who
received a thyroid dose of about 0.1 Gy, and inanother cohort with doses ranging from 0.17 to
7.5 Gy. strongly supports the conclusion that thedose-response relationship for thyroid cancer may beessentially linear. Concurrent irradiation of the hypophysis with higher doses (of the order of 0.5 Gy) has
been suggested as a possible explanation for thisunique observation. However, only an increased secretion of thyroid stimulating hormone (TSH) would be
expected to enhance the risk of thyroid carcinoma,
while irradiation of the hypophysis would be expected
to result in a decreased secretion. Data from anexperiment aiming at answering this question are also
in conflict with the explanation referred to above[L29]. A smaller group of2213 children [S36] irradiatedto induce epilation did not produce an excess of
thyroid cancer. However. because of the low statisticalpower of the study, this result is consistent with
reported values of FTA·
392. Holm [H 17] published a retrospective study on
patients given 13 11 for diagnosis of thyroid diseases in
the Stockholm area in 1952-1965. The populationconsisted of 10.133 persons, of average age 44 years,
followed for an average period of 18 years afteradministration of the nuclide. Of these, 95% received
131
1 when 20 years or older (2086 males and 8047
females). The diagnostic tests were administered forsuspected thyroid tumour (32%): hyperthyroidism(44%); hypothyroidism (16%); or other reasons (8%).
Thus. from the viewpoint of thyroid physiology
and/or pathology. the population studied was aselected one. Persons with cancers diagnosed within 5
years of administration of l3IJ were excluded from thestudy as were those given any therapeutic irradiation of
the thorax, head and neck.

389. The follov.ing numbers of cancers were foundin the three groups: IS, 29: PC, 6: SC. 2. They wereascertained from the Israel Cancer Registry with anefficiency of recovery of about 80%. The relative riskof thyroid cancer, estimated by using the MantelHaenszel method for cumulative data. amounted forthe whole group to 5.4 (95% confidence interval 2. 710.8). The absolute risk may be estimated betweeen 12
and 14 10- 4 Gy- 1 a- 1, depending upon the efficiency
of detection assumed ( 100 or 80%. respectively). There
was a clear influence of sex upon the incidence. therelative risk and absolute risk ratios females:males
being 1.2 and 3.8, respectively. Subjects in the age
bracket 0-5 years were twice as sensitive as those in
the 9-15 years group. A significant ethnic difference
was also seen because the children of Moroccan andTunisian origin (contributing about one-half of thetotal) had an absolute risk twice as high, and a relativerisk 6-9 times higher than the rest of the cohort.

393. The mean activity administered was 2.2 MBq,
and doses to the thyroid were calculated on the basis of ameasured retention of about 40% at 24 hours afteradministration. The assumed mean effective half-lifeof 131 I was 7 days and the mass of the thyroid wasestimated in a representative sample (about 10%) of
the population under study from scintigraphic measurements and palpation. In persons above 20 years, themean weight of the thyroid was 50 ± 33 (S.D.) g, andin those below 20. JO± 5 g. The resulting mean doses
were 0.58 and 1.59 Gy. The population average(adjusted for age) was 0.62 Gy.

390. The FTA from this study is about 3-4 times
higher than that derived by Shore et al. [S60] for acohort with an average dose of 1.38 Gy. This however,does not indicate that the risk is truly higher at thelower dose of about 0.1 Gy, because the tinea capitis
sample is composed entirely of people of Jewish
origin. From the results of Shore et al. [S38]. it
follows that this factor alone could account for a twofold difference. and the contribution of individuals of
Moroccan and Tunisian origin may have added
another factor of 2. Any systematic bias in dose
estimates due to inadvertent movements of children
during irradiation would have resulted in higher, andnot lower, doses to the thyroid.

394. The expected number of thyroid carcinomas
was computed from country-average age. sex andcalendar-year specific rates derived from the Swedish
Cancer Registry statistics. The assumed period at risk
was the period of follow-up since administration of131
I minus 5 or minus I O years. In the first case, thenumber of expected cancers was 8.3. in the second 5.9.
The Swedish Cancer Registry was searched for names
and identity code numbers of all the patients enrolled
in the study. Nine cancer diagnoses among them wereidentified and 8 confirmed. Thus, there was no excess
cancer among the subjects given diagnostic amountsof 131 I.

228

395. Holm et al. [HI 7) compared the number ofcancers diagnosed with estimated numbers calculated
from UNSCEA R risk coefficients of 5000-15,000 cases
10- 6 Gy-l [U6) (derived predominantly from surveys
on children) or from Hiroshima and Nagasaki surveys[U6] of 1400 10- 6 Gy- 1• In the first case, the numberof expected cancers would be 47-124. which is
obviously very different from the observed 9 cases.
For the second alternative, the authors quote a figureof 19 cases. which they claim to be not significantly
different from the 9 cancers diagnosed.
396. However, when the lack of the excess incidence
in that study was compared [N JO] with the expectation in adults, taking the risk for adults to be one-halfthat in children [S60). to account for the age-related
lower sensitivity. the difference appeared statisticallysignificant on two tests applied. This would suggestthat the effectiveness of 131 I for induction of thyroid
carcinomas is lower, at least by a factor of 2. The
question whether this is a true dose-rate effect, and towhat extent other factors play a role, cannot beanswered at present.
397. Several factors, separately or in combination,
could be responsible for the difference between thepredicted and the observed numbers of cancers. First,
the linearity of the dose-response relationship in
Figure XXVII may be more apparent than real,
because the positive dose-squared term for initiationand the negative term for cell killing may compensate
each other. Secondly, the subjects are a selectedunhealthy population. with a high percentage ofthyroid involvement, to whom specific rates of thyroid
cancer induction. valid in the general population, may
not apply. Thirdly, the treatment given after the
diagnosis (surgery. thyroid hormones) could havesuppressed the risk. This appears rather unlikely, as
more than half the patients were not given any
treatment and the nine with diagnosed cancers weretreated \\ith hormones (2 cases) and surgery (4 cases).
which did not prevent the manifestation of tumours.
Fourthlv. a non-uniformitv of dose distribution from131 1 in p~thologically enlarged glands could be anotherconfounding factor. Fifth. it cannot be excluded thatrisk coefficients are being compared for populations
which may differ in their average iodine uptake andhence in activity of the thyroid and hypophysis (TSH
stimulation). Finally. other dietary or environmentrelated factors could further confound the comparison.
398. In summary, two studies on humans [R45, S60]
argue persuasively that the contribution of the linear
term is very strong in the dose-response relationshipfor induction of carcinomas of the thyroid. This isalso the conclusion to be drawn from the experiments
on rats by Lee et al. [L29] discussed in chapter IV. If
this conclusion were true. a dose-rate effect, should
not be expected. However, the results of Holm's study[H 17] are not consistent with this picture. Further
investigations in this field are certainly called for.

D.

CANCER OF THE RESPIRATORY TRACT

399. Induction of lung cancer has been discussed
repeatedly in many UNSCEAR reports [U6. U7,

U9- U 12, U24) and risk estimates were given based on
various groups' findings ([U6]. annex G). Most of thedata on lung cancer induced by external irradiation
appeared unsuitable for analysis of the dose-response
relation. The most numerous group. the atomic bomb
survivors, is still affected by uncertainties in organ
dosimetry. As a result, there are large statisticaluncertainties in excess rates in various exposure
categories ([U6], annex G ).
400. The most interesting case for a discussion of the
shape of dose-response relationships is the prolonged
exposure of miners to radon and its daughter products. The difficulties in this case are:(a)

The long period of exposure, often at a variablerate. Exposures toward the end of the follow-up
period are increasingly less effective, in view ofthe long latent period of these tumours:(b)Possible changes in susceptibility with age, which
is itself a variable correlated with the length ofthe exposure:(c)

Possible interaction of radon and its daughterswith other factors, particularly smoking habits ofminers [A8, A 16. W 17];(d)

The dosimetry. which is based either on measured
concentration of potential alpha-energy in the air(WL)d or on estimates of radon concentrations,on the assumption of some degree of radondaughter product equilibrium. Translation ofthese quantities into an absorbed dose in the cells
at risk (basal layers of bronchial epithelium) is
uncertain, but a recent ICRP review [I4] gives.
for mining conditions, a range of about 3 to
8 mGy per WLM. The use of cumulative WLM
as an indirect measure· proportional to dose isprobably adequate for discussions of the derived
dose-response relationships.

1.

The risk expressed in absolute terms

401. In Newfoundland, a group of 2120 fluorspar
miners were exposed to an accumulated mean exposure
to radon of about 550 WLM. They were followed forabout 25 years and those who accumulated more thanI WLM had a relative risk of cancer of the respiratory
tract of 5.58 (95% C.L. 4.54-6.72). The absoluteannual excess risk coefficient amounted to 6 (4.6-7.5)
cases per 10 6 PY per WLM. The excess lung cancer
incidence rose roughly in proportion to the exposure[M5].
402. Several studies were published on the epidemiology of cancer of the respiratory tract among
uranium miners in the United States. The 1977
UNSCEAR report [U6] reviewed those by Archer et
al. [A8] and by Lundin [Ll8]. To sum up thesituation, the study by Archer [A8] referred to 3366
white and 780 non-white miners who had worked one
or more months in underground uranium mining
before I January 1964. Mortality analysis was terminated on 30 September 1968. and only 1% of people
dScc footnote c.

229

enrolled were lost from the survey. The death certificatesof those deceased before the closing date wereobtained. There was a substantial excess of deaths(437 observed versus 276.6 expected) among which
there were 70 cancers of the respiratory system against
11. 7 expected (p< 0.01 ). The diagnoses were ascertainedusing all sources of evidence (clinical findings, x rays.
autopsy. histology, biopsy, cytology, sputum analysis).
Numerous cancers occurred after 1968, or were
evaluated as probable ones. These were not used in
the assessment of risk or for characterization of thedose-response relationship [B20].

>0..

0:

w

0..

