-d

United Nations Scientific Committee
on the Effects of Atomic Radiation

1977 report to the General Assembly, with annexes

NOTE
The report of the Committee without its annexes appears as Official Records of the General
Assembly, Thirty-second Session, Supplement No. 40 (A/32/40).
In the text of each annex, Arabic numbers in parentheses are references listed at the end.
The designations employed and the presentation of material in this publication do not imply theexpression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning
the legal status of any country, territory, city or area, or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

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ANNEX I

Experimental radiation carcinogenesis

CONTENTSParagraphs

Paragraphs

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

1-8

I. METHODOLOGICAL ASPECTS OF RADIATION CARCINOGENESIS . . . . . . . . • .
A.
Experimental approaches . . . . . . . .
B.
Choice of experimental animals
C.
Experiment planning . . • . . . . . . .
D. Data collection . • . . . . . . . . . . . .
E.
Statistical analysis . . • . . . . . . . . .

9-27
9-12
13-14
15-17
18-21
22-27

U. MECHANISMS OF RADIATION CARCINOGENESIS • . . . . • . . . • . . • . • . . .
A.
General hypotheses . . . . . . . . . . .
B.
Combined actions • . . . • • . . . . . .
C.
"Theories" of radiation carcinogenesis
D. Etiopathogenesis of radiation-induced
tumours • • . . . . • . . . • . . . . . . .
E.
Cell transformation in vitro . . . . . . .
F. The immune system . . . . . . . . . . .
G. Hormonal actions . . • • • . . . . . . .
H. The role of cell proliferation . • . . . .
L
Other modifying factors . . . . . . • . .
ill. PHYSICAL PARAMETERS IN RADIATIONCARCINOGENESIS (EXTERNAL IRRADIATION) • • . • . • • • • . . • • . . . . . • . . . .
A.
General • . . . . . . • . . • . . . • • . .
B.
Dose-effect relationships in radiation
carcinogenesis . . . . . . . • . . . . . .
1.
Theory and practice . . . . . . . .
2.
Experimental dose-effect relationships • • • . . . . . . . . . . . . . •3.
Conclusions . . . • . • . . . . . .
C.
Radiation quality and the effects ofdose rate and dose fractionation in
carcinogenesis
I.
The concept of RBE . . . . . . .
2.
Dose-RBE relationships . . . . • .
3.
Conclusions • . . . . . . . . . • .
4.
Effects of temporal distribution ofirradiation • . • . . . . . . . . . .
5.
Dose-rate effects • • . • . • . . . .
6.
Lifetime irradiation . . . . . . . .
7.
Split-dose irradiation • . . . . . .
8.
Conclusions . . . . . . . . . . . .

28-86
28-33
34-38
39-44
45-52
53-58
59-67
68-73
74-79
80-86

87-215
87-88
89-154
91-111
112-139140-154

155-215155-157
158-175
176-178
179-183
184-204205-210211-213214-215

IV. CARCINOGENESIS BY INTERNAL E~IITTERS . • • • . . . . . . . . . . . . . • . . . .
A. General . • . • . . . . . . . • • . . . . .
B.
Bone-seeking beta emitters . . • . . . •1.
Bone tumours ..•.•.•••..
2.
Myeloproliferative diseases andother tumours ...•.••••.•
3.
Conclusions . • • . . . . . . . . •C.
Bone-seeking alpha emitters . . . . . .
1.
Radium isotopes . • • . . . . . . .
2.
Thorium isotopes . . • • . . . . •3.
Plutonium . . . . • . . . . . . . .
4.
Other actinides . . . . . . . . . . .
5.
Conclusions . . . . . . . . . . . .
D. Inhaled alpha emitters . . . . . • . . . .
V. BIOLOGICAL VARIABLES IN RADIATION CARCINOGENESIS . . . . . . . . . .
A. General
B.
Genetic variables . . . . . . . . . . . . .
1.
Species . . . . . • . • • . . . . . .
2.
Strain . • • • . . . . • • . . . • . .
3.
Internal irradiation ••••....
c. Age effects . . . • . . • • . . • . . . . .
1.
Post-natal irradiation . • . . . . .
2.
Pre-natal irradiation . • . . . • . •3.
Internal emitters . . . . . • . . . .
D. Tissues at risk . . . . . . . • . • . . . . .
1.
General . . . . . . . . • • . . . . .
2.
Conclusions . . . . • • . . . . . .

216-277216-219220-242220-235236-240241-242243-27 I
243-251
252-254
255-261262-268269-271272-277278-220278
279-288279-282283-284285-288289-300
289-293294-297298-300
301-320301-319320
321-334

VI. SUMMARY AND CONCLUSIONS . . . . . .
A.
General . . . . . . . • . . . . . . • . . .
B.
Methodology . . . . . . . . . . . . • . .
C.
Mechanisms • • • . . • . . . . . . . . . .
D. Dose, dose-rate and RBE . . . . . . . .
E.
Internal emitters . . . • . . . . . • • . .
F.
Biological variables . . • . . • . . . . . .

321
322
323-326327-331332-333
334-335

VII. NEEDS FOR FUTURE RESEARCH

336-339
Page

References . . . . . . . . • . . • . . . . . . • . . . .

625

565

Introduction
1.
Induction of neoplasia by iomzmg radiation
represents one of the first recognized radiobiologicaleffects described in man soon after the discovery of xrays (715). Bergonie and Tribondeau (42) in 1906 in an
attempt to rationalize the use of radiation for thetreatment of tumours drew the attention of radiologists
to this harmful consequence of over-exposure. The first
documentation of sarcoma induction after repeatedexposure to x rays of an animal's skin followed a few
years later (424, 425), and the origin of what ispresently known as experimental radiation carcinogenesis may probably be traced back to these classicalreports.
2.
In spite of some scattered papers which extended
the initial observations to practically all common speciesof laboratory animals and to a variety of different tissues(for good historical reviews see 364. 675, 677). the years
that followed until the middle 1940s did not, however,
witness the configuration of experimental radiation
carcinogenesis as a chapter separate from the field ofgeneral carcinogenesis, which was especially concernedat the time with the various aspects of chemicallyinduced neoplasia. Important advances in radiation
carcinogenesis were brought about by the experience inman with the reports of radiation-induced lung cancer
among uranium miners (577) and of bone sarcoma indial painters (428). Starting from the middle 1940s on.
as a result of the A-bomb experience and within theframework of the renewed interest in biological andradiobiological research, a steady increase in concern
and reports on the induction of tumours by radiation
has taken place, amounting at present to an estimatedfew thousand specific bibliographic references. From
time to time, the newest acquisitions have been reviewed
and the relevant references may be found in Colwell andRuss (125), Furth and Lorenz (208), Lacassagne (362,363), Furth and Upton (209), Brues (68), Lacassagne etal (364), United Nations (668, 669), Harris (258),
Casarett (91), Upton (672, 673, 675, 679), Curtis (140),
Van Cleave (697), Casarett (92), Mole (459) .andMoskalev and Streltsova (477).
3.
Yet, after almost 80 years of arduous research inexperimental animals and observations in man, it must
be recognized that the complexity of the problem has so
far defeated any effort for a reasonable understanding of
its numerous implications. The growing concern fromthe wide-spread use of radiation in industry andmedicine (see 562 as a general reference): the progress
made in very recent years in all specialized fields ofcarcinogenesis, with special regard to the role of viruses
and their interplay with radiation and to the role of theimmune reaction in the development of neoplasia (see38 for an updated treatise on all aspects ofcarcinogenesis); the availability of new experimental
data in the specific field of neoplasia induction byradiation to be dealt with in the course of the present
report: the desirability to keep under close scrutiny thenewest development in the experimental animal systems
for their implications in human radiation protection; theneed to identify areas of special importance where effort
might be preferentially addressed in the future (see 564
and 670 as general references); all these, have prompted566

the· Committee to reconsider the information on the
induction of neoplasia in experimental animals, after thelatest review on the same subject appeared most recently(670).
As in the preceding case (670), the present review
4.
is not meant to provide an exhaustive and comprehensive treatment of the subject-a very difficult undertaking in view of the vast amount of information
available-but a selection of illustrative papers. An effort
has been made to identify those reports where therelevance of the hypotheses to the subject, the accurate
planning of the experiments, the numerosity of theobservation, and the application of careful statisticaltreatments to the data, render the conclusions amenable
to a general interpretation and evaluation. Along theselines, the main scope of the review is therefore that ofsetting the newest acquisitions in the light of the general
problem of cancer induction and of its recent
developments, and to identify generalities and regularities emerging from the animal experience that may beof help for the interpretation of the human data.
5.
The 1972 report of the Committee (670) has
already discussed extensively the scope and thelimitations of animal experimentation in radiation
carcinogenesis and its role with respect to theinterpretation of the epidemiological data. It should
again be stressed that animal data are of great value in
illuminating the effects in man but may not be used fornumerical estimates. They are therefore as such an
inadequate substitute for the existing paucity of data in
the human species. There are at present insurmountabledifficulties in extrapolating between different conditionsof exposure, between high and low radiation doses anddose rates in the same species, and even more in theattempts to make generalizations about species having
widely different physiological and pathological characteristics. But, partly for pragmatic reasons. owing to thepressing need to project the available data in man toconditions other than those where they were derived.
and partly on scientific grounds, in view of thequalitative similarity of cancer induction in man and inother mammalian species, the experimentation on
animals has acquired great significance for theunderstanding of the carcinogenic risk in man.
According to the conclusions of the 1972 report ( 670)
which are still valid at present, the contribution ofexperimental work to the general problem of risk
evaluation in man may come about from three mainlines of approach.
6.
The first and most basic of these lines relates tothe clarification of the mechanisms of carcinogenic
action. It is obvious that this line still retains its
overwhelming value since. in spite of the continuous
advancements in our understanding of these mechanisms, we are still far from their detailed comprehension.
It must, on the other hand, be realized that research inradiation carcinogenesis is a difficult and slow
undertaking. where results cannot be expected within ashort time.
7.
The second line of approach, discussed by Mole
(457), attempts to establish qualitative and possibly
quantitative generalizations with respect to a number ofphysical parameters (dose, dose rate. radiation quality)and biological parameters (age, sex, weight, body ororgan size, metabolic rate, rate of DNA synthesis) which
are known or suspected to affect radiation carcinogenesis. This course of action in fact yields useful data,
although by no means adequate at present for thequantification of parameters generally applicable to all
species with the necessary degree of certainty.
8.
Finally, the search for experimental models ofcarcinogenesis which might respond to radiation in amanner qualitatively similar as in man, has been
identified as the third possible objective of well foundedexperiments. It is thought that knowledge of therelationship of effect with dose and dose rate in suchanimal models (especially in the conditions relevant toradiation protection) could perhaps allow refinements in
our risk estimates for humans, possibly by a consistentfactor (564). The development of other models whichfacilitate the study of relations between tumour
induction and such phenomena as radiation-induced cellkilling and cell transformation, division and differentiation, could also be useful for that purpose.

cellular and subcellular levels during the action of the
carcinogenic agent can hardly be carried out on verylarge groups of animals.
12. For this reason and also because extrapolation of
mechanisms between different animal species mightperhaps be easier than the extrapolation of rates of
induction of diseases which are typical of each species. a
different experimental approach has been advocated.
The new strategy is perhaps.Jess ambitious since its main
scope is to provide answers to very specific questions bydesigning and testing simplified models of radiation
carcinogenesis in vitro and in viva ( 127, 564). The
conversion to this new, experimental approach willprobably be very gradual and in any case will not
exclude entirely the traditional large-scale experimentation. Indeed, just as experimental work on model
systems was also carried out in the past years, large-scale
work may still be necessary in special cases in the future.
However, the trend is towards a new equilibrium
between both approaches. and only time and experience
will allow a definite judgement on their merits.

B. CHOICE OF EXPERIMENTAL ANIMALS

I. METHODOLOGICAL ASPECTS OF
RADIATION CARCINOGENESIS
A. EXPERIMENTAL APPROACHES

9.
The work on experimental radiation carcinogenesis
offers unique features that might be considered in acommon context, partly to emphasize the difficulties indesigning, performing and analyzing radiation carcinogenesis work, partly to draw attention to the many
pitfalls that should be taken into account whenreviewing results, and partly to warn the reader of theneed for caution when generalizing the relevant
conclusions.
10. Experiments on radiation carcinogenesis have been
performed, especially in the past, on large populations ofanimals. There were well founded reasons for thisexperimental strategy, since quantiative assessments of
the risk of late effects were needed and the use of large
groups of animals was rightly considered as a reasonable,
direct solution to the problems of obtaining overall
estimates of the risks. The so-called "Greenhouse
Experiment" carried out by a task force of scientists andpublished in its final form in 1960 (688) is probably thebest known example of this type of approach involving
major scientific efforts and complex organizational
problems. The importance of this early experience isoutstanding since through it the major long-term effectsof irradiation could be documented and basic information about the significance of radiation quality, dose andtime factors in mammalian carcinogenesis became
available.
11. However. it became gradually apparent that acomprehensive approach involving actuarial, epidemiological and pathological observations of all possible lesions
expressed by irradiated animal populations was unsuitable for a detailed investigation of mechanisms. The
study of structural and functional modifications at the

13. From consideration of the available literature it
appears that in some cases not enough attention has
been paid to the choice of the experimental animals usedin radiation carcinogenesis work; this can probably be
attributed to unavailability of the relevant specificknowledge at the time when the experiments wereplanned. The choice of the animal species and/or thestrain is however of paramount importance and should
primarily be a function of the specific effect to beinvestigated. In this context. susceptibility of theexperimental animal to the particular form of neoplasia
under study is often the main consideration. Examples
might be offered by the tumours of the kidney to which
the rat is particularly susceptible (36, 422) or by the
specificity of host-virus relationships in radiationinduced leukaemogenesis in mice (237).
14. In other cases, however, the choice of the animal is
primarily dictated by the need to facilitate theextrapolation of the effects by extending the observations to different animal species (730, 638) or by thedesire to simulate more closely the exposure of humans
by using medium- and large-size mammals such as thedog (545,622,435), the pig (281,278) and the monkey(440, 259). Within each species, however, the characteristics of particular inbred strains with respect to thespontaneous (630, 16, 413) or induced (566) rate ofoccurrence of special tumour types should also be
considered as well as the effect of sex (paras. 68-73) andage at irradiation (paras. 289-300). As a very general
proposition and for reasons to be examined later, a goodmodel of carcinogenesis is one where the spontaneous
incidence of the neoplastic lesion under investigation isvery low in the intact animal and increases considerably
after treatment; examples of such systems may be theradiation-induced mammary neoplasia in the young
Sprague-Dawley rat ( 138) or the thyrnic lymphoma of
the C57BL mouse (326). In special instances, however,
the reverse condition (high spontaneous incidence ofsome tumour in normal animals. which is depressed byradiation treatments) may also be of value ( 135).
567