1500

w

I-

~

403. The exposure was assessed by radon daughtermeasurements (nearly 43.000 from 1951 through 1968
in approximately 2500 mines). Measurements taken ina mine over yearly periods were averaged, but, inmany instances. exposure over a number of years
could only be estimated approximately. particularly inthe early years of highest exposure. In addition, afraction of miners had a history of hard-rock mining,
before the work in uranium mines, which also
required approximate assessment. Cumulative radon
daughter exposure values were calculated with theabove approximations for each miner and for eachmonth of his employment.
404. Person-months of risk of dying by single calendar year. for 5-year age groups, and for each timeinterval after the start of underground uranium
mining, were calculated by a modified life table
technique. These values were related to cumulative
radon daughter exposure in WLM. Individuals who
were lost to follow-up were considered to be alive
throughout these analyses. A miner often contributed
person-months to more than one exposure category if
during the course of employment he passed from one
category to the next. The expected number of deaths
was calculated by applying the specific rates for age,
race, calendar year and cause of death for white
United States males to the appropriate number of
person-years at risk.
405. The number of expected and observed cancersof the respiratory tract as a function of cumulative
exposure in WLM during the whole period of observation was converted to incidence rate by BEIR [820],
weighing the incidence in each group of white miners
by its inverse variance. The fit was as shown in Figure
XXVIII. Consistency with linearity is evident and theslope is about 3 I0- 6 person-year WLM- 1 for thewhole range of exposure.
406. There were confounding variables, like cigarettesmoking, metropolitan versus non-metropolitan residence, possible mis-classification of miners into exposure categories. and dependence of WLM calculations on quality of the work histories, which could
have distorted the data to some extent. It is difficult to
see what their combined effect could have been.
However. the authors suggest that the influence of
these variables should not basically alter the trend of
the dose-response relationship. Also, the excess ofcancer cases even in the 120-359 WLM category isbeyond doubt.
230

400

BOO

w
u
z
w

- 10000
-"'
0

u

z

"'uw
X

w

0

White miners• Non-white miners

500

3000

4000

5000

Figure XXVIII. Dose-response relationships for lung cancer In
uranium miners in the United States. Error bars Include 900/o
range based on Poisson statistics.
Modified from [820].

407. The mortality study of the uranium miners
from the United States was extended to September
1974 [A 16] with essentially the same methodology as
in a previous study [A8]. Lung cancer rates were
calculated for eight exposure categories and for thetime after starting uranium mining. The total numberof person-years at risk was 62.556: the average periodof work in uranium mines was 9 years: the mean
accumulated exposure was 820 WLM; and the averagefollow-up period was 19 years. The incidence rateincreased approximately linearly up to 480 WLM,
then the slope of the response decreased to give alower risk per WLM. a feature possibly related to cellkilling, which was also seen in the series from
Czechoslovakia [S3]. Miners exposed to higher rates
were usually followed for longer times. and mostminers were middle-aged when they entered theoccupation. Cigarette smoking. and constitutional
factors such as stature and eye pigmentation were
found to be correlated with the effect. Stature wasthought to be correlated to lung volume in the sense
that. for the same work at comparable oxygen
consumption, a smaller lung volume means enhanced
ventilation rate and higher lung doses. More recently,
uranium miners from the United States have been
followed through 1977 [W 13). but the data. asreported, do not provide new information, as alluranium miners examined by the United States Public
Health Service medical survey team were alreadyconsidered in the study by Archer et al. [A 16].

408. The data from the United States miners were
tested by Myers and Stewart (M43] for their fit tovarious dose-response functions. The fit was made to~m equation of the form iTA(WLM) =a+ bEi where
ITA is the annual net incidence rate (10- 6 a-•) and E
the cumulative exposure in WLM. The j exponent was
fixed at 1.0, 0.5 and 0.25, and maximum likelihood
estimates were obtained in each case for a and b.
Allowing all parameters to produce a maximum
likelihood estimate led to a preferred value of j notsignificantly different from unity and to a positive
value of a, indicating that an excess cancer of the Jung
may obtain even in the absence of radon exposure. A
linear fit to the data was found to be the best. withb = 3.5 10- 6 WLM-1 a-1.
409. The latent period from the start of the exposure
to diagnosis was examined as a function of the age at
the start [A 16]. It declined from about 45 years toabout 10 years in those who started mining at 20 or
60 years. respectively. Smokers usually had a shorter
induction time (see annex L of the 1982 UNSCEAR
report [U24] for a discussion of the influence of
tobacco smoke). There was also a shorter latent
period associated with higher exposure rates, whichappeared to contribute to shortening more thancumulative exposure.
410. Sevc, Kunz and Placek [S3] reported onlung cancer incidence among uranium miners inCzechoslovakia. The number of miners was not
specified. but the group was similar in the number ofpeople to that studied by Lundin et al. [LI 8, Ll9] inthe United States. which consisted of 3366 workers.
According to [15), the study was based on about
60.000 person-years at risk. and a follow-up in therange of 21-26 years, JO years of average working
period in the mines and a mean cumulated exposureof 310 WLM. Fifty-six per cent of these miners started
uranium mining between I948 and 1952 inclusive(group A). the rest between 1953 and 1957 inclusive(group B). Miners were also subdivided into 3 age
groups at the start of exposure:< 29 years (45%),
30-39 years (28%), and> 40 years (27%). The age
structure in groups A and 8 was very similar. Eachage group was subdivided into eight exposure subgroups. the exposures being expressed as WLM. The
numbers in each sub-group were approximately equal.
Exposure estimates were based on about 120,000
radon concentration measurements made since 1948.
Estimates of potential alpha energy concentration
were made from radon measurements by choosing
average values of equilibrium between radon and its
decay products, typical for given ventilation conditions
and practices (which were available from records) andradon daughter measurements which were introduced in
1960. Attempts were made to estimate the variabilityof dose measurements. The rates of exposure accumulation in the three age groups were comparable.
411. In each sub-group of miners (belonging to eachexposure category and age group), the expected rate ofJung cancer was calculated by year from the beginningof exposure up to 31 December 1973, on the basis ofage- and calendar-specific Jung cancer mortality rates
for Czechoslovakia. A statistically significant excess(at 5% level) started to appear in the 100-149 WLM
category.r The presumption of linearity for the doseresponse relationship in group A (start of the exposure
1948-1952. follow-up 21-26 years) could not be rejected
at the 5% level of significance.
412. The same data [S3] were fitted by Myers andStewart [M43] to quasi-threshold functions of probit
and logistic response on the logarithm of cumulative
WLM. When results were tested by means of z2
distribution for significance of deviations from theseassumed functions, the z2 values were tenable at
P = 0.98-0.99. However, the quasi-threshold was lessthan 3 WLM. Thus, the mathematical analysis, using
maximum likelihood as the criterion. does not provide
any reason to reject linearity, for which the x2 test
gives a P value of 0.82.
413. Cumulative exposure E (WLM) and lung cancer
incidence (!TA) in group A were also fitted by Jacobi[J4] to a function of the form ITA = a E e-"E. A better
fit was obtained than that resulting from assumptionof linearity throughout the whole range of exposures.
The most likely estimates of a and k were 320 excess
cases 10- 6 WLM-1 and 6 10- 4 WLM- 1. respectively.
414. The excess cumulative cancer incidence in thevarious age groups shows that for the older age groupthe incidence was significantly elevated (5% level) at
100 WLM or more. For the two younger groups, thissignificance was reached at exposures above 150 WLM.
The risk per unit exposure (WLM) increased with age,with some irregularity of response in miners who wereolder than 40 at the beginning of the exposure. In theyounger age groups, linearity. with different slopes,
could not be rejected at the 5% level of significance.
The differences in incidence between the groups
disappeared above 300 WLM.
415. Cigarette smoking did not appear to be a
confounding variable because it was not dependent on
exposure categories, although it was correlated withage. From random sampling, the frequency of smoking
was similar to that in the country for which specificmortality rates were used for computation of the
expected numbers of cancers. Also, hard-rock mining
was not a complicating factor in assessment of the
exposure.
416. In another paper, Kunz et al. [K22] studied
the excess lung cancer incidence in miners inCzechoslovakia over the period 1948-1975 and related
their findings to different time distributions of exposure.
The previously mentioned group A composed ofminers who started work between 1948 and 1952 wasfollowed for 26 years on average. The cohort was
divided into five exposure categories and also, according to duration of exposure, as short (4.0-7.9: mean
5.6 years), intermediate (8.0-11.9; mean 9.5) and Jong(> 12: mean 14). The same group was also divided
alternatively, according to exposure rate. into group II
with nearly constant accumulation rate; group I for
which the earlier rates of exposure were higher thantMore recently, it has been reported (SSJ] that the excess isalready significant at an average exposure of 72 ± 2 WLM.

231

later ones; and group Ill where the rate of accumulation increased with time and reached highest values
in recent years.
417. The additional lung cancer incidence for thegroup as a whole, when related to duration of
exposure and its cumulated values, is shown in Figure
XXIX. For the group as a whole, a linear exposure-

"'
....z
"'
:c
0
0

150

~

...
... 100

"'
c..
"'
u
z

<:
u

z
"'
::,
_,

_,

<:

z

8

50

!::
0
C

<:

0

100

300

500

700

EXPOSURE (WU4)

Figure XXIX. Relationship between additional lung cancer
frequency and cumulated exposure In all uranium miners from
Czechoslovakia. Error bars represent 95% confidence limits.
[K22]

response relationship cannot be rejected, but there issome suggestion of saturation at the highest values of
WLM. When divided into three groups in relation to
the duration of exposure. the two groups with shorter
exposure showed saturation very clearly. The early
exposure rates in both groups with shorter duration of
exposure at which a significant deviation from linearity
occurs corresponds to about 50 WLM a- 1• The lower
incidence resulted from a diminished excess of smallcell undifferentiated cancer. The groups with uniform
and decreasing rate of accumulation showed linearityof the response, whereas that with the increasing rate
showed a breakdown of the response in the highest
exposure category (> 400 WLM). This decrease of theincidence was also due to diminished occurrence ofsmall-cell undifferentiated cancer. A similar influenceof exposure rate to radon daughters upon lung cancer
incidence was observed in experiments on rats by
Chmelevslcy et al. (C34] (already discussed in chapter IV).
418. Since all Czechoslovak miners started exposure in
1948-1952. those accumulating their exposure over ashorter period did not have a shorter follow-up, andtherefore the lower incidence in the two groups of 9.5
and 5.6 years of mean exposure duration cannot result
from the shorter time available for manifestation of theeffect (truncation due to long latency and short followup). A more likely explanation would be a killing effecton the transformed cells, which becomes manifest at an
exposure rate of about 50 WLM per year. However, ashorter survival of miners at high exposures was also
232