C. EXPERIMENT PLANNING

15. When dealing with marginal effects, often on theborderline of significance, it is imperative that thevariability introduced by the presence of intercurrent
diseases in the animal colony should not mask theeffects of the radiation treatment. This calls for highhygienic standards in animal maintenance. It has also
been \shown (paras. 80-82) that the conditions of
the animal intestinal microflora as affected by the living
environment may introduce changes in the neoplastic
response. Although such effects are probably not
relevant to all tumour types, these observations stressthe need for a permanent control of the animal facilities
in order to allow a precise evaluation of the healthconditions of the colony at all times during theexecution of the experiments. There is certainly no needhere to discuss in detail all procedures connected withanimal handling (caging, identification, routine inspection, data collection etc.), but it should be stressed that,in view of the long duration of the experiments, evenminor faults in the handling technique might result inthe loss of precious data. In large-scale work,
information storage, retrieval and processing have beenhandled by computers (234, 106).
16. Induction of cancer by radiation is a comparatively rare phenomenon, and to be established with thenecessary degree of confidence by a comparison between
treated and untreated animals this comparison requires
therefore the use of fairly large groups of animals, thesize of which must be related to the expected incidenceof the tumour type and to the accuracy with which theinduced change with respect to background incidence is
to be assessed. Very large animal populations are
particularly required at low radiation doses and dose
rates where the incidence of tumours above thespontaneous level is very small and the resolution of theexperiments critically depends on the number of animals
tested. A good example of the criteria to be followed in
the estimation of the sample size in an experiment on
tumour induction designed for a particularly well known
strain of animals has been provided by Upton et al(681). The situation presented in that report may
however be regarded as an extreme one in the sense that
seldom are the starting conditions of an experiment so
thoroughly defined and also because information is notoften sought at such very low dose levels.
17. Calculations of this type may also be performedby other mathematical models (571), but they require,in general, preliminary knowledge of the tumour system
to be investigated and, in particular, some backgroundinformation on the form of the dose-effect relationshipand on the latency period of the expected lesions. With
regard to sample size, a distinction can probably bemade in practice between those experimental series
where the primary object is the estimation of tumour
induction rates as a function of an independent variable
like the dose, and other series concerned with the studyof mechanisms, where internal comparisons between
groups given different treatments usually allow working
with smaller groups (335). The above considerations,however, emphasize the importance of careful planningand the convenience of utilizing animal model systems
568

where basic information on tumour incidence andinduction is already available so that previous experienceon the model may help in designing further work.

D. DATA COLLECTION

18. The literature reviewed, particularly the earlier
reports. show that there has been a tendency by thepathologists to underestimate the need for goodplanning and for quantitative observations on theirradiated animals and, conversely, that there has been
inadequate attention given to the pathology of theinduced lesions by radiation biologists mostly concernedwith the statistical and epidemiological end-points. Thistendency is disappearing in recent papers since it is now
clear to all engaged in long-term experimentation thatboth types of end-point, the morphological and theactuarial, are equally important for a comprehensive
evaluation of an experiment. It has also been realizedthat experiments on late effects, due to their size andcost, are often unique and the best possible use must
therefore be made of all the information available. Thereis no need therefore in the present context to emphasize
further the importance of regular animal follow-up andof a thorough macroscopic and histological examinationof the animals, particularly at death. Specialized reports
are available on this subject to which reference may
conveniently be made (133, 106).
19. As far as pathology is concerned, it is important topoint out that the object of post-mortem examination is
not only to establish the immediate causes of death, butparticularly to provide a complete description of theanimal's condition at death, for the identification of thevarious syndromes and lesions brought about by theradiation treatment. In special instances more detailed
pathological studies are required, and when theinformation is obtained at the time of death, it isinadequate for a full description of the time of onset,
the rate of development and the final incidence of thevarious neoplastic lesions. To this end, serial sacrificeexperiments are needed (9, 169). In other instances
biochemical, microbiological or functional changes must
be investigated by destructive tests. Animals for suchparallel studies should however be kept separate fromthe experimental groups on which actuarial observations
are made, since withdrawal of animals for sacrifice might
seriously affect the estimates of mortality rates in themain experiment (681, 270).
20. Although it is accepted that radiation can induce agreat variety of tumours having a wide spectrum ofmalignancy, the classification of these tumours into
"benign" or "malignant" causes endless controversy
among pathologists. In fact, the morphological aspectsof the tumour cells, their tendency to invade the normal
surrounding tissues, their ability to metastasize and togrow into host animals after transplantation, thecapacity of the tumour to kill the animal. the immediate
cause of death etc., may be assumed to be singly or
jointly the criteria to assess malignancy. The present
report avoids such a controversial field by referring as
much as possible to the nomenclature of tumour types
used in the papers reviewed.

21. Recording and classification of the pathologicalobservations may follow extensive ( 124) or more
frequently, compact computerized schemes (520, 106)
conveniently adapted to the special needs of theexperiments. Special attention should be drawn to thedesirability of uniformity in the classification of thevarious diseases, bearing in mind that late pathologicalsyndromes in animals are often unique to the various
species. Efforts for standardization in this field are
currently being made on an intcmational scale and to
this end cross-reference programmes between specializedlaboratories are also desirable (667). Similar criteria of
uniformity should also be applied to the conditions ofradiation exposure, for which reference is made to
general publications (294, 295). Programmes ofradiation dosimetry standardization among laboratories
specifically active in the field of late effects are also
being made and should be continued in order to improve
the reproducibility of the physical parameters (550).
E. STATISTICAL ANALYSIS
22. According to Berenblum (38), there are at least
four ways of expressing quantitatively tumour induction
among treated animals. These are widely used inchemical carcinogenesis work, but are as such inadequate
to provide a comprehensive description of the final
tumour incidence and incidence rate in radiation work.
They are: (a) the percentage of animals bearing one ormore tumours; (b) the average number of tumours pertumour-bearing animal or per treated animal; (c) the
average and distributional latency times in theappearance of tumours after the application of the
carcinogenic stimulus; and finally {d} the doses ofcarcinogen to obtain minimal effective and maximal
carcinogenic response in the tumour system under study.
The last type of data is precisely what is usually soughtin radiation work, that is, the establishment of complete
dose-effect relationships; however, the precise assessment of such relationships based on final tumour
incidence rate is to a variable extent influenced by themortality from other diseases in the course of theexperiment.
23.

In spite of the fact that the effect of competingrisks on the induction estimates has been recognized forsome time, and that attention has been drawn repeatedly
to the posSible consequences of not properly allowing
for such risks in radiation ::arcinogenesis work ( 455,175), many reports are still found lacking precise
actuarial analyses. Appropriate advanced statisticaltreatments (144, 318) and guidelines to the analysis oftumour and death rates in the presence of competing
causes of death are however available (569, 270, 533).
Special procedures for the case of continuous exposure
to the carcinogenic agent have also been devised (534).
24. A reasonable analysis of the epidemiological andpathological data in radiation carcinogenesis work rests
in practice on the following steps. First of all, theconstruction of the cumulative mortality curve for eachexperimental group under study, with appropriate
estimates of the fifty-per-cent end-points (mean andmedian) and of their variability. This preliminary step
may be carried out by elementary statistical andgraphical analysis. Consideration of the general trend ofthese curves is however inadequate for the identificationof possible irregularities in the rate of extinction of theanimal population, except in cases where suchphenomena are particularly important. Only a second
step consisting in a careful study of the instantaneousand cumulative rate of mortality intensity as a functionof time, with appropriate corrections for the actual
number of animals -at risk in any particular time interval(343), will allow the identification of peaks or plateaus in
the death rate of the population, which may possibly be
traced back to special pathological lesions or syndromes
operating in the animals at that particular time.
Computation of such death-rate curves at varying timeintervals will help to evaluate the importance of thesechanges, which, especially in small groups of animals,
may sometimes be regarded as the spurious result of thesystem's variability rather than the effect of consistentpathological phenomena. Finally, attention should befocused on any particular disease (or group of diseases)
diagnosed, in order to estimate its age-specific rate ofoccurrence and its final incidence, with appropriate
corrections for competing risks (571, 270).
25. It is appropriate to mention at this point thatcomparisons between different treatment groups inorder to derive numerical estimates of tumour induction(such as, for example, in relative biological effectiveness(RBE) or dose-rate-effect studies) should only be
performed after elementary criteria of homogeneity
between the groups under comparison are satisfied,namely that the mean and median longevity and the rateof mortality of the two animal populations are actuallycomparable. Unfortunately, reference is seldom made in
the reviewed papers to the use of such cautions in thestatistical analysis of the data. Calculation of age-specificincidence curves may be considered the only appropriate
and complete method of actuarial analysis, since itallows the precise evaluation of both acceleration andtrue induction phenomena in radiation carcinogenesis(paras. 92, 93). Although the numerical estimatesof tumour induction obtained from this type of analysis
may not be strikingly different from the results of lessrefined methods in the case of early-appearing tumours
such as the thyrnic lymphoma, age-specific calculations
are absolutely required for all pathological conditions
occurring gradually and late in life, such as the malignant
solid tumours or the systemic lymphoreticular neoplasms. It is desirable that a more extensive use of theseactuarial techniques be made in the future, since they
will clarify the conditions under which numericalestimates of tumour induction are actually made.
26. Many aspects of radiation-induced carcinogenesis
are closely related to life-span shortening, anotherimportant effect of irradiation readily apparent intreated animal groups as a reduction of the mean age atdeath. There have been discrepancies in the interpretation of this phenomenon and its relevance to tumour
induction. On the one hand, the results of experiments
where large groups of animals were irradiated with highinstantaneous whole-body doses (688, 383) has beeninterpreted to favour the hypothesis of a non-specificpremature ageing of the irradiated animals, since all
diseases associated with senescence seemed to appear
earlier, with no evidence that life-span shortening could
be correlated with any particular cause of death. On the569

other hand, as has already been mentioned (para. 19).
the use of data derived from post-mortem examinations
may be misleading and inadequate to give end-points
free from the distortion of the intercurrent mortality(9, 10, 270).
27. Owing to inadequacies of the statistical treatmentof the data, the conclusions of these early experiments
were thus challenged and the non-specific life-span
shortening attributed to a technical artefact (716).
Actually, other experimental series where appropriate
death-rate analyses have been performed (718) andwhere the effects of dose fractionation ( 449), chronic
exposure (451, 227) and age at irradiation (451, 749)
have been tested. have shown rather conclusively thatthe concept of a non-specific ageing effect of radiation is
no longer tenable. At present, the consensus seems to bethat life-span shortening is to be attributed almost
entirely to the induction of neoplasia, especially at low
doses and dose rates. A non-specific component may
however become apparent in the high-dose range (227).

II. MECHANISMS OF RADIATIONCARCINOGENESIS
A. GENERAL HYPOTHESIS
28. Since it is the purpose of the present report todiscuss the problem of radiation carcinogenesis in the
more general context of carcinogenesis as a biologicalphenomenon, it seems appropriate to review briefly
some of the current "theories" of carcinogenesis. It is
becoming increasingly clear in view of much experimental evidence that this phenomenon is extremelycomplex, and therefore one should not expect that earlynaive concepts postulating, for example, that a tumour
might result from the energy imparted to a cell by an
ion-pair or solely from a somatic mutation might apply:
dosimetric calculations or biological considerations(420) may easily disprove such assumptions.

events. This interpretation would also be in accordancewith our notions of the biology of cancer, although it
would be unrealistic at present to attnbute any precise
biological significance to such postulated events.
30. Recently a new interpretation of radiobiologicalphenomena has been published. This approach is known
as the theory of dual radiation action (348). The theory
is based on microdosimetric concepts and takes account,
not only of the mean absorbed energy of radiation, butalso of possible fluctuations of the energy deposited involumes of micron dimensions. According to the theoryof dual radiation action, the primary biological effecttakes place only if two events occur in a sensitive
volume. The probability of each such event is
proportional to the specific energy absorbed in the
microvolume. For densely ionizing radiation, a particle
traversing the sensitive volume has sufficiently highprobability to cause both events. On the other hand, for
ionizing radiation with low linear energy transfer (LET),
two charged particles are often necessary to provide thepair of events leading to the primary biological lesion.
On the basis of these considerations the quantitative
theory of dual radiation action has been developed. This
theory has been applied to the interpretation of the RBE
dependence on dose for a number of biological effects(339), including carcinogenesis (338). Specially interesting for the present report is the consideration of
the induction of mammary neoplasia in the rat (575,613) and of human leukaemia in Japanese A-bomb
survivors (576). Remarkable agreement has been shown
between the experimental observations and the theory
that predicts at the cellular level linear dose-effectrelationships for neutrons and curvilinear relationships
for low-LET radiations. This approach has obvious
implications in practice for the design of new
experiments and for the prediction of certain trends ofthe phenomenon of cancer induction as a function ofradiation quality, dose, dose rate, fractionation etc.
However, from the point of view of the biologicaltheories of carcinogenesis, the good correlations found,though very suggestive, cannot be taken as absolute
proof of the validity of the starting hypotheses.
Unfortunately they also do not identify the mechanisms
involved.

29. The very low likelihood of an event of neoplastictransformation 1 in relation to the number of possible
target cells (429, 459) and the essentially randomcharacter of the processes of energy deposition in
irradiated tissues have often justified in the past analysisof tumour induction in probabilistic terms. On thesebases, mathematical models have been applied to thestudy of human spontaneous tumours (17, 76) and also
to radiation carcinogenesis in man and experimental
animals following external irradiation (452, 30. 430) or
exposure to internally administered radioisotopes (452,453, 430). Inferences have also been drawn concerning
the shape of the dose-risk curve of relevance to radiation
protection (77, 743). In all cases, models of themulti-event type have been supported by the data on
neoplastic incidence as a function of time and dose. inthe sense that such data are consistent with the generalhypothesis that the appearance of a tumour is the final
outcome of a succession and/or interplay of rare discrete

31. Within the framework of a biomathematicalreconnaissance of the most basic problems of carcinogenesis and radiation risks, Mayneord and Clarke (430)have proposed a formulation which relates the dose to
the risk of a rare event such as a neoplastictransformation in a population of cells. In spite of therecognized limitations, this formulation has been used to
examine a number of practical problems, including theform of the dose-effect relationship, the effect of dose
inhomogeneity, the LET, and the estimate of theabsolute carcinogenic risk per unit dose. The main valueof this contribution lies in the attempt to identify anddefine the quantities which may be more significant for
the analysis of these problems. and as such it is of greatinterest to the theoretical. experimental and practicalaspects of radiation carcinogenesis.

1
In the context of the present document the terms"neoplastic transformation" and "cell transformation" are used
in a descriptive sense to include all changes that confer upon anormal cell (some of) the properties of a viable neoplastic cell.

32. In very general conceptual terms. by analogy withthe classical experiments on chemically induced skinneoplasia-following, for example, the application of570

benzopyrene and croton oil in optimal doses-theinduction of any tumour may be envisaged as theoutcome of two independent actions referred to as''initiation" and "promotion" (37). The former isviewed as a fast irreversible process acting on a normal
cell and conferring upon it tumorous characteristics.
Initiation would precede in time the slowly acting
process of promotion but would never result, in thelatter's absence, in a growing tumour, since the induced
cell might remain indefinitely in a "dormant'· state
without further division. These different actions may
experimentally be resolved in time and quality, since thefinal yield of tumours is generally a function of theinitiator's dose, but their rate of appearance is mainly
dependent upon the time and dosage of the promoter.
33. Ionizing radiation. in view of its extreme
unspecificity of action on living tissues, cannot be
considered as either a "pure" initiator or promoter but
shares the properties of both classes, and for this reason
it represents a very special carcinogenic agent. In spite ofthis duality, which might in itself give rise to ambiguous
answers, radiation has been tested in a number ofexperiments in association with chemical carcinogenic
substances known to act, under the specificexperimental conditions, through initiating or promoting
mechanisms. An exhaustive list of references up to 1966
may be found in a review by Kondrateva (356).
B. COMBINED ACTIONS
34. Much of the work on the combined action ofchemical carcinogens and radiation was carried out on
the skin. the tissue where the two-stage mechanism ofcarcinogenesis was originally identified (37) and can be
more easily tested. Electrons or uv light in association
with other carcinogens usually results in a higher yield of
tumours than any of the agents administered alone. Thisapplies to methylcholanthrene ( 113), 7, 12-dimethylbenz[a ]anthracene (I 71, 639) and 4-nitroquinoline I-oxide(276). Reversing the order of administration does notchange the result in case of beta rays (276) but may leadto an inhibitory effect with uv radiation (640). In themouse, the tumour induction rate did not change byincreasing the interval between the exposure to beta
radiationand the subsequent painting with
4-nitroquinoline I-oxide, showing the persistence of thelatent carcinogenic action of radiation (275). The actionof croton oil, which is a typical promoter of chemicallyinduced skin tumours, seems uncertain when combinedwith radiation, since either enhancement of effects withuv (172) and electrons (624) or negative results (233,71) have been obtained. However, it may be said in very
general terms that initiation and promotion have beenverified in the case of skin radiation carcinogenesis. The
results of combining two independent carcinogenic
treatments on the skin might also be interpreted on thebase of other concepts of the fundamental processes ofcarcinogenesis. Some of the previously mentioned
experiments (171, 172, 276) would in fact be regarded
by others ( 486) as clear examples of syncarcinogenic
summation of chemical and physical agents.
35. The situation appears to be definitely more
confused with respect to the induction of tumours inother tissues or to systemic leukaemogenesis. In the caseof the lung, urethane (a specific inducer of lungadenomas in mice) has been used in association with xrays with various dose and time schedules and after
single or fractionated radiation treatments. A reductionin the percentage incidence and tumour multiplicity per
animal has been obtained in one experimental series(200). and this result has been attributed to an
inhibitory action by the high radiation dose on theurethane-induced tumours. Recalculation of these databy another group of workers (388) led to an entirely
different interpretation. Additive effects were reportedby the same authors in another set of experiments. The
resulting effect was explained as the end-point of twocompeting mechanisms., cell killing and celltransformation. whereby. depending on the dose of thetwo agents, any effect becomes possible. As a further
complication, an immunological component might alsointerfere with these phenomena (116). Mice irradiated inutero with a small dose of x rays (36 rad) have shown asignificantly increased incidence of lung tumours
induced by urethane given after birth (511).
36. Concerning leukaernogenesis, an increased effectwith the combined treatment of urethane and radiation
seems to be the general finding (337. 41, 154, 376, 40.
707, 216), especially in young mice (40, 707). perhaps
due to differences in catabolism rate of the drug withage rather than to changes in the intrinsic susceptibilityof target cells (100). However. at least in one case,thymic lymphoma and myeloid leukaemia were foundinsensitive to the combined action of the two agents( 686). Croton oil acts also as an effective promoter ofsystemic leukaemia (297). Differential actions on the
myeloid leukaemia or on the thymic lymphoma havebeen reported in the mouse by the combination of
my le ran ( 695) or novoembichin (12) with radiation.
37. Intragastric administration of 3-methylcholanthrene followed by x-ray (604) or fissionneutron (619) irradiation gave rise to additiveeffects for induction of mammary adenocarcinoma:
however. in another system. brain tumours, where thesame chemical was applied locally, beta-ray irradiation
resulted in an inhibition proportional to radiation dose(423). As far as other tumours were concerned, nochanges were found with respect to x rays alone or inassociation with 3,4-benzopyrene (348). Dibutylnitrosamine (DBNA) or 4-ethylsulphonyl-naphtalene-1-sulphonamide (ENS) combined with x rays showed noeffect on tumours of the urinary bladder but a reductionof mammary tumour incidence (199). A synergistic
action on the production of liver and gastric carcinoma
by fission neutrons in combination with N.N'-2,7-fluorenylenebisacetarriide (2, 1:FAA) was reported, but noadditivity or potentiation for intestinal tumours (713)
was found. Localized x irradiation in association withthe same drug administered in the diet accelerated theinduction of hepatomas (485). and similar effects werereported with the association of x rays and o-aminoazotoluene (342) and of 144 Ce and dimethylaminoazobenzene (OBA) (416). Experiments on additive carcinogenic
effects
of
9,10-dimethyl-l,2-benzanthraceneor
1,2,5 ,6-dibenzanthracene in association with chronicinternal irradiation from 90 Sr were also reported (759,758). Finally, survival and tumour induction were tested
in three strains of rats following x-irradiation in571

association with urethane. In spite of some interesting
differences observed between strains, the overall effectof the joint treatment was not greater than the sum ·ofthe separate effects at the dosage level studies (482).
38. In view of the complex pathogenesis of thetumour systems tested. where the conceptual distinction
between induction and promotion cannot easily be
proven, the conflicting evidences available are consistent
with the assumption that associated treatments decrease,rather than increase the induction of neoplasia, in cases
where the toxicity of the two combined agents
outweighs their additive carcinogenic properties (675). A
possible quantitative approach to these problems could
possibly come from studies at the cellular level (519 and
518). In embryo hamster cells, for example, thetransformation by benzo[a Jpyrene administered prior toirradiation has shown, both per cell and per total colony.
maximum enhancement when the drug treatment wasgiven 48 hours post-irradiation and when the radiation
doses range from 250 to 500 rad. At higher radiation
doses and at longer intervals between treatments thetransformation efficiency actually decreased (149). No
definite conclusion with respect to any special tumour
model system may therefore be drawn before the dose,
dosage schedule, order of administration and modalityof the combined treatment with physical and chemical
agents are properly and thoroughly explored. which isseldom the case in the works reviewed.

C. "THEORIES" OF RADIATIONCARCINOGENESIS
39. The concepts of induction and promotion provide
some insight into the possible mode of action ofcarcinogenic agents, but they don't exhaust the problemof tumour etiology and pathogenesis for which definite
biological mechanisms must be traced. To this effect. agood number of theories have been proposed in the past,
but most of them were gradually abandoned since none
could account for the large array of properties of thetumorous cell. A critical review of most of these theories
in a historical perspective has recently been provided by
Berenblum (38).
40. At present. only a few of the original theories arestill viable and will be discussed in the present reportespecially for their relevance to the action of radiation.
The genetic foundation is common to all of them since it
appears at present as the most logical way to account for
the irreversibility and the continuity of the neoplastictransformation in the course of cell division. This
common molecular genetic basis makes it conceivablethat the distinction that is still drawn between thesomatic mutation and the viral hypotheses of tumour
induction might soon become unnecessary.
41. The somatic mutation theory of cancer induction
stems from the notion that tumours are often carrying
abnormal mitotic configurations which were originallyinterpreted as the phenotypic expression of the genetic
alteration responsible for cell transformation. Also, thefact that unique chromosomal configurations (201. 290.
722, 213, 444) or biochemical markers (382) are often
found in all the cells of primary tumours, as if they572

would be derived from a single mutated clone. lent
support to this theory. However, the fact that aberrant
unviable mitoses are often secondary changes or theend-result of excessive tumour growth rather than its
cause (353, 354), the gradual realization that mutagenesis at the chromosomal level and carcinogenesis by anumber of agents are not necessarily closely linked
phenomena, at least in mammals (198). and the notionthat carcinogenesis is better explained as a multi-stepprocess involving the interplay of many factors andmechanisms ( 120, 141, 143), made the theory lessappealing, at least at the chromosomal level. At the DNA
level. however, the hypothesis of somatic mutation may
still be entertained (although with some difficulties in
explaining the multi-stage nature of malignant transformation) and could well explain the spontaneous
occurrence of cancer as well as its induction bychemical, physical or viral agents. There are as yet nodata at the molecular level to validate such a theory inthe case of radiation-induced neoplasia, althoughmodem techniques of cell and DNA hybridization andof somatic mutation analysis might render this possible
in the future.
42. The refined knowledge of the mechanisms ofdamage and repair in uv-irradiated eukaryotic cells (seefor general references (513)) has developed in recent
years in a new line of research. It becomes apparent that,at least in the case of actinic radiation, lesions to cellular
DNA and defective repair of this molecule might resultin neoplastic transformation of the damaged cells. There
are several arguments pointing in this direction and they
have recently been discussed at the Vllth International
Congress of Photobiology (296). The first argument isthe demonstration that exposure of cells to uv results inneoplastic transformation, that the action of aphotoreactivating treatment decreases the incidence oftransformants and that the initial lesion in DNA isprobably the formation of pyrimidine dimers (600). The
second is the fact that treatment of the uv-irradiatedcells with inhibitors of the repair of photolesions reduces
the incidence of tumours produced by uv radiation(756) presumably by decreasing the likelihood ofmutations resulting from the misrepair of photolesions
in DNA. The third is the detection of defective DNA
repair in some human diseases (xerodenna pigmentosum(55) and ataxia teleangiectasia (526)) showing predisposition to malignancy. It should be pointed out. however,that the correlations observed do not represent direct
proof that derangements in the repair of DNA lesions
might be the primary genetic cause responsible formalignant transformation of the defective cells. Also,
although it may be regarded as an attractive general
proposition, the model of the misrepair of uv-induced
DNA lesions could not as such be acceptable in the caseof ionizing radiation, owing to the profound differencesin the nature of molecular lesions produced by the two
types of radiation.
43. A comprehensive treatment of the numerous viral
hypotheses of tumour induction would be unwarrantedin the present context and the reader is referred to
specialized reviews (237. 38). In experimental radiation
work the neoplastic diseases of importance for which
sufficient documentation of a viral etiology is available
are leukaemia. mammary cancer and osteogenic sarcoma.

and they are discussed in the present report. Since in allof them R.NA oncoviruses are implicated, the molecularmechanisms of induction should at present be viewed in
the context of one of the hypotheses which postulate
the virus to be vertically inherited by the animals andintegrated into the cellular genome as a DNA
intermediate synthesized on the viral RNA under theaction of a specific RNA-directed DNA-polymerase
known as reverse transcriptase.
44. The "oncogene" hypothesis (282,139) is foundedon the notion of the vertical transmission of type-C
RNA virus particles in most animal species. These
particles are postulated to act as the potential etiologicalagents of all forms of cancer, carrying with them thegenetic information, transmitted by an oncogene
integrated in the genome DNA. Derepression of thisinformation by chemical or physical agents or throughspontaneous mutational events would lead to theactivation of the oncogenic action. At variance with theoncogene theory. the "protovirus" hypothesis (654,655) postulates that during normal development RNA istranscribed from a section of DNA of a somatic cell andthen transmitted to another cell which may in tum
synthesize upon this information, via the reverse
transcriptase, new DNA sequences to be incorporated
into predetermined regions of its genome. Thismechanism would be one normally acting in differentiation: cancer would result from the wrong evolution of
the protoviruses caused by somatic mutations or by theirmisplacement in the genome of the cell.

D. ETIOPATHOGENESIS OF RADIATIONINDUCED TUMOURS
45. The most common forms of leukaemia in themouse are the thyrnic, the myelocytic and the reticular
types. The viral origin has been ascertained only for the
first two of them (236, 310), while attempts to isolate aviral agent from reticular neoplasms (253) have not yet
been confirmed. Some strains of mouse develop thedisease spontaneously, such as the AKR strain in thecase of the thymic (237) or the SJL/J for the reticularform (481). After irradiation, leukaemia is found toincrease in strains that do not normally show it, and thisis most typically the case of the C57BL mouse, which,under suitable conditions of dose fractionation, may
develop up to 90 per cent thymic lymphoma (330).
Differences have been reported between strains and evenamong congenic lines of the same strain (317) in thesusceptibility to leukaemia induction by radiation. In
the course of almost thirty years of work (summarizedin 326 and 328), Kaplan and his associates havesystematically explored the various conditions affecting
the radiation induction of this disease, which is a good
example of the complexities of tumour pathogenesis.
Reviews on radiation-induced leukaemias and its viraland host factors may also be found in references 325,
126, 167, 40i, 674,678 and 680.
46. Although the thymus was first identified as thetarget organ for the lymphoid leukaemia type (321 ),local irradiation of the thymic area (322) or of the upper
half of the body (329) was ineffective for induction.
Partial-body irradiation may sometimes accelerate theappearance of malignant lymphoma without increase of
its incidence (596). Protection against leukaemia
incidence was also afforded by shielding of the spleen(367) or the marrow (329) or the lymph node (289) orby transplantation of intact isogenic marrow cells (331) or
spleen cells (99). lsologous thymus grafts to irradiatedthymectomized mice were shown to undergo malignant
transformation (332), and cells of these tumours were
found to be of donor and not of host type (333). All
this definitely pointed to an indirect induction
mechanism which was later to be identified as an RNA
oncovirus (377). Advances in the techniques of virus
titration (254) made it possible to study extensively, in
addition to the morphology of the type-C viral particles,
the biochemistry of the purified "irus (327). its
antigenicity (528. 178), host range (326) and localization (148). It is known that this virus, referred to as Rad
LV, is vertically transmitted through the embryo in
C57BL mice (327) and that the action of physical andchemical agents is required for its activation and releasein young, normally resistant animals (325, 368).
Radiation-induced lymphoid leukaemia in chickens
through a possible activation of a latent virus (365) andin guinea pigs (697) has also been reported.
47. The initial step in the pathogenesis of radiationinduced thymic leukaemogenesis in the mouse is therelease of the viral particles from the injured marrow(247, 238, 304) where they are normally harboured in
an oncogenically inert state. In the course of
post-irradiation thymic hyperplasia (625, 328, 302. 336,303), the virus is then taken up by the thymic target
cells, identified as the immature lymphoblasts of theouter cortex (376, 53, 90). Since these cells areincapable of giving rise to tumours in the absence of theepithelial-reticular thyrnic stroma, it is thought that theircontact with such a cellular microenvironment isessential for their complete progression to full neoplastic
state (327).
48. An important factor in the pathogenesis of thymic
lymphoma is the bone marrow, which either by
favouring the regeneration of the irradiated thymic cells(331) or by effective scavenging viral particles from theblood stream in the course of the post-irradiation
viremia (327), may render their interaction with target
cells less probable. Another humoral factor, mediatedthrough the haemopoietic tissue and capable ofinhibiting the occurrence of radiation-induced leukaemia, has also been described (379, 380) andidentified as a 19S alpha-2-globulin (39). Depression of
the host immune response by the whole-body radiation
treatment is also an important factor in the pathogenesisof the disease (248, 255). Finally, a range of host factors
may influence induction: in addition to the alreadymentioned genetic constitution, age (320, 251 ). sex(319) and other endocrine factors (possibly throughtheir action on the thymus) (323, 334, 483, 484) havebeen shown to interact in various ways with the virus
and the radiation exposure in the development oflymphoid leukaemia (747, 746).
49. Information on the viral etiology and pathogenesis
in the induction of myeloid leukaemia by radiation in
the mouse is far less complete. In the RF strain
incidences of up to 25 per cent have been reported after573

single doses of radiation, starting from an incidence ofless than 1 per cent in untreated animals (67). Age, sex
and hormonal effects on the viral transmission of thedisease have also been shown (686), as well as changes in
the induction rate introduced by environmental factors
such as the microbial flora in the mouse colony (720,719) or by a subsequent re-irradiation (408). Theseobservations clearly point to complex interactions
between viral, host, environmental and physical factors
which remain to be fully elucidated.