suggested [J7]. Thus. lung cancer induction by alphaparticles of radon daughter products can be describedby equation (3.1). with the proviso that the proportionality constant of the cell-killing term is dose-rate
dependent. The slopes of the exposure-response relationships for different times of accumulation in the low-dose
region were very similar. The effect of exposure ratecannot be easily separated from the effects of timecourse in groups that differ in respect of the rate ofaccumulation of WLM. Both the exposure rate andlatency effects may play a role in the decreased
incidence for the 400 WLM category of group Ill.
419. Horacek and Sevc [H25] studied the relationships
between incidence (per 1OJ. ITA.) of various histologicalforms of respiratory cancer in uranium miners from
Czechoslovakia and the exposure (E, in WLM). For all
miners, a function of the type ITA = 0. 16 E gave agood fit to the data. and absence of a threshold could
not be excluded. For epidermoid-type lung cancer, therelationship was different. and a regression line of theform ITA = aE + c = 0. 15E-11.2 could be fitted up to
700 WLM (c was significantly different from zero).
Thus, the analysis suggests the presence of a thresholdof about 75 WLM. There was also a small excess-unrelated to exposure-of other histological types oflung cancer the statistical significance of which cannot
be assessed from the report [H25].
420. It is interesting to note that basically the same
picture was obtained for the miners whose exposure
began at ages less than 40 years. For those above
40 years. the relationship for epidermoid-type lung cancer
was again linear with threshold (IrA = 0.13 E -21.7),
suggesting a threshold of a similar magnitude. but asteeper linear rise of incidence with exposure up to
700 WLM. For small undifferentiated cancer, theexcess at about 60 WLM was already close to 60 10- 3
cases and rose much less steeply to 80 10- 3 cases atabout 300 WLM. with a decline to about 40 10- 3 cases
at about 500 WLM. Other histological types also
showed an increased incidence to about 40 10- 3 cases
at 300 WLM. with a decline to very low levels at
500 WLM: however. the form of the ascending branchof the curve cannot be derived from the report.
421. The relationships of these findings to smoking
could not be studied, due to Jack of relevant information. The reasons why the two main histological typesof pulmonary cancer should have different forms ofthe dose-response relationship (presence or lack ofthreshold) and different age dependence, are unknown. However, there is a causal link between
development of epidermoid lung cancer and metaplastic changes in the bronchial epithelium (S58, S61].
The intensity with which noxious factors (e.g .. tobaccosmoke. radon exposure) act upon exposed individuals
is probably related to the speed with which metaplasia
develops. Therefore. at lower exposure rates, development of metaplasia and epidermoid cancer may
simply be delayed. The percentage of the small undifferentiated and epidermoid cancers varied strongly
with numerous factors, such as calendar time. age at
diagnosis, and iength of exposure. The epidermoid
cancers usually appeared later, and at higher exposures,
than the oat-cell undifferentiated carcinomas. Allthese circumstances call for great caution in acceptinga threshold-type relation for epidermoid lung cancer
in uranium miners, particul~rly because the analysis ofa similar type of cancers induced in rats exposed toradon decay products [C34) (see IV.8.6) did notsuggest any threshold above a few WLM. A detailed
study of the latent periods for the two types of cancer
could give some insight into the problem.

(x 10- 4 )
,.:
VI

.....

..J

co

<
I-

423. Deaths among cohort members due to respiratory
cancers were identified via the Canadian Mortality
Data Base, utilizing death certificates. The expected
number of deaths was calculated using age andcalendar mortality rates for the male population of
Ontario. Smoking habits were not taken into account,but. according to the authors, there were good reasons
to suppose that the miners did not differ in thisrespect from the reference population. Among theuranium miners there was a highly significant excess
of cancers of the respiratory tract ( 121 observed
against 70.5 expected; P < 10-9).
424. When the absolute attributable risk was calculated in 6 exposure groups according to a linear
model, the intercept did not differ significantly fromzero, irrespective of whether a zero. 5- or JO-year
lag in exposure against effect was assumed. The
slopes of !TA as a function of WLM varied between
2.0-2.8 10- 6 WLM- 1 for "special" WLMs and 4.8-7.2
10- 6 WLM-l for the "standard'' WLMs (at 3 different
lag intervals). The slopes were significant at P < 0.001.
An example of a dose-response relationship is presented in Figure XXX. In terms of the absolute
attributable risk, the slope was significantly greater.
by a factor of about 6. for those who lived to age 55
or more than for those who died at younger ages.
Thus. all dose-response relationships were well described by a non-threshold linear function. A single
relative risk model described the relationship for all
attained ages (see paragraph 428).

12

:::,
co

a:

422. By far the largest study on the mortality ofminers, including that from lung cancer, was recently
reported by Millier et al. [M70] from Ontario,
Canada. Out of several groups of miners engaged inmining various minerals. excess oflung cancer mortality
was found in three: uranium miners, gold miners, andthose mining a mixed assortment of minerals. The
dose-response study described below refers only touranium miners. for whom radon daughters in the air
could be envisaged as the sole causative factor. The
group included all full- and part-time undergrounduranium miners with mining experience of one monthor more. They were followed from l January 1955
through 31 December 1981. The cohort numbered
15,984 men, with an average follow-up of 15 years,
average duration of exposure of 2 years. mean
accumulated exposure of 60 WLM. and a total of
241.942 person-years at risk. The exposures to 22 2Rndaughters were calculated in WLM from area monitoring and occupancy data from 1955 through 1967
and, starting in 1968, from personal exposure records.
For each miner. upper and lower best estimates were
derived. called ··special'' and "standard WLM",
respectively. It was postulated that the most likely true
exposure would fall within these boundaries.

16

a:

II-

a

<

.....
I-

:::,

4

..J
0

VI

co

<

0

•
0

50

100

150

200

250

EXPOSURE (WLM)
Figure XXX. Dose-exposure relationships for lung cancer
incidence In uranium miners from Ontario, Canada, who had
no prior exposure in gold mines. Exposure is expressed in
WLM "standard" units.
[M70]

425. Preliminary data were reported from Sweden onlung cancer induction in iron-ore miners exposed torelatively low levels of radon daughters. A typical rateof exposure is 2 to 6 WLM per year of undergroundwork, presumably rather constant over the last 60 years[R35, R36]. The group consists of 1435 miners born
between 1880 and 1919, known to be alive on
I January 1920. The mortality analysis dealt with thecohort alive on I January 1951 (I 294 men) and covered
the period through 31 December 1976.
426. The analysis [R36] is almost a life-long followup. Details and accuracy of exposure evaluation are
not known. The estimates of exposure ranged from
2 to 300 WLM, the average being about 90 WLM.
Detailed histories of smoking were available for eachminer. and the expected numbers of lung cancers were
calculated from the calendar- and age-specific cancer
rates for smokers and non-smokers in Sweden. Theinteresting feature of this study is the very long latent
period, with a minimum of 20-29 years after the startof mining and a mean of about 40 years.
427. From this series. only limited data have been
published [R41] concerning the dose-response relationship. The earlier report [R36] states that " ... thepreliminary data show a reasonable dose-response
relationship over the range of cumulative exposure
from 2 to 300 Working Level Months (WLM). The
significant point is that in the lowest dose range we do
get a significant excess of lung cancer at about
25 WLM. So we have some indication that at these
low doses and dose rates there is a significant lungcancer risk as the linear dose-response would havepredicted.·'2.

The risk expressed in relath·e terms

428. The lung cancer risk of Canadian uranium
miners was also expressed in terms of a relative
increment versus exposure. The intercept of the233function was not significantly different from zero for
all assumed exposure-·risk intervals (0.5 and I O years).
The slopes for relative risk versus exposure varied
from 0.51 to 0.54. and the coefficient for increment of
spontaneous risk per WLM assumed a single value of
I.3%. The slope was significant at P < 0.001. Thus, a
non-threshold linear model. with a constant slope for
all attained ages, was adequately described in the data.

decay products and tobacco effects have been so far
unsuccessful. Whatever the limitations of the fivestudies discussed, they imply basic agreement withexpectations of the linear non-threshold model. irrespective of whether the risk is expressed in absolute or
relative terms.

429. Lung cancer mortality of the uranium miners in
the United States was re-appraised [W 17) using Cox's
proportional hazard model for mortality rates. The
analysis was based on 194 lung cancer deaths recorded
through 31 December 1977 in the cohort of 3362 whiteand 780 non-white miners in the Colorado plateau,
who worked at least 2 months underground. The dataon exposure were the same as used by Waxweiler[W 13). Smoking histories were used to estimate thetotal number of cigarettes smoked until the exposure
cut-off (l 968).

433. The available information on induction of bonesarcoma by bone-seeking radionuclides has alreadybeen reviewed by UNSCEAR ([U6]. annex G). which
also discussed many experiments performed on animals([U6), annex I). Relevant new information on animals
is discussed in chapter IV of the present annex.

430. When considered in terms of the relative risk
(RR). various specific models were tested which
treated the exposure to 222 Rn decay product andsmoking as additive or synergistic factors. The best fit
to the data by the maximum likelihood method was
obtained by a synergistic model of the form:
RR= (I+ a WLM) {I+ b packs)(5.1)

where WLM and packs are accumulated exposure
to 222Rn daughters and estimated total number ofcigarette packages smoked up to 10 years before theminers' current age, respectively. The fit yielded
a= 0.31 10-2 WLM- 1 and b = 0.51 10 3 pack- 1 andwas significantly improved over that obtained when
exposure to 222 Rn decay products was taken alone.
Several additive models could be rejected. For exposure
to 222Rn decay products alone the dose-responsemodel is a non-threshold linear one.
431. An ICRP Task Group [15) re-calculated thelung cancer risk among United States, Czechoslovak
and Canadian miners in terms of the relative risk. The
ratios of the coefficient for the linear slope of the
exposure-response relationships. i.e .. the relative increment of spontaneous lung cancer risk per unit of
exposure are as follows: United States. 0.5-1.0;
Czechoslovakia, 1.0-2.0 and Canada 0.5-1.3 per centper WLM. These values are much closer to each otherthan the respective values of the coefficient FTA (interms of the absolute attributable risk) of 3-8. 10-25
and 4-10 10-6 WLM per year. The relative risk per
WLM also becomes slightly less at high accumulated
exposures.
432. Data on induction of lung cancer are practicallylimited to prolonged exposure to alpha particles
emitted by short-lived radionuclides attached to dust
particles or as free ions in air passage ways (trachea.
bronchi). Moreover, the available data refer to miners
among whom a majority are tobacco smokers. The
latter factor may act synergistically with radiation in
inducing bronchial neoplasms ([U24]. annex L). There
were also other factors in the working environment ofminers whose co-carcinogenic or promoting effects
upon lung cancer induction could not be completely
discarded. Attempts at dissociating these from radon
234

E.