SO. A viral agent (241, 35) in association with hormonesand other factors (54) is also involved in the inductionof mouse mammary tumours by radiation in the strain
020 of mice which do not normally develop suchtumours spontaneously (664). The virus has been shown
to be widely present in many mouse strains; in somestrains however it is released at a young age. with goodcorrelation between the time of release and the onset of
spontaneous mammary tumours. On the other hand, instrains releasing the virus late in life. irradiation early inlife causes the production of viral antigens (34) and of
mammary tumours with infective virus particles (664).
51. It is not known yet whether the viral etiology
would also apply to another important model system inradiation carcinogenesis, namely mammary carcinogenesis in the Sprague-Dawley rat. In these animals
irradiation leads to induction of tumours which is afunction of dose and may go up to 80 per cent (50,611), starting from a background incidence of less than
2 per cent (138). Sex and hormonal influences are also
operating in the mammary carcinogenesis of the rat (63,138, 615, 609), as well as a number of other modifying
factors (608), but primary damage to the mammary
gland is necessary for the occurrence of neoplasia (52).
Recent biophysical evidence (575) indicate the ~ssible
need for interaction between radiation-damaged cells forthe production of a viable tumour in this system. Studies
have been undertaken to elucidate the effect of genetic
strain in radiation-induced mammary carcinogenesis of
the rat. Results of an experiment involving Sprague·
Dawley, Long-Evans, Buffalo, Fischer-344 and WistarLewis rats strongly suggest the presence of a genetic
component (710). Another study (63) on SpragueDawley, WAG/Rij and Brown-Norway animals is still inprogress.
52. Osteogenic carcoma, a rare form of tumour in themouse, inducible by bone-seeking radionuclides such as
90 Sr (198. 185, 196) has been serially passed by cell-free
extracts to isogenic new-born mice of the CF 1 strain. In
the CBA mouse, on the contrary. 90 Sr-induced bonetumours contained very few, virus particles, cell-free
extracts being ineffective in transferring the neoplasms.
A virus termed FBJ (374) is involved in the etiology ofbone tumours of the CF I mouse: its morphology (45)and its interaction with radiation have been described in
the mouse (187, 192). It belongs to the class ofmurine
sarcoma viruses (MSV) which may also induce bonetumours in rats and hamsters (632). There is actuallyevidence that the FBJ virus might require the associationof a helper in a complex with murine leukaemia virus(MLV) for its replication (314). Two other viruses
inducing bone tumours. termed RBF and FBR, haverecently been identified in the mouse (193. 197).
574

Transplantation (199) and immunological evidence (536.
555) seem to imply the extension of the viral etiology
also to human tumours.
E. CELL TRANSFORMATION IN VITRO
53. There have been attempts for a number of years to
study radiation carcinogenesis in cellular systems invitro. There seems to be hardly any doubt that radiation
enhances the transformation of animal cells by chemical
carcinogens {149, 519, 518) and by a number of
infecting DNA viral agents such as polyoma (643), SV40(542) and adenovirus type 31 (114). The existence ofa
linear relationship between the logarithm of the excesstransformation and the dose, with a doubling dose of
200 rad of 250-kVp x rays in the range of 75 to
1200 rad has been reported in one case (542). These
data are consistent with the hypothesis that non-lethal
damage induced by radiation in cellular DNA might
facilitate, in the course of repair, the integration of theviral genome into the genetic material of the host cell.
Rescue of lethally damaged cells by the integration of
the viral genome has also been considered as a possible
mechanism.
54. Induction of a latent leukosis virus in chicken cells(739) and possibly of a murine leukaemia-sarcoma
complex in Balb/3T3 cells (541) has also been descnbed.
It might be reasonable to assume (although it has not yet
been demonstrated) that the activation of an oncogenic
virus could be responsible for the induction of neoplasia
in fragments of rat mammary tissue irradiated in vitro(618, 606). In many reported experiments the criteria
used to assess cell transformation were purely
morphological, based on the multilayer and irregulararrangement of cells in the transformed colonies, but inother cases malignant tumour growth was actually tested
by retransplantation of the transformed cells into thedonors (606) or into suitably conditioned, geneticallycompatible hosts (541 ).
55. Experimental results have been published on thecapacity for transformation of radiation per se in thepresumed absence of viral agents. According to one
group of workers. x-ray-induced transformation ispossible and has actually been shown (59): it would
result in a change of regulatory mechanisms of thetransformed cell lines, such that transformed cells may
be contact-inhibited only by a different and not also by
the same cell type. In another report, a single x-ray doseof 300 rad resulted in a high proportion of transformed
clones in primary and secondary cultures but not in later
passages of hamster embryo cultured cells (60). In
primary hamster cell cultures. these results wereextended down to doses of the order of 1 rad of x rays.
A dose-effect curve for transformation of these cells wasestablished. which on a log-log plot increases up to aplateau of approximately 1 per cent transformed clones
at doses between 150 and 300 rad. Further increases ofdose resulted in a marked decrease of the percentage oftransformation. In some cases, in addition to morphological criteria, neoplastic transformation was also testedby the ability of cells to form clones in semi-soft agar orby their agglutinability by concanavalin A andwheat-germ agglutinin (57).

56. On the contrary, exposure of spleen cell cultures(344, 345) under carefully controlled conditions to arange of weekly irradiation treatments up to a total
accumulated dose in excess of 15,000 rad of 25()..kVp xrays did not result in malignant changes, although thesame cell line did turn malignant under the action of
methylcholanthene. Urethane alone or in combination
with radiation was found similarly ineffective. The
conditions affecting the possible failure to show
malignant transformation in vitro (viability, cellconcentration, presence of damaged or unviable cells)
were investigated recently (346, 347) on mouse cells.
Under certain conditions and on some cell lines,
transformation was actually obtained and tested in vivo.
It was concluded that the presence of large amounts ofdead cells and cellular debris, whether induced byradiation or mechanically, in close contact with viable
cells is a condition favouring the induction oftransformation. This would argue against a direct
carcinogeneic effect of radiation in vitro. This sameconclusion was reached on a different transplantation
system of skin carcinogenesis in vivo developed in thesame laboratory (25).
57. Recently x-ray-induced transformation has also
been reported on a C3H mouse embryo cell line (658,659). In this case the effect was assessed bothmorphologically and by transplantation of the transformed cells: it did not appear to be mediated by
non-specific cell killing. Differences were also noted withrespect to the previously reported data (57, 56). In fact,
the yield of transformation per surviving cell appeared toincrease between SO and 400 rad and then to level off at
higher doses when given to exponentially-growing cells.
However in the treatment of plateau-phase cells thetransformation frequency was enhanced for doses up to
100 rad. These observations suggest the existence of yet
unexplored relationships between the molecular events
responsible for neoplastic transformation and those
processes controlling cell survival and the kinetics of cell
division.
58. Although a certain variability of the results should
be expected (in view of the above-mentioned experimen·
tal variables, the difficulties of relating morphologicalchanges at the cellular level with the actual malignancy
demonstrable in vivo, the possible presence · andactivation of latent tumour viruses, and other biologicalconsiderations by which neoplastic transformation canhardly be viewed as an all-or-none phenomenon), theavailable evidence is too conflicting to allow any firm
conclusions. It seems clear, however, that the use of
these highly controlled techniques in vitro may, in the
future, be a powerful tool to disentangle the problem ofcancer induction at the cellular level in the absence ofother interactions operating at the whole-body level.

F. THE IMMUNE SYSTEM
59. Among the factors which are involved in cancer
induction, the immune reaction has gained muchattention in recent times. However, since transformation
can be obtained by chemical, viral and possibly physicalagents in entirely in vitro conditions, it must be inferredthat immune phenomena play only a secondary role inthe development of neoplasia, perhaps associated withthe development rather than with the induction oftumours. We shall therefore group this factor under thegeneral heading of the promoting agents. The wholeproblem of immunity and tolerance in oncogenesis has
been discussed at length by Severi (601) and the aspects
connected with radiation particularly by Cole andNowell (121). The Committee also reviewed in 1972 therelevant evidence, both the general concepts ( 670,
Annex F, paras. 247-250) and their specific importancein radiation carcinogenesis (670, Annex G,paras.13-15).
Recent reviews may also be found in Kersey (341 ),Martin ( 427), and Weiss (738, 739).
60. Rather than attempting to outline the premisses
on which the current hypotheses of immune reactions in
oncogenesis are based (375), it seems more appropriate
in the present context to review the most recent
advances in the field, in the light of these generalhypotheses. The discovery of tumour-specific antigens inchemically induced tumours and of tumour-associatedantigens as products of the oncogenic viral infection, has
Jed to the general concept that such antigens might bepresent in all tumours and might be relevant to thetumour evolution.
61. lt has been proposed originally by Thomas (660)
and later expanded by Burnet (78), that the immune
response stimulated by such antigens might actually beeffective in controlling and eliminating potentiallymalignant clones, and that only those clones which
escape this mechanism of "immune surveillance"(carried out by the body through cellular ( 132) andhumoral (392) factors) might finally show up as
clinically-evident tumours. According to these theories,
immune reactions could only be effective in inhibiting
tumour growth, but there are data showing that,
depending on the stage and intensity of the reaction,
stimulation or inlubition of tumour growth may actually
result (548, 547).
62. Radiostrontium-induced osteosarcomas were reported to possess tumour-specific transplantation anti·
gem; (504), and the degree of this antigenicity, in any
case rather weak (464), could be related to tumour
histotype (505). Changes fu the an~igenic constitution of
the gastro-intestinal mucosa after a radiation dose whichgave rise to tumours in later age were also reported(147). Animal strains carrying vertically inherited RNAtumour viruses react immunologically when injectedwith such viruses (249, 527). Evidence of thepathological expression of the reaction is found in thekidney of intact non-infected animals: in the course oftime. antigen-antibody complexes which have specificity
for the murine leukaemia viruses are deposited in theglomeruli and their presence results late in life innephrosclerosis.
63. This is the case for the AKR mouse (516), for the
B6C3F 1 mouse (29) and for the RF strain, where
analysis of the leukaemia incidence in glomerulosclerotic
mice has indicated that immune response may reduce
the probability of leukaemia to about one half bycomparison with non-glomerulosclerotic animals (752,753). Viral antigens and infectious virus titres are low inyoung animals but increase consistently in old age (532,575

251 ), and the reduced immune capacity of aged B6C3F 1
mice has been related causally to the subsequentdevelopment of lymphatic and non-lymphatic tumours(246). Evidence against this causal relationship has
however been produced in NZB/W mice (1).

actual importance of the immunity among the manyfactors of cancer induction. The data available howeverseem to point to a secondary role of the immune
reaction in radiation-induced cancerogenesis.

64. An important factor in radiation-induced leukaemia is the transient immunosuppression caused byradiation with respect to endogenous viruses. Data to
support this concept have been reported in the case of
the lymphatic leukaemia of the C57BL strain (248, 250)
and for the reticular, lymphoid and myeloid leukaemiasin the RF strain (753), in which the severity ofnephrosclerosis is shown to be inversely related toleukaemia incidence (108). In accordance with thisinterpretation, stimulation of the immune response
should logically result in a reduction of tumour
incidence. In fact, treatment of C57BL animals withinterferon (379) or with immune and non-immune
foreign sera ( 179) or with methanol extraction residues
of BCG (256) under appropriate schedules of administration, actually reduced the incidence of thymic
lymphoma. A delayed development and a decreased
incidence of 90 Sr-induced osteosarcoma was also
reported after injection of CBA mice with BCG (506).