BONE SARCOMA

1.

Direct studies

434. A group of dial painters who acquired various
amounts of 22 6Ra and 228Ra has now been followed formore than five decades [E3. E4. Rl8-R20. R34) andhas provided knowledge of average doses to bone andto endosteal tissue, in which the cells at risk arethought to be located. Average doses from radiumisotopes in man can be calculated with reasonableaccuracy for groups of subjects who acquired theirbody burdens 50 or 60 years ago [R 18-R20]; however,the precision of individual estimates is difficult toappraise.
435. The 22 6Ra and 228Ra body burdens were measured
in most of the individuals (in some of them on
numerous occasions) and the initial skeletal uptake
was estimated using Norris' [N7] empirical retentionfunction for radium in man. The average skeletal
doses of alpha radiation from both isotopes of radium
and their daughter products were computed by integrating the retention function from the mid-point of
exposure to the end of follow-up. and dividing thereleased energy by the average skeletal mass.
436. A large group of these subjects (dial painters)
has been followed for more than 45 years and theestimated cumulative incidence should be very close to
the complete life-long effect of the radionuclides. It is
still uncertain whether the group might be selected for
dose, i.e., whether or not the subjects with symptoms
are grouped preferentially in higher dose categories
where skeletal effects (including bone-sarcoma) occur
more frequently [M29).
437. Rowland et al. [R34, R46] analysed the doseresponse relationships for bone sarcoma in thispopulation. Female dial painters were selected fromthe total group and were followed until 31 December
1979. Among 1468 individuals with a measured bodycontent of radium, 42 bone sarcomas were found.
whereas 0.4 were expected on age- and time-specificrates for white females in the United States. However,among all recognized sarcoma cases, the body burdens
were not measured in about one-third of cases [R46].
Excess of sinus and mastoid carcinomas was also
reported and they were thought to arise from irradiation of the lining epithelium by 222Rn and decay
products accumulating in the cavities. Their numberwas too small and dosimetry too uncertain for any
reasonable discussion of dose-response relationships.
438. The numbers of cases per person-year at risk
were calculated as a function of the systemic intake ofradium (activity of 226 Ra + 2.5 activity of 228Ra; it had
been shown [R 18) that for induction of osteosarcomasin man 228 Ra is 2.5 times more effective per unit
activity than 226 Ra). All cases with systemic intakes
greater than about IO kBq were used for the fit. The
breakdown of cases into 14 intake groups was made insuch a way that 3 strata covered each order ofmagnitude (Figure XXXI) from about 10 kBq up to
about I GBq. Mean intakes were calculated either as
simple weighted means or as roots of mean weighted
squares. The former ,vas used when linear. and thelatter when quadratic, functions were fitted to the
independent variable. Values of 0. 7 10- 5 and I. 75 10- 5
were taken as expected (control) incidence rates forthe two modes of treatment mentioned above.
439. Various forms of general initial activity (A)incidence-rate expression iTA = (a 0 + a 1A + a 2A 2)e-/l,A
were fitted to the data and tested by 1. 2 statistics for
goodness of fit. Fitting of 13 data points was carriedout by a general weighted least-squares procedure. A
quadratic initiation+ killing expression gives the bestfit (P = 0.73). Arbitrary selection of a positive a 1 stillgave an acceptable fit (P = 0.05) of a 1 = 1.3 10-s. The
parameters of the equation iTA = (a 0 + a 2 A 2) e-/l,A are:a 2 = (7.0± 0.6) 10-s and /J 1 = (I.I ± 0.1) 10- 3, where A
is the initial systemic intake of activity.

440. The pure quadratic and linear-quadratic functions give a similar response at higher intakes, butdiffer markedly in the region of about 4 MBq intake.
To change the response from quadratic to linear while
retaining a good fit, three additional sarcomas would
have to appear in the years to come in the low-dose
region where no sarcoma has yet been seen. This, theauthors judge as quite improbable (although theactivity distribution among unmeasured sarcoma cases
is not known). Arbitrary changes of intake ranges did
not alter the fact that dose-squared plus killing
functions always gave the best fit to the data; only inisolated categorizations of the intake could a linear fit
not be discarded.
441. When the dependence between radium intake
and time of sarcoma appearance was examined, an
inverse relationship was found between intake andmaximum or mean (but not minimum) induction
period. The numbers of observed and predicted bonesarcomas as a function of time after intake were ingood agreement, suggesting that the risk is rather
constant over 65 years after intake. No bone sarcoma
has been observed among the 1680 measured cases (allcategories) with intakes of less than about 2 MBq. The
conclusion is, therefore, that the life-span probabilityof bone sarcoma induction below this level of intake
must be very small. The authors calculated that after
an intake of about 40 kBq 22 6Ra over one year. thecorresponding lifetime risk of bone sarcoma was
5 10- 1-1 and 1.3 10-s per year, for the quadratic andlinear-quadratic dose-response functions, respectively.

0.05
>-

a..

er.

0.04

u.J

a..

u.J

I-

c::c
c:::

u.J

0.0

u

z

u.J

....u

Cl

z

0.02

....J

c::c
:::>
z
z
c::c

0.01

INITIAL SYSTEMIC ACTIVITY (µCi 226 Ra + 2.5 µCi 228Ra)
Figure XXXI. A semi-logarithmic plot of bone sarcoma Incidence rate as a function of systemic
Intake for female dial painters employed before 1950, showing a dose-squared exponential flL The
shaded band Indicates the range covered by the fitted function when the coefficients are allowed
to vary by ± 1 S.D. Error bars represent the binomial standard errors of the observed Incidences.

[R34]

235

442. Schlenker [S50], assumed a binomial distribution
to calculate the probability of observing a number ofbone sarcomas greater than predicted by the relationship iTA = (a 0 + a 2A 2) -exp (J 1A in the zero range, i.e ..
for the activity A below about 4 MBq where notumours were actually seen. For the dose-response
curve itself, the probability was 50%. For pairs ofcurves delineating the 68% and 95% confidence limits(Figure XXXII) there is a corresponding chance thatthe true number of tumours lies between the two
predictions. The curves enveloping the 95% confidence
interval span a factor of 90 and their widest distancegives a feeling for the uncertainty in the estimateddose-response relationship at low activities of radiumsystemic uptake.

was less than 0.1. Mole [ M29] plotted. as a function ofdose. the cumulative incidence of bone sarcoma per
10 3 individuals for the group of dial painters whostarted work before 1930 [M27] and who were
followed through 1972 [AIO]. He assumed equal
effectiveness of doses from both radium isotopes. as
quoted in [A JO]. Functions of incidence !TA against
dose {D) in Gy. of the form !TA= a 2o2e-/l,D and!TA= a 1De-//,D gave fits of comparable goodness(P = 0.26 and 0.45, respectively). The fit to a linear
equation is
ITA(D) = (111 ± 22)10- 4 D e-<B.5± 2-2llo- 30

characteristic of the linear model for high-LET radiation. which could be used for interpretation of thedata on incidence. The slope gives the risk of bonesarcoma from the absorbed dose from radium alpharadiation. Very low values of (1 1 cannot be interpreted
in terms of a very high lethal dose to the transformed
cells for a variety of reasons. including the long
duration of exposure with possible repopulation of theirradiated cell pool.

443. Because of the inverse relationship between
activity and latent period, it might be expected thatthe upward concavity of the dose-response curve
would result from the choice of the variable (rate peryear) and would vanish when expressed as cumulative
incidence. In annex H of the 1972 UNSCEAR report([U7]. Figure IX). the results of the follow-up through1969, expressed in this way, showed a downwards
concave dose-response relationship. In 1972, Mays
and Lloyd [MI I] investigated the dose-response relationship for all United States subjects containing
radium in their bodies, thus continuing the combined
MIT and the Argonne series updated to May 1971. In
all, 762 individuals below 200 Gy average skeletaldose were included, 48 of whom developed bonesarcomas. The dose-incidence relationship had a linear
trend with a slope of 0.46% per Gy. However, theprobability of seeing the deficit of cases below JO Gy
as observed, on the basis of the regression analysis.

444. Schlenker (S50] approached the same problem
theoretically by calculating the life-time probabilitylTA of bone sarcoma. corrected for the presence ofcompeting risks. expressed as a function of timeaverage tumour rate from 226Ra + 228 Ra derived from
Rowland's equation referred to above (Rl8]. Thus,
IOU

!TA=

•

f da iTA e-{ (ITA + SJ da

where A is the age at exposure: a is the age in years;
i,.A is the time average tumour rate, equal to zero,,,,,, ,,,

9%

68%

Cl.

er:

w
w

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~

w
u
z
w

10- 4

,,,

,,, /

C

u

z

_J

,,, /

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:::>

z
z
<(

/

., .,,.

/;,,,,,, ,,,

,,,

/

/

95%

Cl.

/
,,, ,,,,,,,, ,,

,,,

,,,
., ,,

,,,

,,, /

/

I

I
I
I

I

I
I

/

I
I

/

1
I

I

/

I

/

10-s

INITIAL SYSTEMIC ACTIVITY (µCi 226 Ra + 2.5 µCi 228 Ra)
Figure XXXII. Plot of bone sarcoma Incidence rate In female dial painters, as a function of theInitial Intake of radium. Three pairs of curves denote probabilities that the true number of bonesarcomas, In the region of Intake where no tumours were observed, falls within the calculated
envelopes [S50]. The shaded area covers two standard deviations on either side of the doseresponse curve iTA = (a 0 + a~2) e-P,A, aa calculated from the standard errors of the parameters[R34].

236

(5.3)

A

Envelopes
::.-

(5.2)

until a five-year latent period has passed and constant
thereafter: and Sa is the death rate from all othercauses as a function of age.
445. For single 22<,Ra intakes at ages 20, 45 and70 years, the results are presented in Figure XXXIII,
10°
10- 1
<I'.
,-

.....
u
z:
.....
0

10-2

u

10- 3

z:

AGE
20
45

10- 4

70

10- 5
101

102

10 3

INITIAL SYSTEMIC ACTIVITY {µCi 226 Ra + 2.5 µCi 228 Ra)
Figure XXXIII. Predicted Ille-time Incidence ol bone sarcoma
in the presence of competing risks, as a !unction ol a single
Intake of 226,228Ra.
[SSO]

together ,vith 68% confidence limit envelopes for a
70-year-old. For other ages. the envelopes are very
similar. lt is quite obvious that an approximately
linear dose-response for cumulative incidence !TAagainst intake of activity into the blood might be theprevailing trend over the range from about 200 kBq toabout 8 MBq. This conclusion. of course. excludes
neither the possibility of a .. practical threshold" northe absence of a life-shortening effect such as thatreferred to above. nor that a dose-squared relationshipmay be fitted into the envelopes.
446.

The linear trend of bone sarcoma incidence(ITA) against alpha-ray dose in the human skeleton isin accordance with the bulk of the evidence fromanimal experiments. as reviewed in chapter IV. However, more refined analyses of bone sarcoma integral
tumour rates, induced in beagles by 239 Pu injections,
support a dose-squared dependence of the rate [Pl7,
W!4]. For radionuclides emitting low-LET particles
like 90Sr. an upwards concave dose-response relationship was invariably observed [Ml2-M 14].
447. Several thousand patients in the Federal Republic of Germany were given repeated intravenous
injections of 224 Ra in the course of therapy fortuberculosis and ankylosing spondylitis. In contrast
with 226 Ra. 22-IRa, with its short half-life of 3.64 days,
decays on the surface of bone where it becomesdeposited early after injection due to rapid ionicexchange. The fraction of the mean dose to theskeleton delivered by 22 4Ra to the target cells is muchhigher than that for 226 Ra. The effectiveness of themean skeletal dose is therefore about 7 times higher
for : 2-1Ra. The patients were of both sexes andincluded adults as well as juveniles. The most recent
report on these patients through I 980 [M57] includes
2 I 8 juveniles and 680 adults. Bone sarcomas had
appeared in 35 patients injected as juveniles and in
18 adults. The follow-up times ranged from O to
36 years; deaths accounted for most of the shortfollow-up times, whereas 582 patients were followed
for more than 19 years and 78% were still alive in
1980. The mean skeletal doses from a-particles were
estimated to be I 0.98 and 2.05 Gy in juvenile andadult, respectively: the corresponding injection spans
averaged I 1 and 6 months. Virtually all bone sarcomas
are ascribed to radiation, as only 0.2 cases would be
expected, based on general population rates.
448. The shortest appearance times were 3.5 and5 years in juvenile and adult patients. respectively; thecorresponding average values were I 0.4 ± 5.1 and11.6 ± 5.2 years, and were not significantly different.
The time distribution was similar to that for leukaemias
in atomic bomb survivors, as described for those
exposed within 1500 m of ground zero by Bizzozero etal. [882] for which the average appearance time was
9 years. The peak of bone sarcoma appearance was
6-8 years. No additional cases were discovered since
the previous report in 1974 [S21]. It may be concluded,
therefore, that by 25-30 years after injection the vast
majority of bone sarcomas have already become
manifest.
449. There was some tendency towards a lower riskof bone sarcoma per unit dose with advancing age at
injection. but this could be an artifact due touncertainties in dosimetric assumptions, a possibly
non-linear response, or a more pronounced fractionation of injected activity in juveniles. Fractionatedadministration appeared more effective: a protracted
weekly administration over a few years carries a
5-times greater risk per unit dose than single injection[S 18]. This observation is in agreement with studies on
mice injected with 224Ra in various fractionation
schemes [L20, M67]. Original data from reference[S 18] were examined [P8] for partial correlations
between the increment of incidence per unit dose.
average injection span and the average skeletal dose.
Significant positive correlations were found between
the span and dose. and also between the incidence
increment and the span. The correlation between theincrement of incidence and the fractionation span
itself was non-significant (in fact it was negative) when
the above partial correlations were accounted for.
Thus. the suggestion of an increased effectiveness offractionated versus single administration of 224 Ra,
based upon human experience. appears unfounded.
The dose-response relationship for bone sarcoma
incidence in the treated patients was compatible withlinearity. The slopes for juveniles and adults differ bya factor not greater than 2 (Figure XXXIV, [S21]).
However. a dose-squared trend of the effect could not
be rejected on statistical grounds. No carcinomas of
the head sinuses were observed in patients injectedwith 224 Ra due to lack of sufficiently long-lived radon
nuclides in the thorium decay series.
237

452. Marshall and Groer assumed that there areabout I O11 cells at risk in the endosteum of a"reference man". These cells are subject to sarcoma
initiation in two steps, but also to cell killing, thekilling being by a factor of 10s more probable thaninitiation (0 0 for the cells must be of the order ofI Gy). Thus, doses which produce bone sarcoma (ata rate of a few tens of mGy per day) should also
completely sterilize the population of cells at risk
before any transformation could have occurred. To
eliminate this difficultv, the authors assumed that cells
within a 0-10 µm dis{ance from the bone surface, if
killed by alpha particles, can be replaced at a rateof 0.1 per day from a stem-cell compartment whichitself is beyond the range of 5. 7 MeV alpha particles. A conceptual outline of the model is shown in
Figure XXXV. At all stages of malignant development,

50

40

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w

u

z

w

30

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0

u
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STEM
CELLS

0

cc

•

o

AdultsJuveniles

10

10

0

20

30

SKELETAL DOSE (Gy)

~INITIATIONINITIATION

steosarcoma
cell

Figure XXXIV. Bone sarcoma Incidence versus skeletal dosefrom 224Ra. For lhe linear non-threshold lines shown lhe
cumulative risk of bone sarcoma during 14-21 years postexposure is 0. 7% (adults) and 1.4% Quvenlles) per unit averageskeletal dose.
[S21]450. Schlenker [S50] calculated the dose-response
relationship for 224 Ra-induced osteosarcoma cases.
For incidence ITA (uncorrected for competing risks) in
subjects older than 16 years at injection. the function
had the form ITA = l - e- 3-0 10 - 5 "· At the widest
separation, the 95% confidence limits span a range of
750. reflecting much less information at low doses for2? 4 Ra than for 226 + 228Ra. This can be explained by thesmaller number of cases and shorter follow-up times.

2.

The model of Marshall and Groer

451. Theories of bone sarcoma induction were developed in the past [B2 l, M26] but the most comprehensive one based on human epidemiological data has
been presented by Marshall and Groer [M4]. They
based their model on several observations. The first isthat a linear dose-response relationship gave a poor fit
to the incidence rate of bone sarcoma versus dose(bone averaged) from n 6 Ra and 22 8Ra. as discussed indetail by Rowland [Rl8-R20]. There were no cases ofosteosarcoma below 9 Gy, and pure linearity ofincidence rate versus dose was therefore highly unlikely
on statistical grounds. They postulated, therefore, that
two events produced by alpha radiation in a cell at
risk are necessary to initiate the malignant transformation.
238

PRc»IOTION

Figure XXXV. Schematic representation of the Marshall andGroer [M4] model of bone sarcoma Induction by alphaparticles. An original endosteal cell Is Initiated twice andpromoted to become an osteosarcoma cell; cells killed at any
stage before promotion are replaced by stem cells. The rate ofkilling, F.., Is 10 5 limes larger than the rate of Initiation Fa(F = endosteal dose rate). The rates of replacement p and ol
promotion l are Independent of radiation dose.

the cells arc at risk of killing, which is proportional totheir numbers (M 0 , M 1, M 2) and to the dose rate F.
The dose rate in turn is proportional to the content ofradium per unit mass of the diffuse radium component
in bone. The fully transformed cells (M 3) promoted tocellular division are not assumed to be at significant
risk for cell killing due to a rapid multiplication of theclone and escape of the tumorous cells from thevolume irradiated by alpha particles.
453. To summarize. the model incorporates thefollowing parameters:(a)initiation probability per cell per unit dose (a):(b)

killing probability per unit dose (k):(c)

number of cells at risk (s):(d)

promotion probability per unit time().);(e)

replacement probability of killed cells (p):(f)

growth time of a tumour to become recognizable
(g);

(g)

dose rate (F) proportional to activity per bodyweight (c).

These parameters were incorporated in a set ofdifferential equations to give a probability of appearance, P(t), of an osteosarcoma per unit time perindividual and unit activity of radium reaching theblood stream. The values of p, a and s were held fixed,
and initiation probability, promotion rate, tumour
growth time and dose rate were adjusted through asolution of the model by best fit of the data obtained
from observation of individuals with radium bodyburdens followed through December 1973 at the
Argonne National Laboratory [A I OJ.

100

~

10

!

Data (S.E.)

Model
0 t+.-.......a.-+....+-----r----+-"""T010
100

INTAKE (µCi/kg body)454. From the solution of the model for man, it
follows that the time of sarcoma appearance after
radium uptake should increase with decreasing valuesof the intake q reaching a constant plateau at about
30-35 years at the level of 40 kBq per kg body weight.
The theory predicts [G23, M4] an enhanced effect onbone sarcoma induction by fractionated administrationof a short-lived bone-seeking alpha emitter. The
existence of such a phenomenon was, in fact. suggested
when bone sarcoma incidence was studied after
injections of 224 Ra. When the isotope was administeredover one month, the incidence was lower than thatseen after prolonged (average 2 years) administrationof the nuclide (P = 0.16) [SIS). The lower sarcoma
incidence in this case should result, according toMarshall and Groer (G23. M4], from suppression of
the population of viable endosteal cells M 0 by very
high dose rates delivered over short intervals (theempirical basis to support this contention is open to
critique, see paragraph 449).
455. The theory fits satisfactorily the preliminary
data on the induction of bone sarcoma by 226 Ra in
Utah beagles. in which the cumulative incidence
reaches a plateau of about 92%, a factor of 3-4.5
higher than in man. The parameters of the theory,
which give a good fit to the experimental situation.
were rather similar to those for man. with the
exception of higher promotion and initiation rates(both roughly by a factor of 10). Reasons for thisinterspecies difference in initiation probability are notclear.
456. Marshall and Groer [M4] correctly stated that
fit of the model to the measured data does not provecorrectness of the postulates. Some results of thetheory were not envisaged a priori. e.g., the plateau ofincidence rate at high doses (Figure XXXVI). This
point of agreement enhances the credibility of thetheory. However, in the light of the evidence that the
cumulative incidence of 226Ra-induced bone sarcoma.
both in man and in beagles, can be reasonably
approximated by a linear model, the basic assumptionof two-hit initiation is open to question. A model
similar to that of Marshall and Groer. but postulating
a one-hit initiation has been proposed [P23]. The
model explains the non-linear part of the activityincidence rate curve by the promoting action of alpharadiation exerted via repopulation of the target cellpool (osteogenic cells).