G. HORMONAL ACTIONS

65. Effects in line with the above findings were also
reported after immunosuppression which resulted in
activation of murine leukaemia virus in animals graftedwith foreign skin (266), and also in other cases it
resulted in a higher incidence of tumours ( 121, 360,
359). Data have also been reported on the role ofimmunolof«cal factors in the induction of leukaemia inswine by O SR (279, 202). The role of immunologicalsurveillance against neoplasia and the possible influenceof immunodepression have been discussed (203, 24).
66. Radiation-induced immunosuppression is however
not the sole immunological factor implicated in thepathogenesis of tumours since the virus itself may
depress the immune response. Although there may beuncertainties as to the importance of this lattermechanism in view of the lack of correlation between
the immunosuppressive effect and the actual development of tumours (528), it has however been shownrather conclusively that the viral infection per se may
result in an impairment of the animal's capacity tomount an immunological response to various agents.
This is true in the case of both the mammary tumour
virus (235) and the murine leukaemia viruses (541, 102).
Analyses of the cellular bases of these phenomena point
to a great specificity of action. In fact, not only has thevirus derived from C57BL mice no suppresive effect on
SJL/J animals (602), but in tl)e case ofC57BL mice theimmunosuppressive effect is expressed at the level of
immunocompetent thymus-derived cells (529, 102),
while in SJL/J mice the viral infection depressed both
thymus- and marrow-derived immunocytes (602).
67. In essence, it might be concluded that there is no
doubt as to the presence of an immunologicalcomponent in carcinogenesis related both to viral or toother etiological factors. The evidence available points
rather to an inhibition than to an enhancing action of
the immune system on radiation-induced tumour
development. The problem is one of ascertaining the576

68. Consideration of the hormonal influence onradiation carcinogenesis seems appropriate, since it has
been amply documented that the action of hormones
may affect tumour induction. This action is not only
evident in the cancerization of hormone-responsive
organs but may also be present in tumours of othertissues where hormonal control is not readily apparent.
Reports on this subject have dealt mainly withradiation-induced carcinogenesis of the ovary, thethyroid. the mammary tissue, the bone and thehaemo-lymphopoietic system.
69. X-ray-induced neoplasia of the ovary in the mouseis inhibited by oestrogen treatment (211) and this effectseems to be in accordance with the finding thattransformation of irradiated transplanted ovaries isdecreased if ovarian function is intact (324). In the rat,
local ovarian irradiation produced a high yield of
tumours, unaltered by treatment with chorionicgonadotropins (603). Promotion of the sequence of
events leading to pennanent hyperplasia and/or carcinogenesis of the thyroid gland by the thyroid stimulating
hormone has been reported in the dog (406) and inother species (389, 159).
70. In the Sprague-Dawley rat the incidence of
spontaneous tumours of the mammary gland is
extremely low in the intact male (615) and approaches 2
per cent in the intact female at 1 year (138).
Orchidectomy raises this incidence to 6 per cent (615)
and ovariectomy results in a decreased incidence (138).
Irradiation with 400 rad of x rays induces breast
tumours in 50 per cent of the male (615), and in 79 percent of the female, rats (138). Ovariectomy produces adecreased yield of tumours in irradiated animals and theimplant of nonnal ovaries restores the incidence toabout 80 per cent (138). Thus. the presence of afunctioning ovary is required in this system forexpression of maximal neoplastic response, althoughcycling ovarian activity is only a secondary mechanismwith respect to the radiation damage to the target organ(52, 606). The effect of thyroid hormones in mammary
carcinogenesis is very minor, on the other hand theadministration of stilbestrol depresses the neoplastic
response to irradiation (614). This latter observation is
however at variance with what was reported in the AxC
rat strain, where stilbestrol acts synergistically withradiation in producing mammary tumours (598) and thecontinuous administration of progesterone shows aprotective effect against this synergistic action (597).
Alterations in the ovarian and pituitary hormonal
regulation have also been invoked to explain the changes
of mammary tumour incidence in irradiated parabiotic
rats (66). The combined action of pituitary isograft andneutron irradiation in B6CF 1 mice produced a reductionof the latency period and an increased incidence of
mammary tumours. Harderian gland tumours also

showed a shorter latency, a marked increase in incidence
and a greater tendency to metastasize. The inductive
versus promotive role of the pituitary isograft has not
yet been ascertained (206).
71. The endocrine functions related to gestation andlactation lead to a significant delay and to a reduced
incidence of 9 0 Sr-induced bone tumours in the CBAmouse (495). This effect is probably related to changes
in 9 0 Sr retention induced by pregnancy and lactation(503, 568). Treatment with oestrogens, on the contrary,increases considerably bone tumour induction, perhaps
through a stimulation of osteoblast repopulation (507).
The important role played by the parathyroid hormone
was shown in the case of the induction of bone tumours
by 45 Ca (152, 153). When the action of 45 Ca and thehormone are combined, the incidence of osteosarcomasin rats is a factor of about 2 higher than with 4 5 Ca
alone. On the other hand, the removal of theparathyroid glands decreases the osteosarcoma incidence
by a factor of 3. It appears therefore that the reductionof the hormone level decreases carcinogenesis in bone.
72.

Hormonal effects in radiation leukaemogenesis

have been reported by many authors. Susceptibility to
myeloid leukaemia is higher in male than in female RF
mice (694, 686), while the response to lymphoma
induction in the same strain is higher in females than inmales ( 694), or about equal in both sexes in the A
mouse (436) and in the C57BL (323). Splenectomy
reduces susceptibility to myeloid leukaemia but does notalter the induction of lymphoma in the RF (694) and in
the C57BL mice (323); thymectomy, on the contrary,
does not influence the induction of myeloid leukaemia in
the RF (694) but effectively prevents the occurrence oflymphoma in irradiated RF (694) and in C578L mice(323). As for the action of the gonads, ovariectomy
decreases lymphoma incidence and does not alter
myeloid leukaemia in RF mice {694) nor does it affectthymic lymphoma in C57BL (323). Orchidectomy has
no effect on both types of leukaemia in the RF (694)and on lymphatic leukaemia in C57BL (323). However,in another report, castration has been shown to increase
lymphoma incidence and this effect is brought back tonormal levels by oestrogen treatment. When administered to intact C57BL animals of both sexes, oestrogens
markedly increase the incidence of lymphoma; thiseffect is not seen in the Balb/C strain (665). On theother hand, the induction of myeloid leukaemia invirus-infected RF mice is inhibited by estradiol
treatment (686, 309). Hypophysectomy does not alter
the induction of thymic lymphoma by radiation (483).
Hypothyroidism inhibits the incidence of this neoplasia
in females but not in males implanted with thymic grafts( 484). Finally, pregnancy and lactation increase all typesof leukaemia in 9 0 Sr-treated CBA mice (495).
73. It is impossible from this long list of scatteredobservations to draw any consistent conclusion. Clearly,
various radiation-induced tumours are differently affected by the animal's hormonal balance in the course of
the carcinogenic processes. The effects vary with thetumour system, with the animal strain and sex. and it istherefore likely that the mechanisms of action, atpresent completely unknown, may be very different in
the various experimental conditions.

H. THE ROLE OF CELL PROLIFERATION
74. A discussion of the role of cell proliferation among
the promoting factors in radiation carcinogenesis may
reasonably be centred around two questions: whether
there is any relationship between the rate of tissue
renewal and the induction of cancer and whether thephenomenon of cancerization is linked with any specificbiochemical or kinetic changes of the transformed
tissues. At present, the precise formulation of thesequestions is very difficult, due to the following
considerations.
75. Firstly, cell proliferation often results from theapplication of a variety of toxic stimuli to any tissue andmany physical and chemical carcinogens are toxic tocells: it is difficult therefore to recognize any specificity
to the phenomenon of cell division as such. Secondly,
the identification of target cells for neoplastictransformation is not always possible and therefore
evaluations of kinetic changes on the whole tissue may
not be relevant to the target-cell compartment. Thirdly,
the usual parameters for the quantification of cellular
proliferation in any tissue compartment (mitotic index,
labelling index, labelled-mitoses curves, rate of DNA orof specific protein synthesis. etc.) are entirely
inadequate to describe the kinetics of the tissue as awhole, including the stem, proliferating, maturing andfunctional compartments and, in any case, only for avery few animal tissues has such a comprehensive
analysis been performed. A series of papers with adetailed quantitative analysis of different cell populations in the course of mouse leukaemogenesis may bepointed out as a first original attempt in this direction(593, 595, 594). Finally, the tissue steady state, which isoften the necessary condition for kinetic estimates invivo, is completely disrupted by the application of
toxic stimuli and, under such conditions, the descriptionof fine kinetic changes becomes practically impossible.
76. In spite of the above limitations, which substantially confuse the problem, there have been a number ofattempts to stimulate by various treatments the cellular
proliferation of tissue in order to modify theirsusceptibility to cancer induction. In the rat, thestimulation of unspecific tissue reactions by stablecaesium hydroxide in conjunction with exposure to thedaughter products of radon and thoron has resulted inaccelerated lung tumour induction (530, 97. 380).
Treatments with hormones which are known tostimulate cell division in the mammary gland haveincreased the yield of breast tumours following x
irradiation (207). Treatments of animals with growth
hormone increased the incidence of radiation-induced
osteosarcomas, and treatment with thyroxine produced ashorter induction period (96). The application of
goitrogen substances such as methylthiouracil inassociation with external x-ray treatment or internal
exposure to 131 I has produced a higher incidence of
thyroid neoplasia (158, 389, 724, 728), and the sameobservation was made in hamsters (105). In mice,stimulation of osteoblast formation by oestrogens has
increased appreciably the incidence of 9 0 Sr-inducedbone tumours (507, 508), although bone fractureattempting to enhance tissue proliferation before theapplication of 224 Ra has not significantly modified
577

bone tumour formation (222). Proliferation of themucosa of the stomach induced by immunologicaltreatment of the animals has increased the incidence ofgastric carcinoma by x irradiation (264).
77. The role of hyperplasia during the post-irradiation
regeneration of the thymus is an important factor in thepathogenesis of leukaemia (326,327,593,336, 176): inagreement with this finding, urethane, which also caused
injury and regeneration in the thymus (252), has beenshown to increase the incidence of thymic lymphoma inassociation with x rays (40). Stimulation of cell divisionin mouse liver can increase the yield of various types ofradiation-induced tumours: thus, carbon tetrachloride
intoxication before or after x rays and neutron
irradiation produces a considerably higher incidence ofhepatomas ( 119. 124). and the same applies to a purely
proliferative stimulus like partial hepatectomy following
gamma or neutron irradiation (740). Urethane inassociation with x rays produced an increased incidenceof lung adenomas (44) and the incidence of neoplasms
approached 100 per cent after uninephrectomy inirradiated kidneys (570, I 20, 123). Isoproterenol, an
agent promoting DNA synthesis in cells of the salivary
glands, has been shown to enhance the induction oftumours of these organs when given in combination withx rays (649).
78. Specialized reviews of the cellular and kinetic
changes induced by radiation have been published (51,13). In very general terms. there is nothing in thesechanges that would point to any specific pattern ofcellular and tissue reaction with respect to othercarcinogens (561, 27, 553, 38). The assumption that a
rapid rate of renewal is a favouring condition for theneoplastic transformation seems therefore unwarranted,
without adequate qualifications pertaining to thespecific model of carcinogenesis under discussion.
Exceptions to this general assumption, sometimes
justifiable on biological grounds (393), may be ascommon as the general rule, and the preceding
discussion has made it abundantly clear that thecomplexities of radiation carcinogenesis hardly point toa simple scheme of mechanism of action.
79. Cellular proliferation is implicit in the notion ofpromoting action and is clearly necessary for the tumour
progression, and the evidence reviewed is generally inaccordance with these concepts. However, so far there isno unequivocal evidence that the induction of
proliferation in the target cells is a key event in radiation
carcinogenesis: on the contrary, there is recent evidence
from work in chemical carcinogenesis showing that
hyperplastic changes and promoting action are quite
independent phenomena (552). In any case, a systematiccomparative analysis of events associated with theinduction of tumours in target cells would be required
before any postulated promotional role of cellproliferation could be fully elucidated.

I. OTHER MODIFYING FACTORS
80. Environmental conditions have been reported toinfluence the induction of specific tumour types in
irradiated animals. through their action on the

microflora and possible intercurrent diseases. The
response of animals to carcinogenic stimuli. including
radiation, may thus be affected to a variable degree bychanges in the number of target cells and in cell turnoverrates or by immunological factors which may interferewith the expression of carcinogenic damage. These
effects have recently been reviewed (717), especiallywith regard to possible differences in the immunologicalcompetence of gnotobiotic and germ-free animals (245).
It has been shown rather conclusively that the humoral
immunological competence of germ-free and conventional mice is qualitatively and quantitatively very
similar (62, 421, 599). In the very old animals. however.
a great variability of response is noted, leading generally
to a depression of the immune competence both in
BC3FI and in SJL/J mice. The immune competence isminimal in animals affected by lymphoreticular tumours(421, 599). suggesting that in ageing mice such tumours
may arise as a result of a decline in their immunologicalcapacity. As with the primary response, the living
conditions of the animals do not affect to a great extent
the secondary formation of JgG antibody-synthesizing
cells (420). Infectious diseases, totally absent in the
germ-free state, have little influence on the life span ofmice (103, 719). In intact animals the development of
spontaneous non-haemopoietic tumours is practicallyunaffected by the germ-free condition; among haemopoietic tumours, reticulum cell sarcoma incidence ishigher in conventional than in germ-free mice. but
thymic lymphoma and myeloid leukaemia have similar
incidences in both conditions (719).
81. After irradiation, the incidence of myeloid
leukaemia is decreased in the absence of microbial flora(719) and this effect is attributed to the reduced
myelopoietic cell proliferation in the germ-free animals(720, 717). Radiation-induced lymphatic leukaemia, on
the contrary, is not altered under germ-free conditions in
Swiss, C3H, C57Bl, ICR and C57BL mice (539, 721,
719). There are no qualitative differences in thepathological lesions of gnotobiotic and conventional
animals and virus particles are found in germ-free just as
in conventional mice (539). The induction of other solid
tumours in irradiated animals gives variable results {15,717). No special features were seen in radiation-induced
malignant and benign tumours of the germ-free rat(540).
82. In summary, the data available at present showthat the etiology and the pathogenesis of radiationinduced cancer are essentially similar in conventionallyreared and in gnotobiotic animals: the host's microbial
flora may only play a secondary role in the developmentof some haemopoietic neoplasms, perhaps throughmodifications of the immune competence, as in the caseof the reticulum cell sarcoma or through the abnormal
proliferation of target cell lines, as for myelogenous
leukaemia. It seems doubtful that non-systemic tumours
may respond to these actions.
83. The need to investigate in more detail specificmechanisms of radiation carcinogenesis and special
conditions of practical importance, has often in the pastjustified attempts to modify tumour induction in
irradiated animals by physical. chemical or biologicaltreatments. The relevant work is reviewed in this report,

---but owing to the heterogeneity of the conditions andagents employed, no general conclusions are really to be•
expected.
84. Among the physical treatments, the influence of
permanent ( 466) or of transitory (467) high-altitude
exposure has been tested in irradiated RF mice. It was
found that the overall incidence of tumours was lower inmice kept at sea level after irradiation for the durationof their life. although thymic lymphoma and granu·
locytic leukaemia were higher at all radiation doses inthese mice. Animals residing at high altitude for only
three months after irradiation showed also an enhanced
induction of leukaemia owing perhaps to the abnonnal
stimulation of the bone-marrow stem cells before theirfull recovery from radiation damage. The combined
effects of high or low temperature and radiation werealso investigated in the rat (88, 89), but only longevity
data without tumour pathology were reported. The
carcinogenic action of mechanical damage and x rays on
intramandibular tissue of the mouse was also reported(173, 174). Finally, severe metabolic stresses such as
starvation, water deprivation or prolonged physicalexercise had no additional influence on tumour
induction by radiation in the rat (559, 556).
85. In regard to chemical treatments. a number ofstudies have appeared on radioprotective drugs, but theirresults appear rather conflicting. Mewissen and Brucer( 441) reported a signific~ntly higher incidence oftumours in cystearnine- an9 cystamine-protected mice,but treatment with another radioprotective chemical(AET) failed to produce any change in the induction of
the most common neoplasms of the mouse after
whole-body irradiation (129), in ovarian tumour
induction by localized x irradiation ( 129) or inbreast-tumour induction in partial-body irradiated rats
( 616). Protection was reported in the case of kidney
irradiation ( 168). AET alone or mixtures of fivedifferent radioprotectors reduced the total incidence ofcancers and leukaemias by a factor of about two in mice
irradiated with 1350 rad with respect to non-protectedanimals; complex dose effect relationships might havebeen operating in this case, since at a dose of 700 rad,the difference between protected and non-protectedanimals disappeared ( 418). Protection by cysteamine
upon fractionated irradiation was also reported in thecase of leukaemia induction (488). Clearly, moreexperiments are required to clarify this issue.
86. Among the biological treatments tested, parabiosis
has been used in order to permit longer survival inanimals irradiated with an otherwise lethal dose of1000 rad of x irradiation. Under these conditions,radiation-induced osteogenic sarcoma was found in
about 5 per cent of the animals (732), kidney tumours
in about 8 per cent and leukaemia of the irradiatedparabiont was lowered, although not to the level of the
spontaneous incidence (587). There are indications thatparbiosis per se may alter the incidence of some fonns ofcancer in the treated rats. Autologous, homologous andisologous haemopoietic chimaeras were also studied fortheir susceptibility to tumour induction. The incidenceof lymphosarcoma and reticulum cell sarcoma isdecreased by spleen shielding ( 403, 271 ), lymph-nodeshielding (289) and bone-marrow shielding (329). 134).