Figure XXXVI. The cumulative Incidence of osteosarcomas In
man versus the total Intake (µCl per kg body weight) of radlum226 plus radium-228. Up to about 1 µCl per kilogram bodyweight systemic Intake the slope of the line, according to themodel of Marshall and Groer [M4], Is close to 1.

F.

INTERSPECIES COMPARISONS

457. In numerous instances in the course of thereview of experimental (chapter IV) and human data(chapter V), qualitative similarities have been pointed
out between animal and human data that may usefully
be summarized here. From such comparisons. thepattern seems to emerge that the shape of doseresponse relationships may be basically similar invarious species.
458. Thus, the linear non-threshold type of doseresponse relationship for female mammary carcinoma
induced by x rays finds its counterpart in the results ofstudies on at least four strains of rats: (a) the SpragueDawley females irradiated externally by x rays and/or
gamma rays. and internally by fJ particles fromtritium: the linearity applies to adenomas but theresults for adenocarcinomas are also consistent with
the notion: (b) females of the WAG/Rij rat strain and
the AC strain irradiated externally with x rays
showing linearity for adenomas and carcinomas,
respectively: and (c) non-inbred female rats irradiatedfrom a /J-particle source also showing a linear rise ofincidence of mammarv carcinomas. The dose-response
curve for mammary ~arcinomas induced in BALB/C
mice by gamma rays shows irregularities that defy any
possible comparison.
459. A strong linear component is manifest in the
non-threshold dose-response relationship for x-ray
induced thyroid carcinoma in man; effects of dosefractionation are virtually absent. Data on LongEvans rats. even if the number of animals is limited
and the observations were terminated 2 years after
irradiation, are compatible with linearity. They also
show a Jack of a pronounced dose-rate effect, asshown by the comparison of x-ray and 131 I doseresponse curves. The absence of an excess of thyroid
cancers in humans exposed to diagnostic quantities of
131 I is not consistent with the above observation, but
239

the relevant sample is highly selected and the observations made on this cohort do not necessarily
in\'alidate the basic similarities between the doseresponse relationships from the human species and therat.
460. Cancer of the respiratory tract induced inseveral groups of miners, exposed to daughter products of mRn, consistently yields a non-thresholdlinear dose-response relationship up to a cumulative
exposure of about 300 WLM, with some decline of therisk coefficient (FTA) at higher exposures or exposure
rates > 50 WLM per year. A very similar relationshipis observed in male Sprague-Dawley rats made toinhale 222 Rn decay products or exposed to fission
neutrons. The analogy holds when the data from thetwo species are analysed in terms of both the absoluteand the relative risk model.
461. Dose-response relationships for bone sarcoma
induced by long-lived isotopes of radium in man,beagles and mice are compatible with linearity between
dose and cumulative incidence over the initial part ofthe curve. In all three species a decline of the tumour
yield is seen at high and very high doses in theskeleton. In the three species there is also a pronounced inverse relationship between dose (or initialactivity in the body) and the latent period.
462. In summary, it appears that the shape of thedose-response relationship for radiation-induced cancerof some organs in man generally follows the patternseen in a number of experimental animal species. Thisqualitative finding will have to be verified in the lightof future data. The similarity may not be surprising
for those types of human malignancies that have areasonable counterpart in other mammalian species.
in view of the basic similarity of patho-physiologicalphenomena on which rests the rationale of using
experimental animals to predict the response of man.
However, the regularities pointed out do not imply
that data from experimental animals may be used toderive risk coefficient applicable to man, because, sofar. such similarities may not be shown to apply to thequantitative expression of the carcinogenic effect invarious species.

G.

SUMMARY AND CONCLUSIONS

463. Epidemiological data useful for an analysis of
the shape of the dose-response relationships forradiation-induced cancer are limited. This applies toexternal and internal, to instantaneous and prolonged
exposures. Caution should therefore be exercised informulating broad generalizations. Several factors are
known to affect the magnitude of the neoplastic
response. Among those identified. age at irradiation.
sex and genetic or ethnic characteristics are ofimportance. but the extent to which these factors may
affect the form of the dose-response curves is almost
totally unknown. For some tumours. e.g., cancer ofthe lung, the characteristics of the environment andthe living habits may consistently affect the expressionof malignancies.
240464. With the Hiroshima and Nagasaki atomic
bomb dosimetry still uncertain, the epidemiologicalinformation on leukaemia incidence in the survivors
cannot yet be fully utilized. Information on inductionof leukaemia derived from the follow-up of spondylitis
patients is insufficient to allow firm conclusions as
to the most likely form of the dose relationship.
particularly because leukaemia incidence in this group
may have been influenced to an unknown extent by
dose-fractionation effects. Therefore. further discussion of dose-response relationships must be postponed
until new information on the atomic bomb survivors
becomes available.
465. Regarding breast cancer, there is no suggestionof a threshold for low-LET radiation; either a purelinear relationship with dose or one with a small dosesquared term might apply. This conclusion is supportedby the small or absent effect of dose fractionation andby the lack of a detectable relationship of latency todose. For this tumour, there is, however, a pronounced
variation of the risk with the age at exposure. as
women in the age range of 0-30 years are at thehighest risk.
466. Dose-response relationships for carcinoma of
the thyroid have a strong linear component and thedata do not suggest a threshold. There appears to be
no inverse relationship between latency and dose andthis is consistent with the observed linearity. Infants
and children are more susceptible to cancer of the
thyroid than grown-up persons. Dose-rate effects
cannot be excluded. and data on patients given 1>1I for
diagnostic purposes might be interpreted in this way;
however. other interpretations are also possible, particularly since dose-rate effects have not been seen inrecent ~nimal experiments. The induction of benign
thyroid adenomas is linearly related with x-ray doses
at low doses. but with a decrease of the slope at doses
above I Gy.
467. The available data on lung cancer induced byexposure to radon and its decay products in mines
shmv. without exception. linear exposure-response
relationships, with a decreasing slope at the highest
exposure rates (above 50 WLM per year): there is no
indication of a threshold. This type of relationship has
also been consistently observed for airborne shortlived a-emitting radionuclides in animal experiments.
For low-LET radiation the form of the dose-response
curve is essentially unknown.
468. Alpha-emitting bone-seeking radionuclides. suchas ~26Ra and 228 Ra. may induce bone sarcoma in man
with a significantly elevated frequency at mean skeletal
doses above lO Gy. Plotting the incidence or incidence
rate against cumulative dose results in relationshipsthat may be interpreted as either linear or quadratic.
In the latter case, below about JO Gy there is asignificant deficit of tumours when a linear interpolation to zero dose is attempted and IrA fits very
well a dose-squared model with a cell-killing term. In
this case. linearity may be rejected. It appears impossible at present to decide whether linear or
quadratic models, or a combination of both. provide
better fits to incidence UrA) versus dose from radiumisotopes over the initial portion of the curve. Animal
experiments suggest linearity. Bone sarcomas induced
in man and animals by a-emitting bone seekers show apronounced inverse relationsnip of latency to dose.
The deficit of tumours in man, at the lowest end of thescale mentioned above, could therefore reflect anapparent "practical" threshold, and a decreasing
tumour-related life shortening with lowering of thedose.
469. A dose-response relationship for bone sarcoma
induced in man by short-lived a-emitters (2 2~Ra) is
compatible with linearity, even though alternativemodels may not be excluded. The latent period forbone sarcoma appears to be rather short; the age atthe beginning of exposure has no strong influence.
There are no human studies of bone sarcoma caused
bv low-LET irradiation. However, irradiation ofe~perimental animals by P-emitting bone seekers ( 45 Ca,
9oSr, 89Sr) invariably resulted in upwards concave
relationships and a pronounced inverse relationshipbetween dose and latent period. It would be expectedthat the same kind of relationship might also apply toman.
470. In summary, the model applying to the doseresponse relationship for leukaemia is unknown andmust remain so until new dose-incidence data foratomic bomb survivors become available. The reviewed
evidence suggests that incidence of lung. mammary
and thyroid cancers is probably related with dose by ageneralized linear or linear-quadratic relationship.
However. dose-incidence information is not available
for Jung cancers after low-LET and for breast andthyroid after high-LET irradiation.
471. In a comparison of data from experimental
animals. reviewed in chapter IV, and from human epidemiological studies in the present chapter. UNSCEAR
has identified a number of tumours for which thedose-response relationships appear to follow the same
basic pattern in various species. Such a comparison
will have to be verified as more data are accumulated.
In any case. the qualitative similarity of the induction
kinetics does not justify any simple quantitative
extrapolation of incidence data from animals to man.

VI.

SUMMARY

472. In order to estimate the absolute risk ofradiation-induced cancer (number of induced tumours
per million people exposed per unit dose, i.e .. cases
10-6 Gy- 1), or the relative increase of tumour frequency
per unit dose over the •·natural" incidence at low
doses and dose rates. two types of information are
required: first, empirical data on the incidence ofvarious forms of malignancy at relatively high doses
where observations have actually been made; second,knowledge of the mathematical form of the relationships linking the incidence of cancers with the dose ofradiation. Such data would allow predictions to bemade of the cancer incidence at doses (and perhaps
also at dose rates) very much lower than those atwhich direct observations in man have been gathered.