The injection of syngenetic bone-marrow cells-but notof homologous marrow {146)-was repeatedly shown tobe very effective in protecting the mice from theinduction of lymphoma (331, 129), myeloid leukaemia( 11) and reticulum cell sarcoma ( 135). The incidence ofother neoplasms was practically unaffected by bonemarrow transplantation {129, 135). Acute loss of blood(2 ml) before exposure (to 270 R) was reported toincrease the incidence of tumours in male rats (557).
Similarly, an acute anaemic stress has been reported toact as a trigger mechanism for the induction of
myelogenous leukaemia in unirradiated (221) andirradiated RF mice (179). but iron-deficient chronic
anaemia is ineffective to this end in irradiated Wistar rats
(307).

III. PHYSICAL PARAMETERS IN RADiATION CARCINOGENESIS (EXTERNALIRRADIATION)
A. GENERAL
87. The purpose of this chapter is to discuss the main
physi~al variables influencing radiation carcinogenesis. in
an attempt to identify from the vast amount of scatteredinformation in various animal systems common trends inthe effect of such variables. and with the aim of assessing
their qualitative and, if possible, their quantitative role.
Since obtaining precise relevant data in man is extremely
difficult, animal experimentation in this field isabsolutely necessary to interpret and support the humanevidence: this is the reason why such studies, very
interesting in their own right for their fundamental
implications. are also very important for humanradiation-risk assessments, and therefore relevant toradiation-protection development.
88. The relationships of tumour induction with dose.
radiation quality, dose rate, fractionation and protection
will be examined, with main emphasis on the biologicaleffects themselves and little discussion on the proceduresof estimating the values of the physical parameters. It
should be realized that technical and dosimetric
uncertainties do affect in practice the determination of
the physical parameters; they are, however, lessimportant than the uncertainties associated with thebiological end-points, probably by an order ofmagnitude at the doses where the carcinogenic effect isusually studied. Physical parameters will therefore beconsidered as independent and well controlled variablesin the present context, since the variability of thebiological end-points outweighs the errors of thephysical measurements.
B. DOSE-EFFECT RELATIONSHIPS IN
RADIATION CARCINOGENESIS
89. As usual in radiation biology, any attempt toanalyze quantitatively the carcinogenic action ofradiation must of necessity be based on the observed
relationships between the dose delivered to the
biological system and the ensuing effect of tumour
induction. It should immediately be pointed out,579

however, that the establishment of precise dose-effectrelationships in animal systems is by no means an easy
undertaking and that the interpretation of the relevant
data must take into proper account a number ofmethodological and technical deficiencies encounteredin research at various levels. At the most basic level, thevirtual absence of adequate in 11itro techniques is atpresent the main obstacle to the understanding of thefundamental mechanisms of tumour induction. Essential
cellular properties like the susceptibility of single cells toneoplastic transformation, the distribution of susceptibility among cell populations having different division anddifferentiation potentials, the influence of initiation andpromotion actions, the interplay of other cellular effectsof radiation such as the loss of reproductive integrity,
must somehow be reflected at each dose level in the final
number of tumours scored. However, there is no meansat present to resolve these phenomena in highlyorganized tumour models in vivo and, consequently, it is
to be expected that the analysis of the dose-effectrelationships may not be of great help in the study ofbasic mechanisms.

function of dose. If, instead of the probability of theeffect, the probability of its absence is plotted(S = 1 -W), "survival curves" are obtained. Usuallysurvival curves are shown on semilogarithmic plots. The
sigmoidal characteristic of multi-event curves persists insemilogarithmic plots and the "shoulder" of such curves
becomes more clearly expressed the larger the values of n.

90. In chapter II it has been shown that after the eventof neoplastic transformation has already taken place in
one or a few cells, several permissive, enhancing or
inhibiting actions may still affect the capacity of thesecells to give rise eventually to visible tumour nodules.
Thus, the balance between cell production and loss in atransformed clone, the complex immunological relationships between the antigenic stimulation by the newly
established neoplastic cells and the immunologicalsurveillance system of the host, and the promoting or
inhibiting actions of the endocrine system influence thefinal yield of tumour nodules and, ,consequently, thegeneral shape of the dose-effect relationships. Information on these actions is however very inadequate atpresent to evaluate their relevance.

96. For a dose-effect relationship with a real
threshold, there is no observable effect for doses up to
the threshold. In practice, however, the difference
between threshold and quasi-threshold relationships
cannot be defined. In the case of tumour induction the
distinction is made impossible by the high frequency of
spontaneous tumours. The variability of tumour
incidence in the control group is for example shown on
figure l(c) by the shaded band. In this case even a
two-event curve would appear to have a thresholdDqtt·

I. Theory and practice
91. Modern concepts of quantitative radiobiology, as
well as practical considerations, must be taken into
account when dose-effect relationships for tumour
induction are discussed. The most firmly definedconcepts of quantitative radiobiology are reflected in theclassical hit-and-target "theories''. According to these
the occurrence of the biological effect under study
requires l, 2 or n "hits" in some "sensitive volume". or·'target", of the biological system under consideration.

92.

In figure l(a) theoretical dose-effect curves areshown for cases where I, 2, 10,or 50 events in one target
are required for the occurrence of the effect. The doses
in figure I are expressed as multiples of Dso%, which is thedose inducing effect in 50 per cent of the irradiatedspecimens. The one-event curve is exponential. However.
if the required number of events is larger than 1, thecharacter of the curve changes and it becomes clearly of
the sigmoidal type.
93. When the effect under study is the loss of a cell's
reproductive ability. the same type of information isrepresented in the form of the so-called "inactivation
curves." plotting the probability of the effect W as a580

94. The most interesting part of the dose-effect curve
js that corresponding to low doses. In that region ofdose. simple one-event exponential relationships areapproximately linear and multi-event curves can beapproximated by power functions or by power function
combinations. These approximations are known aspolynomial functions (fig. l(c)).
95. An intrinsic peculiarity of multi-event curves is thatobservable increases of the effect occur only after somedefinite dose, which can be called the "quasi-thresholddose". In fact, the probability of effect is amonotonically increasing function of dose but theincrement up to the "quasi-threshold" is negligible.

97. Different from the multi-event models discussed so
far are the multi-target models which have been used todescribe the survival of mammalian cells. These models
postulate that several targets must be affected to kill thecell, each of the targets having to receive at least one hit(event) in the most simple case. A "survival" curve
corresponding to such a model is shown in figure I(d).
The curve is also sigmoidal, but in contrast to the curves
shown in figure I(b ), this curve becomes exponential forlarge values of dose. The slope a of the exponential partin a semilogarithmic plot can be characterized by theinactivation dose, D 0 (Do =I/a). The intersection of theextrapolated exponential part of the curve with theunity survival line can be considered as a quasi-threshold
dose, Dqt·
98. Sometimes the relationship between dose andeffect is presented in a log-log plot (fig. I(e)). Apart fromthe fact that this presentation permits the inclusion of awide range of values. it also emphasizes the variation of
the effect at low doses. From the slopes of the straightlines in the Jog-log plot it is possible to assess the
exponents of the power functions involved. In thesimplest case a slope of 45° corresponds to an
exponent = 1.
99. It is also of interest to consider a simple model
postulating two types of competing processes: (a) theprocess leading to the effect (in this case to tumour);and (b) the process leading to cell death and therefore
avoiding the manifestation of the effect. The combination of both processes, working in the opposite

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Figure I. Theoretical dose-effect relationships for effects at the cellular level581

directions, leads to a dose-effect relationship with amaximum of the type shown in figure I(f). As will be
discussed in paragraph 143, a number of dose-effectrelationships found for carcinogenesis are similar to thecurve of figure I(f).
100. In experimental work, the most frequently usedindicators of carcinogenesis are the mean number oftumours per animal at time t, R( t ), and the frequency ofanimals with at least one tumour, the "incidence" l(t). If
Poissonian statistics apply, the two quantities are relatedby the simple expressionl(t) = 1-e-R<r)(1)

When the two quantities are much smaller than one, it
may be assumed that R(t)::::: I(t), and both indicators ofcarcinogenesis become identical.
101. Several statistical approaches can be used fortreating experimental results ( 571. 613). One approach(613) for the calculation of the mean number oftumours per animal at time t isnR(t) =

1

Ji N (tJ(2)

where ti is the time of appearance of the tumour number
n in the experimental group, and N(t;) is the number ofanimals still under observation at time t;.
102. Either of the quantities R(t) or I(t) may be plotted
as a function of dose. l(t) can be obtained out of R(t) by
the use of equation (1). The validity of this equation
requires that all scored tumours be real primary
tumours. To avoid possible complications, it is possible
to score only the first tumour of the animal. However, inpractice it was shown that there are no statisticallysignificant differences between the results obtained
when all tumours are scored or when only first tumours
are scored ( 620).

103. In this review the results will be expressed mainly
in terms of the total tumour incidence over lifetime I in
per cent. It must be mentioned that such an approachleads to some loss of experimental information, namely
the temporal variations of I(t). Another approach ispossible (620) where the indicator is the time-integral ofR(t)P(t) =CRJr)dr(3)•0

By such an approach it is possible to collate all theexperimental data for the period of observation.
Furthermore, the number of tumours are weighted
according to their time of appearance. The quantity P(t).
called the "effect period", is expressed in "tumourdays" and represents the mean number of tumours per
animal multiplied by the time the animal bears thesetumours. The use of the "effect period" should, inprinciple, decrease the statistical uncertainty of theexperimental results.

582

104. For any approach which may be selected it is also
necessary to take account of the influence of thefollowing factors: the competitive risk of other diseases
or causes of death (see paragraph 13), the modifications
introduced by spontaneous death of the animals or by
the serial sacrifice techniques (see paragraph 19), and thepossible effect of radiation-induced life-span shortening(see paragraphs 26 and 27). Additionally, the questionof tumour acceleration versus tumour induction needs
separate consideration_
105. A widespread observation which refers generally to
all radiation-induced tumours is that their latency time,that is the time from irradiation to the occurrence of theactual neoplastic changes, usually follows some functionof the dose and frequently is shorter in highly irradiatedanimals. Since radiation-induced neoplasms cannot be
distinguished from spontaneous ones, the shorter latency
could conceptually be interpreted in some cases as anacceleration of the occurrence of the neoplastic diseases
rather than as a true induction of new tumours. Thesephenomena are readily analyzed using curves describing
the age-specific cumulative rate of incidence of tumours(see paragraphs 24 and 25), and there are two extreme
conditions that may be observed in comparing intact andirradiated animal groups under such circumstances.
106. In the first condition, typical of animal strains
having a particularly low spontaneous yield of sometumour type, radiation may act by inducing this tumour
within a confined time period, and a good example may
be the thymic lymphoma of the C57BL mouse. The
probability of observing such a tumour will beessentially zero in the normal animals at all times, but in
irradiated animals this probability wilJ gradually increasearound the time which is characteristic for appearance ofthe thymic lymphoma (200-400 days) (330) and will
eventually reach a plateau well before the irradiatedanimal population is extinguished. Clearly, if theappearance of tumours is very unlikely before thenormal animals die, the tumours arising at thecharacteristic age in the · irradiated animals may be
attributed to a true induction phenomenon brought
about by the radiation treatment.
107. The second extreme condition is observed, on thecontrary, in animal strains having a high probability ofneoplasia in the control population, as, for example.
with the mammary neoplasia in the ageing SpragueDawley rat. In this case the cumulative incidence oftumours in normal animals will continuously increase
with time and this rise will eventually be terminated by
the extinction of the whole animal population. In theirradiated animals, however, the rise of the curve will
begin at an earlier age and will proceed roughly parallel
to or somewhat steeper than the control curve, until all
animals die. Such a phenomenon might be interpreted asa radiation-induced anticipation or acceleration in theoccurrence of tumours that might possibly haveappeared in the normal animals, had they lived longenough.
108. The experimental situations to be dealt with inpractice rarely conform to these extreme examples,
since, depending on the dose of radiation, both effects
of induction and of anticipation or acceleration canoften be observed, even in the same tumour system. For
the purpose of comparing the overall effect of different
doses or of different experimental treatments. theparameter of importance is the total number of tumours
expressed by a population of animals from the time ofirradiation to death. An alternate indicator would be the"effect period" referred to in previous paragraphs. In
any case, the comparison between groups is often madedifficult by the fact that their life spans may be different
and also depend on the radiation dose.
109. A reduction of the latency time with irradiation
appears to be a rather general phenomenon in mosttumour systems studied in many animal species and for
all types of radiation. To cite only a few of the many
possible examples: In the mouse, skin tumours tend to
appear earlier after higher doses of low-energy electrons(285): lung tumours are accelerated but not induced in
RF mice (687) and CBA mice (726): the mean ages atdeath of both male and female LAF 1 animals withthymic lymphosarcoma, non-thymic lymphoma, granulocytic leukaemia, hepatoma, ovarian and mammary
tumours decrease progressively with increasing gammaray doses ( 688); myeloid leukaemia occurs earlier at highdoses of x or gamma rays in RF mice (685);
osteosarcomas (284) and ossifying fibromas (222)
induced by 22 4 Ra injection show a steeper rate ofinduction with increasing isotope dose; the cumulative
incidence of bone malignancies at death in CFl mice
after 2 2 6 Ra treatment is similarly increased inproportion to dose (191); bone tumours (499, 701) andcarcinomas of the mucous membranes of the head (496)
are accelerated in the CBA strain following intraperitoneal injection of 9 0 Sr; oesophageal cancer after local
6
Co irradiation shows an acceleration at increasing
doses (733).