473. When the incidence of a given tumour in
exposed animal or human populations is followed as afunction of increasing dose. several observations may
usually be made. At relatively low doses (at about
0.1 Gy of sparsely-ionizing radiation), only seldom(and then mostly in controlled animal experiments)
can a statistically significant increase of cancer or
leukaemia be shown. At higher doses (up to a few Gy,
but with considerable differences between different
tumours). the incidence of such malignancies may beshown statistically to exceed the level observed in nonexposed control populations, following some increasing
function of the dose. At still higher doses (many Gy),
the incidence gradually starts to fall off because of cellkilling. Dose-response relationships of this type, going
through a maximum at some intermediate dose, areoften found in experimental animals. They are termed''biphasic".
474. A common interpretation attached to such ashape advocates the concurrent presence of two
different phenomena: (a) a dose-related increase of the
proportion of normal cells that are transformed into
malignant ones: and (b) a dose-related decrease of theprobability that such cells may survive the radiation
treatment. Both these phenomena are normallyoperating in the region of doses where data are
available, but to a different degree for various doses
and different types of cancer. What may happen at the
low doses. where direct information is lacking, may
only be inferred from a combination of empirical data
and theoretical assumptions, linked together intosome models of radiation action.
475. The models referred to are simplified semiquantitative representations of complex biologicalphenomena. Present knowledge of the mechanisms ofcarcinogenesis, including radiation carcinogenesis, isinadequate to design comprehensive models accounting for all physical and biological factors known to
influence the induction of cancer. To avoid some of
the complications involved. UNSCEA R suggests thatthe range of doses over which extrapolations may
meaningfully be performed should be limited to low
and intermediate doses. Under these conditions, it
seems likely that no serious distortions would result
from other radiation effects, called non-stochastic,that are observed when doses exceed fairly highthresholds, typical for each tissue and each effect.
476. The formulation and analvsis of models ofradiation carcinogenesis must reiy on a few basic
assumptions, as follows:(a)

The observed dose-response relationships forclinically visible tumours in vivo approximatelyreflect the relationships between dose and frequency of the initial triggering events in the cells
where cancer will eventually arise, despite hostreactions and the effect of latency. which may
modify such relationships to some degree. This
assumption is based on the overall similarity ofthe dose-response curves for cancer induction
with those of various other cellular effects ofradiation. UNSCEAR postulates this concept
simply as a working hypothesis:
241

(b)

(c)

(d)

Cancer initiation is basically a unicellular process
occurring at random in single cells. This is also aworking hypothesis that has not yet definitely
been proved. However. evidence lo the contrary,i.e., that cancer initiation takes place in several
cells, is not entirely convincing. The uni-cellulartheory of cancer induction is compatible with thenotion that some, still ill-defined, influences
resulting from irradiation of other neighbouring
cells or other organs may modify the probabilityof an initiated cell to develop into an overt
malignancy. Firm biological evidence in favourof this latter notion is very fragmentary:
Absence of a dose threshold is characteristic ofmany, if not all, tumours. For some animal
tumours (e.g., tumours of the ovary or thymic
lymphoma of the mouse) threshold-type doseresponse relationships are observed. In othercases (e.g., tumours of the skin) cancer is only
induced with great difficulty, i.e., after high dosesof radiation. In still others (i.e., epidermoid lungcancer in man) the data are unclear, owing
perhaps to a short follow-up of the patients.
However, in spite of these exceptions, absence ofa threshold dose for the development of cancer isassumed by UNSCEAR as a working hypothesis
for the time being;
Susceptibility of an irradiated animal or humanpopulation to tumour induction is assumed tofollow a unimodal distribution. Although genetic
predispositions to the development of someforms of malignancy are well documented (seeannex A), efforts to show that such phenomena
apply also w radiation-induced human cancer
have not been successful so far. Therefore,
pending further studies, the same unimodal
distribution of susceptibilities LO the induction ofcancer in irradiated and non-irradiated populations is also provisionally accepted as a working
proposition.

477. On the above assumptions, it is possible to infer
likely shapes for the dose-response relationships ofradiation-induced cancer. Such inferences rely on theanalysis of various other radiation effects observed at
the cellular level. These effects involve the cells'
genetic material, which is also thought to be theprimary target for cancer initiation. The production of
mutations and chromosomal aberrations in somaticand germinal cells, and the oncogenic transformationin vitro of mammalian cell lines, are examples of such
effects. If cancer induction in vivo involves mechanisms
similar to, or related with. those underlying the effects
listed above, one would expect all these phenomena to
respond similarly in respect of changes in dose, dose
rate and fractionation. As such similarities haveactually been observed, it may be possible to extrapolate the shape of dose-response relationships between
such effects and the phenomenon of cancer induction.
478. Three basic non-threshold models of radiation
action as a function of dose have been discussed withrespect to such cellular effects and co cancer induction:
the linear, the linear-quadratic and the pure quadratic.
Notwithstanding some exceptions, these may provide
242

a general envelope for a variety of radiation-induced
end-points at the cellular level, as well as for tumour
induction in experimental animals and human populations.
479. The vast majority of dose-response curves
for induction of point mutations and chromosomal
aberrations by sparsely-ionizing x and gamma rays
may be described by a linear-quadratic model. For thesame end-points, when cell killing is corrected for, alinear model usually applies to densely-ionizing neutrons or alpha particles. As a rule. for a number ofchromosomal structural abnormalities. curvilinearity(upward concavity) is observed for low-LET radiation,
while, for the same effects and a wide range of doses.
linearity prevails for high-LET particles. Linearity ofthe dose-response for somatic mutations and terminal
chromosomal deletions has been found in some celllines, even for low-LET radiation. but these findings
are relatively infrequent.
480. Approximate estimates of proportionality constants linking the chromosomal effects with the doseor its square may be obtained experimentally. They
allow the frequency of such effects to be predicted at
low doses and dose rates from observations at higher
doses. For cancer induction, however, only fragmentary information supports the notion that similar
quantitative relationships with the dose might apply.
UNSCEAR has estimated that if the risk of tumour
induction at I or 2 Gy of sparsely-ionizing radiation(at high dose rate) were extrapolated linearly down tozero dose, this procedure would over-estimate the risk
by a factor of perhaps up to 5 in typical situations.
481. Over the last few years much information onradiation-induced oncogenic transformation of mammalian cells has become available. The cancerous
nature of the transformed cells is shown by the factthat after transformation in vitro they are able to form
malignant tumours upon transplantation into an
animal of the same species. Transformation in vitro istherefore regarded as a model. albeit a simplified one,of radiation carcinogenesis at the cellular level. Cells
exposed in vitro to sparsely-ionizing radiation 24
hours after seeding are transformed according tocomplex kinetics that cannot be fitted to models used
for other cellular effects. Moreover, fractionation of
the dose (below 1.5 Gy total) enhances transformation,
which effect is contrary to what would be predicted bya linear-quadratic model. If similar phenomena would
apply to the induction of cancer in vivo. extrapolation
to low doses and dose rates might result in asignificant under-estimate of the risk. Further researchis needed to elucidate these phenomena, but several
experiments indicate that the observations on in vitro
systems referred to above may result from non-typicalconditions of cellular growth during the early periods
after establishment of the culture. Actually, irradiationof non-dividing cells or cells under exponential conditions of growth {which are thought to be more
representative of an asynchronously dividing cell
population) produces results that are compatible withthose obtained for other cellular effects; thus, forexample, high-dose-rate gamma irradiation results in agreater frequency of transformation than Iow-doserate exposure.

482. There are indications that when cells are irradiated with neutrons. low-dose-rate or dose fractionation may increase the rate of transformation, evenat low doses: however. whereas some observations on
tumour induction in experimental animals clearlysupport these findings. others do not. In otherexperiments, enhanced transformation by neutron
fractionation or protraction were seen only at intermediate and high doses. In view of the scarcity of suchdata. and of the uncertainties regarding the mechanisms involved, further research is needed before
enhancement of cancer induction by neutron fractionation and protraction (relative to single or high-doserate exposure) may be accepted for the purpose of risk
assessment. Such a possibility should. however. be
kept in mind even though the theoretical basis toexplain such phenomena is uncertain at present.
483. Recent experimental findings on radiationinduced tumours in experimental animals have notsubstantially changed the main conclusions reached inannex I of the 1977 UNSCEAR report. Most data
support the notion that dose-response relationships
for x and gamma rays tend to be curvilinear andconcave upward at low doses. Under these conditions,tumour induction is dose-rate dependent, in that a
reduction of the dose rate, or fractionation, reduces
the tumour yield. A linear extrapolation of the risk
from doses delivered at high rates to zero dose would
thus, as a rule, over-estimate the real risk at low doses
and dose rates. However, in one experimental mammary
tumour system (matched by epidemiological data on
human breast cancer) x and gamma radiation produced
a linear dose-response with little fractionation and doserate dependence. This was recognized as an exception in
the 1977 UNSCEAR report. It appears likely that asimilar dose-response relationship could also apply tothe induction of thyroid cancers, but the data are too
limited to permit any definite conclusion to be drawn inthis respect.
484. For densely-ionizing neutron irradiation, tumour
induction in animals follows, in general. a very nearlylinear curve at the lower end of the dose scale and shows
little dependence on dose rate. In some cases, however,enhancement upon fractionation (and possibly protraction) has been noted. Above about 0.1 Gy or so, thecurve tends to become concave downward. markedly insome cases. Under these conditions, a linear extrapolation of the risk down to zero dose from intermediateor high doses and dose rates would involve a \'ariable
degree of under-estimation.
485. Having reviewed existing data on dose-response
relationships for radiation-induced tumours in man,
UNSCEAR considers that this whole matter must betreated with caution because at the present timeobservations are fragmentary. Those for neutrons aretotally absent, and definitive data for atomic bomb
survivors at Hiroshima and Nagasaki are still notavailable. For example, dose-response information forsparsely-ionizing radiation have not been reported forlung and bone tumours. and data for densely-ionizing
radiation have not been reported for thyroid andmammary cancer. For sparsely-ionizing radiation, insome cases (lung. thyroid, breast), the data available areconsistent with linear or linear-quadratic models. For
breast cancer, however, predominant linearity may
apply. as the incidence is little affected by dose
fractionation. Linearity of the response for lung cancer
after irradiation by alpha particles from radon decay
products does not contradict the above statement,
because with alpha particles the dose-squared component is practically absent. Some doubts still remain,
however, as to osteosarcoma induced by bone-seeking
alpha- or beta-emitting radionuclides. However. in spiteof the fragmentary character of the human data, ageneral picture may be emerging from which several
tentative conclusions can be derived.
486. For sparsely-ionizing radiation, linear extrapolation from about 2 Gy down would not overestimate the risk of breast and possibly thyroid cancer. 1t
would slightly over-estimate the risk of leukaemia. andit would definitely over-estimate the risk of bone ·sarcoma. For lung cancer. lack of direct evidence does
not permit any assessment to be made of the magnitudeof the over-estimate.
487. For densely-ionizing radiation, the risk of lungcancer from accumulated exposures to radon decay
products at low dose rates from 300 WLM down(roughly corresponding to 20 to 50 Sv) would not be
over- or under-estimated by linear extrapolation.
However. extrapolation from observations made at
higher cumulative exposures might result in a significant under-estimation due to observed flattening(saturation) of the dose-response curve in this region.
It should be stressed that absolute risk coefficients
derived for male miners, of whom a high proportion
are smokers, should not be applied to the generalpublic without due corrections for various factors(intensity of smoking. Jung ventilation rate. presenceof other contaminating pollutants, etc.) that arethought to increase the risk in the miners.
488. The incidence of bone sarcoma after internal
irradiation by alpha particles from long-lived boneseeking radionuclides is distorted by the existence of apronounced inverse relationship between accumulated
dose and latent period. This results in an apparent
threshold at low doses, and in a reduced loss of life
span per induced tumour, as a function of decreasing
dose, down to zero loss at low doses. If this is acorrect explanation for the upward concavity of thedose-response relationship. a linear extrapolation froma few tens of gray mean skeletal dose down to the grayor milligray region would grossly over-estimate therisk.
489. No human data for induction of breast cancer
and leukaemia by densely-ionizing radiations areavailable at present and, therefore, no direct inferences
can be made about risk extrapolation to the low-dose
domain. On the basis of general knowledge. if the risk
at intermediate doses could be derived from data on
sparsely-ionizing radiation (suitably corrected for thehigher effectiveness of the densely-ionizing particles),a linear extrapolation down to low doses might either
under-estimate or correctly estimate the real risk inthese cases.
243490. For radiation-induced cancers of other organs,only experimental data are available. For sparselyionizing radiations upward concave curvilinear doseresponse relationships with pronounced dose-rate andfractionation effects are usually found. If similar
curves should apply to cancers in man, a linear
extrapolation of risk coefficients (obtained at theintermediate dose region after acute irradiation) to thelow dose and low dose rates. would very likely overestimate the real risk. possibly by a factor of up to 5.
For densely-ionizing radiation, should relevant values
become available, a linear extrapolation would probably under-estimate the risk.