°

110. In the rat, skin tumour appearance is hastened byirradiation with fast electrons and alpha radiation (80) as
well as with x rays and fission neutrons (312); theinduction of mammary cancer in female Sprague-Dawley
rats within one year of 6 Co irradiation is progressively
accelerated by the dose administered with a possible
saturation effect of 500 rad ( 611 ): fast neutron andx-ray irradiation show a similar effect within 700 days
from exposure (714); the latency time of ethlonineinduced liver tumours is decreased by treatment withradiation (653). In the swine, acceleration phenomena in
the induction of myelo- and lympho-proliferative
diseases are observed after 9 0 Sr feeding (280).

°

111. In the dog, alpha radiation from 2 2 6 Ra and beta
radiation from 9 0 Sr accelerate the induction of
myeloproliferative disorders and of osteosarcomas inproportion to the dose level of the two nuc!ides (218),
and a consistent decrease of the latency time is observed
for the induction of malignant tumours of the bone by a
. . ofb one-see king ISO. t opes sue h as 239pu, 228Th ,vanety
226
90
228
Ra,
Ra and Sr (163). It is to be expected thatthe time of evolution of the neoplastic disease and also
the time of its occurrence with respect to the age of theanimals should influence the precision of estimates of
the acceleration as a function of dose, and in this respect
rapidly killing tumours of high malignancy occurring
early in the life span of the animals will produce themost reliable estimates.

2. Experimental dose-effect relationships
112. It seems appropriate at this point to examine indetail the existing data on the dose-effect relationships
for the induction of the most common radiation-induced
malignancies in various animal species and strains, inorder to see whether and to what extent common
features and trends can be identified. For this purpose
published final cumulative tumour incidence data will be
used. These data have inherent limitations due to thefact that corrections for intercurrent competing diseases
and death were applied only in some instances. Single
exposures of short duration to various types of radiation
will be examined in thi~ context, leaving the effects ofother radiological factors such as radiation quality.
fractionation and dose rate for consideration under
separate headings. Some of the most informative
experimental series to be discussed have been plotted infigures II-IX. The bars superimposed on the data points inthese figures represent the standard errors of theestimates when the necessary information was available.
113. Myeloid leukaemia. LAF I mice exposed to
gamma-ray doses up to 697 rad showed a corrected final
incidence of granulocytic leukaemia rising from less than
1 per cent in the control to a maximum of 1.5 per centin males at 578 rad and of 1.7 per cent in females at
223 rad. At higher doses the incidence seemed todecrease, but the changes observed were on the whole
too small to allow any definite statement as to the shapeof the induction curve {688). Susceptibility to myeloid
leukaemia is higher in the RF strain and fairly complete
data are available on the dose-effect relationship (694,671, 685, 686) (fig. II). When several hundred male mice
were whole-body irradiated with x or gamma doses in asingle brief exposure early in adulthood, the incidence of
myeloid leukaemia was increased from a backgroundlevel of about 5 per cent to about 40 per cent at
200-300 rad and then declined gradually at higher doses
to a level of about 10 per cent at 500 rad (685). In
female mice susceptibility was generally lower andattained a maximum of around 20 per cent in the twomost complete series available, involving thousands ofanimals studied by macroscopic and microscopic
pathology (685, 107). The peak incidence occurred at
300 rad in one case (685) and at 200 rad in the other(107) after exposure to x rays: exposure to high-energy
protons yielded a maximum at around 300 rad (107). In
both cases a tendency to decrease with higher doses wasreported. Other data on RF male and female mice are in
general agreement with the above findings (692).
114. After 5-MeV neutron irradiation in males a plateau
incidence of about 40 per cent at 200 rad and a further
decline were observed. A lower peak incidence wasobserved in females (692). After 14-MeV neutron
irradiation in female mice a monotonic rise up to 28 percent at 400 rad was described (145). In summary. afterx, gamma, proton and neutron irradiation the overall
relationship between incidence and dose appears to becomplex. Over the dose range of 0-200 rad of sparsely
ionizing radiation the tumour yield has been reported tovary with the square of the dose (671, 685), although
the presence of a linear component cannot confidently
be excluded (686). Upon neutron irradiation the linear
component might be prevailing at the lower doses (613).
583

per cent60

50• RF o -, r1V1 (6921

0 RF 9 -, rays (1071• RF d - 5-MeV neutrons (692)
9 - 5-MeV neutTOns (6921

I>. RF

40

30

20

I
200

100

400

300

500 rad

DOSE

Figure II. Dose-effect relationships for the induction of myeloid leukaemia by x rays and neutrons in RF micedose levels of 200 rad or more. Less consistent effects
were described in the case of 5-MeV neutron irradiation(692). After 14-MeV neutrons the incidence increased
from 3 per cent in the controls to 19 per cent in the
200 rad group, with a slight decrease at 400 rad (145).
The initial rise with dose might be described as
approximately linear.

but the plateau and the later decline are still observed.
Some of the data (671) were analysed by Gray (233)
and mechanisms were proposed to explain the rise,plateau and ensuing decline; the significance of thesemechanisms will be discussed later (see paragraphs
151-154).
l15. Thymic lymphoma (fig. III). In the RF mousestrain, the incidence of this disease shows a positive
relationship with dose for both x rays and 60-MeV
proton irradiation up to approximately 300 rad, whichmight be curvilinear both in male {694) and in female
animals {107, 686). A plateau is observed at higher doses
up to 400 rad of 300-kVp x rays or of 60-MeV protons{I 07) or 600 rad of sparsely ionizing radiation (683),
but no actual decrease in incidence has been reported. In
both sexes, x- or gamma-ray exposures produced astatistically significant increase of thyrnic lymphoma at

116. In the LAF 1 strain, susceptibility to thyrnic
lymphoma is lower than in the RF in both male andfemale animals and, within the scatter of theexperimental points, the corrected incidence of thistumour appeared to rise until approximately 700 radwith what might be regarded as a roughly curvilinear
trend. Within the large variation of the estimates, anapproximately linear rise up to a dose of about 140 rad
was observed following fission neutron irradiation (688).
The susceptibility to thymic lymphoma is however

per cent

60

50,,.._ ------ --- --.
,

30

,

,, '
,/

~~

20

100

200

JOO

400

0 RF 9 - , rays 1107!
6 RF 9 - 5-M<V neut,oru; (5921
C RF 9 - 14-MeV neutros, (1451• CS7BL d and 9 - , ••vs (3301

500

600 ra-d

DOSE

Figure III. Dose-effect relationships for induction of thymic lymphoma in RF and CS7BL mice irradiated with x rays andneutrons584

-maximal in the C57BL mouse where the dose-effectrelationship shows a curvilinear trend up to about
450 rad of x rays with an incidence of approximately 40
per cent. An ensuing plateau but no further decline isseen up to about 570 rad (330). It may therefore beconcluded that the efficiency of the induction of thethymic lymphoma by sparsely ionizing radiation isgreatest in the intermediate dose range between about
I 00 and 400 rad and lower at doses outside this range,
but no clear-cut decline below the peak incidence has

been reported. It seems possible that a linear rise at low
doses could occur after neutron irradiation and it should
be noted that neutron treatment often seems to give abiphasic response with a peak, a trough and a further riseat higher doses, which, if true. would indeed be a very
difficult phenomenon to explain.
117. Reticulum cell sarcoma and other reticularneoplasms (fig. IV). The dose response relationship in
RF female mice shows a continuously decreasing trend

pucuu

C.

RF 9 -

14·MeV ntuttoni I 145)o RF 9 - x rays {1071• CC57BL • CJHJ F. d- xr..,.1438)
o RF 9 - 5-M,~V neutrons 1692)

''

'

''

'

'

''
'

500

600

..

700

BOO

900 redO•)SE

Figure IV. Dose-effect relationships for reticulum cell sarcoma and other reticulartumours in RF (female) and (C57BL X CJH)F 1 (male) mice irradiated witJ1 x rays andneutronsfrom the control incidence levels of 30-50 per cent(according to various reports) to 15-25 per centincidences between 300 and 400 rad of x rays ( 694, 681,
130. 466). The most complete experiment carried out
with 330-kVp x rays and 60-MeV protons, suggests thatthe decrement might be more appreciable at low than athigh doses since the incidence tends to level off at about
25 per cent between 300 and 400 rad of both radiations( 107). Discrepancies in the pathological classification
between non-thymic lymphomas and reticulum cellsarcomas among various workers may have contributed
to the considerable variability observed between thereports cited. In the RF male the spread of resultsappears somewhat smaller and a linear function could
possibly be fitted to all data in the interval 0-450 rad ofsparsely ionizing radiation (694. 686, 681. 692, 130).
The same decreasing trend with dose applies after 5-MeV
neutron irradiation in both sexes (692) and after_14-MeV neutron irradiation in females (145), although
the slope of the curve appears to be generally steeper
with neutrons than with x rays in the same experimental
series. Also in the LAF 1 strain, non-thymic lymphoma
incidence varies inversely with gamma dose between O
and 487 rad, with considerable differences between thetwo sexes (688). The changes induced by x rays infemale (IOI X C3H)F 1 mice-a strain with a particularly
low control incidence of these reticular tumours- were
negligible up to 750 rad (129).
118. In
male
miceof thehybridstrain(C57BL X C3H)F 1 having a spontaneous incidence ofreticulum cell sarcoma approaching 60 per cent,radiation had a small effect on the final incidence up to
doses of 400 rad of x rays, but higher doses (up to
900 rad in bone-marrow-shielded (134) or in transplanted animals (I 35)) produced a reduction of tumours to 3
per cent or less. It was pointed out that the final portionof the curve approached the slope of the survival curvesof haemopoietic stem cells in this strain of mouse (629).
Finally, although induction on non-thymic leukaemia
was reported in CBA females irradiated to a dose of
500-rad fractionated x rays, it was also remarked thatlarger fractional doses tended to reduce the incidence of
these neoplasms, an effect which would be in line withall the above data ( 446). It may therefore be concluded
that. within a rather large strain and sex variability. bothdensely and sparsely ionizing radiation decrease theincidence of reticular tumours in an inverse relationshipwith dose. It should be pointed out that a decrease oftumour incidence with dose is a rather frequent findingin tumour model systems in which a high spontaneous
incidence is encountered.
119. Lung tumours. In the case of lung tumours a
distinction should be made between whole-body andlocalized irradiation. Although no complete dose-effectrelationship was obtained. a lower incidence ofpulmonary adenomas was reported with respect tocontrols (24 per cent) after treatment with 800 rad andisologous marrow infusion (8 per cent) or after
whole-body doses of 290-580 rad of 8-MeV neutrons in
LAF 1 mice ( 514). In the same strain a generally585

decreasing dose-effect relationship was observed for lungtumours (essentially adenomas) up to 700 rad of
gamma rays: the slope of the curve was steeper in males,
which had almost five times as many spontaneous lesions
as females (688). Scattered data on pulmonary tumour
induction in male LAF I mice after single whole-bodydoses of 300 rad of x rays were also reported by Coleand Foley (116), while 15-MeV electron doses up to
about 450 rad produced little change in the incidence oflung tumours in SAS/4 mice of both sexes (325). In the
RF female mouse a decreasing trend up to about 400 rad
was reported after x-ray and proton irradiation (107) orafter neutron treatment at energies of 5 MeV (692) or
14 MeV (145). Some acceleration of lung tumour
occurrence but no real induction was also found in RF
females after 500-600 R of x rays (687). In male miceof this same strain, graded doses of x rays and 5-MeV
neutrons produced an inverse relationship without any
apparent difference in slope between the high- andlow-LET radiation (692).
120. In an experimental series compnsmg 1149 male
(C57BL X C3H)F I animals, the final observed incidenceof lung tumours increased from 9 per cent to 15 per centfollowing a curvilinear function up to 500 rad of x raysand decreased thereafter up to 900 rad down to control
levels (137). After lung cancer induction had beenreported in rats and hamsters irradiated on the chestwith doses of 3 and 4 krad (239), a complete set of data
was published more recently, obtained by localized
x irradiation of RFM male mice (754) (fig. V). The
incidence of pulmonary nodules and the mean numberof nodules/mouse scored at 11 months post-exposure
showed an increase directly related to exposure(probably following a curvilinear function) up to 1500 R
and sharply declined at higher exposures, reaching
control level at 2750 R. There can be no question about
the significance of these latter data but they are difficult
to reconcile with the previous ones obtained bywhole-body irradiation in other strains or even in thesame strain, since some small increase, rather than theactually observed decrease in incidence would be
expected after sublethal doses. Differences in theexperimental design or in biological factors could
possibly justify the discrepancies (754).
121. Ovarian tumours. A list of early references onradiation-induced tumours of the ovary is given by
Garner (211 ). The data referred to are very scattered andinsufficient for a reconstruction of a tentative
dose-effect curve. The incidence of ovarian adenomas
increased consi~tently, over the control level of 11 percent in LAF 1 mice. after doses of 800 rad of x rays
(36 per cent) or of 290-580 rad of 8-MeV neutrons (52per cent) (514). More complete data were published on
gamma-irradiated animals of the same strain (688),
showing an increased incidence to about 40 per cent ataround 350 rad and an ensuing fall up to 700 rad. The
data in the low-dose range seem insufficient to draw
conclusions as to the initial shape of the dose-effectrelationship. Similar considerations apply to the dose
incidence curve for tumours of the ovary in SAS/4 mice(385) and in ddY/F or C3H/Tw animals (355).

:I

122. In the RF strain (fig. VI) acceleration andincreased induction of ovarian tumours by single dosesof 500-600 rad of x and gamma rays was first reported
by Upton, Kastenbaum and Conklin (687). In a more
extensive experiment performed with 14-MeV neutrons,
the incidence of ovarian neoplasms markedly increased
from 15 per cent in the control group to a maximum of
62 per cent at 100 rad, with a plateau at higher doses.
The induction rate between O and 50 rad might behigher than between 50 and iOO rad (145). The latter
observations are in contrast with the results oflower-energy neutrons (692), although in the sameseries. doses as low as 50 rad of gamma rays consistently
increased the incidence of ovarian neoplasms. In thiscase the dose-incidence relationship followed a sigmoid
curve, rising from the control level of 9 per centsomewhere between 25 and 50 rad and reaching amaximum of 45 per cent at 200 rad, declining at
increasing doses. Oscillations over a generally decreasing
trend were observed further up to 700 rad (692).

Figure V. Dose-effect relationships for induction of lungtumours in the RFM mouse123. A similar large increase of ovarian tumour
induction was shown in a recent report where 300-kVp
x rays and 60-MeV protons were used in single
whole-body exposures. The dose-effect curves producedby the two radiations were almost superimposable andshowed an extremely high susceptibility without apparent threshold at doses of 50 rad. a further but smaller
rise to 100 rad, and a gradual decrease from 100 to
400 rad. the highest dose used (107). Finally. sevendifferent dose-effect relationships at different dose rates
were reported for the induction of ovarian tumours by
gamma-ray irradiation of the BALB/c mouse. At thehighest dose rate of 112 rad/day, a curvilinear

per cent
100

2.0

90

1.8

80

1.6

70

,..