is probably very relevant to the initiation ofcancer. Studies on the relationship between
transformation of cells to a potentially malignant
state in vitro, and the production of malignancies
in vivo. should be particularly pursued. Mechanisms by which sub-transformation and potential
transformation damage is repaired in cells after
exposure to low- and high-LET radiation should
also be explored.
(b)

In experimental animals, a better understandingof the pathogenesis of radiation-induced tumours
should allow the formulation of quantitativemodels more firmly founded than those available
so far. More attention than in the past should be
paid to the end-points tested and to the experimental design which will allow a correct statisticalanalysis of the experimental data. In particular,
studies should aim at elucidating the mechanisms
by which radiation interacts with oncogenes andthe genetic material. Recommendations in respectof experimental work on animals were formulated
in annex 1 of the 1977 UNSCEA R report and. inview of the rather slow rate of accumulation of
the data for such long-term effects, many of theserecommendations are still valid at present. Particular auention should be devoted to studies in
the range of low doses. Comparative studies
would be useful of dose-response relationships
for those tumours that presumably represent
adequate models for human malignancies. andespecially those for which quantitative information on dose-response relationships is likely to
become available in man in the not too distantfuture. Studies could usefully be devoted to the
RBE of different types of low- and high-LET
radiation. particularly in those instances wherereliable epidemiological information does notexist, as is now the case for fast neutrons. A
subject which remains to be explored in greater
depth is that of effects of exogenous and endogenous factors on the shape of dose-response
relationships for radiation-induced cancer, pani·cularly the influence of the immunological state
and the effects of promoting and inhibitory
factors. Another important subject concerns themechanisms by which downward-concave doseresponse curves and enhanced fractionation (orprotraction) effects are seen after various dosesof neutrons.

(c)

In human populations, the follow-up of groups
already under study should be continued as amatter of high priority. New studies on groups
that might potentially yield further information
should also be considered and, if warranted.
carefully undertaken. The topics on which further
information would be required are, in general,
the following:(i) The shape of the dose-response relationships for a wide spectrum of tumours andan extended range of doses, with special
attention to the correct assessment of doses,
as well as its distribution in space and time;(ii) The time distribution of the latent periods
for tumours with long latencies;

491. Upon close inspection. some regularities seemto emerge that may indirectly help in assessing thecharacter of dose-response relationships in man. A
similarity of the shape of the relationships was noted
between man and experimental animals for tumoursof several organs for which reasonably good information exists. These are: mammary and thyroid cancers(low-LET radiations), and lung and bone cancers(high-LET radiations). Should this pattern be confirmed, knowledge of epidemiogical studies in man atintermediate or high doses, and of the shape of thedose-response relationships from several animal species,
might make it possible to assess the bias introduced bylinear extrapolation of the risk coefficients to low
doses.

VII.

RESEARCH NEEDS

492. At the conclusion of this analysis, it appears
quite obvious that there exists a wide intellectual gap
between the abstract and general nature of the models
discussed and the very complex biological reality,
particularly in respect of the molecular mechanisms oftumour induction that are gradually being uncovered.
Assigning a biological meaning to the numericalconstants ofche models. searching for the compatibility
between the mechanisms identified and the models'predictions, and formulating new models based on
hard data rather than on a priori generalizations. are
the formidable tasks facing this type of research today.
Any advancement in the field of radiation carcinogenesis will presumably come in parallel with progressin tumour biology, of which the former is only aspecial aspect. Within these very general guidelines,
specialized studies in the following subjects could bevaluable and UNSCEAR would like to recommend
them to the attention of the interested research
worker:(a)244

Studies on the nature of the cellular and subcellular changes involved in the transformationof normal into cancerous cells. These should aim
at establishing and possibly identifying the stages
in the induction process that have been postulated.
Within these studies. the mechanisms of oncogenictransformation on a wide range of cell types invitro, and the influence of the main radiobiological variables on the form of the relevant
dose-effect relationship. should have a special
place, because the biological end-point in question

(iii) The existence and the possible form of a
relationship between the length of the latent
period and the magnitude of dose;(iv) The influence of age, sex, genetic factors
and some habits (e.g., smoking) on thequantitative characteristics of dose-response

relationships and the resulting variability inrisk estimates;(v) The adequacy with which relative and absolute risk models for different cancers
permit projection of the risk for long
periods after irradiation.

T a b 1 e

Observed (0) and expected (E) breast cancers w\th relat\ve r\sk estimatesas a funct\on of radiation dose for the \nterval 10-34 years
after radiation treatment for mastit\s[ Sl 6)A.

Analys\s of persons w\th average dose to both breasts

Breast cancer
Dose range( Gy)

4.50-12.00
3.5D-4.49
2.50-3.49
1.50-2.49
0.40-1.49
ControlB.

Mean dose
( Gy)

5.84
3.92
2.94
l. 93
l. 12

PY

a

[

RR

~I

Q_/

r;_/

Q/

974
693
l 084
2971
2620
1576 7

4

l. 79
1.27
3.09
5.22
4.78
28.0

2.24
3. 14
2.91
2.30
1.47
1.0

4
9
12
7
28

Analysis of single breasts with total dose per breast

Breast cancer
Dose range( Gy)

6.00-14.00
4.00-5.99
3.00-3.99
2.00-2.99
0.60-1.99
Control
!I
Q_/

~/

&/
tl

Mean dose
( Gy)

B.00
4.67
3.49
2.49
1.50

PY

a

[

~I

Q_/

r;/

1328
3183
2430
3271
1843
37857 tl

2
7

1. 12
2.58

11

l.96

11
2
31

2.73
1.47
31.0

RR
Q/
l. 78

2.71
5.60
4.03
1.36
1.0

For benign tumours no latent period was assumed, so theperson-years at risk include the full interval 1-34 years
after irradiat\on for the single breast analyses.
Observed cancers.
Expected values were calculated by the combination x2
method, w\th adjustment for age at irrad\ation and yearlylntervals since 1rrad\at1on, and were standard\zed so that
0/E =RR= l 1n the control group.
Relat\ve r1sk.
Observed cancers and person-years at risk for control group
1n this analysis include 392 non-\rrad\ated breasts (withthree cancers) of women w\th unilateral \rradiat\on.
245

T a b 1 e

2Curve-flttlng analyses of breast cancer datafrom Massachusetts fluoroscopy ser1es[L22](All parameters are scaled by a factor of 106)

Massachusetts fluoroscopy serles
Model

Goodness of flt~,

Estlmate

Unear

a1

Llnear-quadratlc

:I:

s.o.

X. 2

df

p

560±120

1.6

4

0.81

a1
a2

450±300
29± 76

l. 5

3

0.68

a,
a2

450±230
0 Q_/

1.6

3

0.66

a,
a2
a2

450±860
29±570
0 Q_/

1.5

2

0.47

Quadratlc

a2

130± 40

3.0

4

0.56

Quadratlc + k11 llnga2
a2

220±140(l.6±2.2)104

Unear + ldlllng
Llnear-quadratlc+ k1111 ng

0.48

Parameter~I The dlmenslons of the parameters are as follows:

2.5

3

a 1 : 10-6 a-1 Gy-1
a 2: 10-6 a-1 Gy-2
a 2 : 10-2 Gy-2.
Q_/ The best-flttlng parameter would be negatlve; the value of zero
results from the prlor constralnt that the parameter be non-negatlve.

246

T a b l e

3Curve-f1tt1ng analyses of breast cancer data from Rochester mast\t1s ser\es[l22](All parameters are scaled by a factor of 106)

Mean doses bo both breasts
Model

Goodness of f1t

Parameter~I

Estimate± s.o.

Uneara.1

L\near-quadrat1c
L1near + k1111ng
L1near-quadrat1c+ k1111 ng

Curves for dose to single breast

x2

df

p

560±150

2.0

4

0.74

a.1
a.2

560±430
0 Q/

2.0

3

a.1
132

(1.8±1.4)104

1.2

3Goodness of f1t
Estimate± S.D.

x2dfp

390±180

12.8

4

0.012

0.57

390±540
0 !1./

12.8

3

0.005

0.75

980±370(3.4±1.6)104

3.9

3

0.27

860±290320±1140
370±690780±1480
100±660

a.1
a.2
132

(4.8±4.0)104

1.1

2

0.58

(4.2±4.9)104

3.9

2

0. 14

Quadratica2

11 O:t:600

5.5

4

0.29

55.t 4927.0

40.00002

Quadrat1c + k1111ng

a.2
132

550±170(5.6:tl.5)10 4 1.2

3

0.75

470±210(6.6±2.4)10 4

4. 1

3

0.25

~I See footnote a/ 1n Table 2.
!1.I

The best-f1ttTng parameter would be negative; the value of zero results from the pr\or constraintthat the parameter be non-negat1ve.

247

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