60

,, __ ,
I

I

I

I

l 1.2

/

I

I

40

I

~

!.

I

rl.O I-

I

.!

I

I

!

E

I

<o.s

I

I

I

I

.'

E

I

]

r·6

~o.•

J

I
RFM d - • u1v~.1ocahhd uG)Oturo llS41:; me11n nunmirr 01• lncld,nc•'"""°""'' per mouse

I
~0.2

I
1000

2000

3000 •od

DOSE

586

per Cl!fl!

so70-----0._ ____ _----- ...

o Rf - x ,ay, 1107)
6 Rf - 5-M•V neutrons 1692)
o AF - 14-MeV nei..trons (145)• Rf - 60-M,V p,otom 1107)

I---1-l-I
300

100

400

500 rad

COSE

Figure VI. Dose-effect relationships for induction of ovarian tumours in the RF mouse

relationship was found between zero and about 200 rad,with an ensuing plateau up to 390 rad. The non-linearityof the dose-incidence curve was confirmed by theobservation that at constant exposure time, theincidence varied as the square of the dose (750).
124. In conclusion, the great majority of the reports
seem to confirm that the dose-effect relationship for the
induction of ovarian tumours has a very steep rise fordoses of radiation between O and 50 rad. The maximum
yield of tumours is then obtained between 100 and
200 rad and a decrease foUows at higher doses.
Biological factors such as the strains and radiologicalvariables such as LET and dose rate influence theinduction of ovarian tumours.
125. Mammary tumours. The RF mouse has a low
spontaneous incidence of mammary tumours and is noteasily susceptible to the induction of this neoplasia:
histological observations on more than 2500 female mice
irradiated with x rays or fast protons failed to show any
consistent trend with doses up to 400 rad (107). The
hybrid B6CF 1 mouse also has a low susceptibility tomammary tumour induction by gamma rays or fission
neutrons (206). In the LAF 1 mouse, on the other hand,
the incidence of breast sarcoma declined monotonicallyfrom 15 to 0.5 per cent between O and 700 rad, while
the observed incidence of carcinoma increased from 1 to
5.5 per cent at around 350 rad and then decreased up to
the highest tested dose of 700 rad. The high correlation
between mammary sarcoma and granulosa cell tumoursof the ovary observed in these studies (688), as well asother data in rats (138) point to a strong influence ofhormonal factors in the induction of mammary tumours(see paragraphs 68 to 73). Limited or lifetime
whole-body exposures to gamma rays in doses of30-2100 rad and exposure rates of 0.062-121 R/day

were carried out on RAP mice, possibly harbouring a
mammary tumour virus. In accordance with other data
(see paragraph 70), a similarity of the dose range forovarian and mammary tumourogenesis but no correlation between the two types of neoplasia was found in
this strain. Complex systemic changes in the inductionof breast tumours were confirmed (736).
126. The Sprague-Dawley rat is the animal where moststudies on the dose-related induction of breast tumours
have been carried out (fig. VII). Female ariimals
irradiated with x or gamma rays at the age of about
40 days, were examined during about one year after
irradiation for the presence of mammary nodules, whichwere then excised and histologically diagnosed (614,611). A fairly good linear relationship with exposure of
the observed percentage incidence of tumour-bearing
animals or of the cumulative number of tumours. per rat
was found in the range of 16-250 R for both types ofradiation. From this observation it was concluded (50)that a threshold did not exist, the data extrapolating
satisfactorily to control incidence. The linear relationship holds (with different slopes) for both the
adenofibromas and the adenocarcinomas (611). The
response to fi~sion neutrons was examined in the same
tumour model system with a range of doses and in thiscase the animals were followed for the entire life span.
The observed percentage incidence of rats carrying
mammary neoplasia rose from 48 per cent to 78 per centafter only S rad of neutrons and then a plateau withvalues up to 87 per cent at 150 rad was observed; afurther increase of the dose to 250 rad produced a small
decline to 76 per cent. A close similarity of response tosimilar doses of x or gamma rays was also confirmed inthese experiments (714). Other data on mammary
carcinogenesis in various strains of rats irradiated withsingle doses of x rays or fast neutrons are to be found in
587

'

f\

.

/.-

_. -

----

so:\ ;9tI \1,'/
'

:
70 i
I

I

•'

-- -• ...........

.........

·-·-------.-.

I

'

I

60 I
I
I

40

0 Spr111u•·Dawley 9 - 60to-1' (6111
total 1umour incidence
at 11 months pon•irrldiation• Spr-D•wlev 9 - Fut neutrons (7141
total tumour incidmc:e It death

100

200

300

400

500 rad

DOSE

Figure VII. Dose-effect relationships for induction of mammary tumours in the Sprague-Dawley rat
irradiated with cobalt-60 gamma rays or neutronsa paper by Shellabarger (607) or will soon become
available from experiments in progress (63, 605). In the
dog a lower yield of mammary tumours (10 per cent)has been reported (621, 579) in animals irradiated with amixed gamma-neutron field, with respect to a control
incidence of 40 per cent.
127. The evidence reviewed allows the conclusion thatthe dose-effect relationship for mammary tumour
induction in the rat after x or gamma irradiation appears
to be linear down to very low doses. In the mouse theneoplastic response of the mammary gland is morevariable. and depends on the strain and on tumour
histotype.
128. Kidney tumours. Low incidence of kidney
neoplasia after whole-body irradiation with x, gamma or
proton radiation up to doses in the mid-lethal range havebeen frequently reported in various mouse strains (351,
36, 688, I 07), but no reasonably complete dose-effectrelationships have yet been produced. Similarly, in therat (which is more susceptible to these tumours) mostinformation was obtained after single or only a few
doses of x rays (366. 569, 570, 36). A thorough series
was however carried out by Maldague (422) with Wistar
male rats irradiated locally with x-ray doses ranging from
570 to 14 250 rad (fig. VIII). Spontaneous
kidney carcinogenesis in this strain is absent and doses
up to 570 rad were ineffective in inducing tumours. A
few tumours appeared at 855 rad and the dose incidence
curve rose sharply thereafter up to a maximum ataround 1700 rad. which may be considered in this strain
588

as the optimal carcinogenic dose, producing tumours in
84 per cent of the animals. The dose-effect relationshipdeclined at doses in excess of 1700 rad down toincidence levels of 5 per cent at the highest dose. Bothbenign and malignant lesions followed the same general
pattern. The initial part of the dose-incidence curve forthis type of neoplasia appears therefore to be of thesigmoid type. with a very definite threshold at about
500 rad.
129. Skin tumours. The frequency of skin neoplasms in
LAF 1 or RF mice irradiated with x or gamma rays,
protons and neutrons is only affected to a small extent
by radiation up to the mid-lethal dose range (688, 692,
I 07). Higher doses of localized irradiation are necessary
to induce this type of tumour. In CBA mice irradiatedwith low-energy beta particles, tumours were observed
after doses of 750 to 12 OOO rad (285). A plot of thenumber of tumours per irradiated area of skin gavedose-effect relationships of different shape according to
the type of the tumours (benign or malignant) and totheir origin (dermal or epidermal). Although for sometumours a linear non-threshold response would not be
incompatible with the data within the experimental
errors, curvilinear relationships seem to fit the data
better. A plot of tumour yield per rad. allowing for dose
distribution in the skin layers, shows a very rapid
increase up to 1650 rad and a considerable fall-off at
higher doses for both dermal and epidermal neoplasms(285). A dose-effect curve for the induction of skintumours in Swiss mice was reported by Albert et al (7)i11 the range of 500-4000 rad of fast electrons. The initialper cent

90

BO

70

60

50

40
0 BENIGN• MALIGNANT
4 ALL TUMOURS

30

d Wist¥ ra1 -:i.

rays (4221

20

10

1000

2000

3000

4000

5000

6000

7000

8000

14000

15000 ,ad

DOSE

Figure VUI. Dose~ffect relationships for induction of kidney tumours after x irradiation of the Wastar rat

shape of this curve appears to be highly curvilinear forboth epithelial and connective tissue tumours. There is apeak at around 2500 rad for the induction curve of
epidermoid carcinomas, while sarcoma induction con·stantly rises up to the highest dose. The problem of therelative susceptibility of mice and rats to skin tumour
induction has also been discussed in this paper, and therelatively lower susceptibility of the mouse has been
attributed to its failure to develop tumours of the
cutaneous annexes, which are the predominant type ofneoplasms in the irradiated rat skin. Dose-effectrelationships for the induction of skin tumours in CD-1
mice by accelerated helium ions of various energies havealso been reported (369).
130. In Sprague-Dawley rats whole-body irradiated withtwo doses of x rays or fast neutrons, a considerable
incidence of skin tumours was reported (up to 60 per
cent of animals with tumours, starting from a control
incidence of about 18 per cent). The data were analyzed
carefully on the basis of age-specific incidence rates, butthey are insufficient to establish detailed relationships
with the dose and type of radiation (94). Good
dose-effect curves were obtained, on the other hand, inCD male rats irradiated with the cyclotron-accelerated
helium nuclei in the dose range of 210-6950 rad andwith high-energy electrons from 910 to 12 300 rad (80)(fig. IX). Tumour incidence per animal increased at thelowest doses of electrons as the fourth power of thedose, levelled off between 2 and 4 krad and gradually
declined at doses up to 9 krad, which produced severe
skin ulceration. The dose-effect curve for alpha particles

showed the same general shape but was displaced
towards the origin of the abscissa by a factor of about 3.
The low number of tumours obtained at the lowest
doses did not allow a definitive evaluation of the initial
shape of the dose-effect curve for alpha particles.
131. It seems reasonable to conclude therefore that theinitial slope of the dose-effect relationship for the
induction of skin neoplasia by sparsely ionizing radiationin mice and rats is curvilinear and that a power function
with smaller exponent may apply to densely ionizing
particles. A progressively decreasing yield of tumours isobserved in both cases at very high doses.
132. Tumours of the liver and of the gastro-intestinal
tract. Partial data on the occurrence of hepatoma in
LAF 1 mice have been published repeatedly (514, 515,
122, 11 7, 119). Complete dose series were reported by
Furth, Upton and Kimball (210) and by Upton et al.
(688). The latter paper shows that the control incidenceof hepatoma in males (22 per cent) is graduallydepressed to about 2 per cent after 700 rad of gamma
rays from a nuclear detonation. In the female animals,on the contrary, the background incidence of 1.5 percent is raised to about 8 per cent at 368 rad and again
brought back to control levels at 697 rad. The
occurrence of hepatomas in the SAS/4 strain is 10 per
cent in males and 2 per cent in females and is hardly
changed at all by 15-MeV electron doses up to 460 rad(385). In the RF mouse the spontaneous incidence ofliver tumours is very low (less than 1 per cent in females
and less than 2 per cent in males); radiation does not
589

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Figure IX. Dose-effect relationships for skin tumour induction in CD rats irradiated with electrons and alpha particles

appear to affect it to any appreciable extent (I 45, 692,
I 07). Radiation-induced hepatic tumours in the rat havealso been described by Zatsamaya and Bykorez (760).
133. High localized radiation doses to the variousorgans are usually required to elicit the formation oftumours of the gastro-intestinal tract (212, 263, 666),
but the observation of some tumours at lower doses is
not infrequent. The dose-effect data for the occurrenceof hyperplastic and tumoural changes of the gastrointestinal tract in whole-body irradiated mice werereviewed by Cosgrove et al. (131) and by Upton et al.
(684). By combining the three series available of LAF 1
mice exposed to A-bomb radiation (688) and to x raysor neutrons of various energies (514) and CF 1 mice
exposed to radiation from nuclear detonations (409), it
was concluded that the incidence of gastro-intestinal
tumours increased up to a maximum of 5 per cent as acurvilinear function of the dose for both sparsely anddensely ionizing radiations, the latter being definitely
more effective. Intestinal polyps in dogs and rats
following exposure to mixed gamma-neutron beams or
feedings of 210 Po or 144 Ce were also reported, mostly
occurring in the large intestine with a tendency tomalignant evolution and showing different latencies inthe two animal species (367).
134. Tumours of the bone. Bone tumour production
has been reported in the mouse after partial-body
x irradiation of the hind limbs of 70-day-old CFI
females. Results at 442-575 days (I 94) and at 650 days
post-irradiation ( 185) showed a linear correlation
between dose and osteosarcoma incidence (expressed astumours/mouse) in the exposure range of 250-1000 R.
590

In the rat, irradiation of the knee joint with aradium-iridium source induced a total of 34 osteosarcomas appearing between 300 and 800 days in 116 micewith doses of 3000 rad. The incidence of neoplasia washigher in animals treated with growth hormone;
thyroxine treatment reduced the induction period (96,28). The histological changes and the induction of bonetumours were followed in the hind limbs of 257 rats
exposed to x-ray doses of 500-3000 rad. In some cases
the highest dose was subdivided into 3 or 6 equal
fractions. The greatest number of tumours was foundwith 3000 rad; one tumour arose in the 500 rad group(32).
135. Male F 1 (Marshall X August) and August strain
rats, 6-8 weeks old, were irradiated with 3000 rad of
x rays on the right limb or with doses of I OOO rad each
at 0, 2 and 4 weeks, or with 6 doses of 500 rad each at
0, 1, 4, 5, 6 and 7 weeks on both limbs, and thenobserved for 27 months. Twelve tumours were found in
34 rats of the first group within 6 and 12 months; thegroup receiving 3 doses (15 rats) had only 1 bonetumour: in the group receiving 6 doses, 7 bone tumours
developed in 34 irradiated limbs. No significant
difference between the 3000 rad group and the
500 X 6 rad group was seen at 27 months (177). A
4-per-cent incidence of osteosarcoma was reported in
125 Wistar rats whole-body irradiated with 600 rad(222) and about 5 per cent of osteogenic tumours werealso found in parabiosed rats receiving an x-ray dose of
1OOO rad (732). Finally, osteosarcomas developed in
rabbits irradiated by gamma rays (500-1400 rad) or byfission neutrons (200-600 rad). The induction period
was shorter with neutrons and an RBE value of about

-three was proposed. The data however appear too scanty
to allow any conclusion about the form of thedose-effect relationship (286). Additional scattered dataon bone tumour induction under various conditions may
also be found in Upton et al. (694, 688, 692), Darden etal. ( 145), Hori et al. (274) and Clapp et al. ( l 07).
136. Tumours of the thyroid. This organ can be
irradiated both by external radiation and by theadministration of iodine radioisotopes. Data on doseeffect relationships are available in several animal
species. In the mouse an extensive series of papers on
thyroid damage by radiation reported by Walinder andcolleagues have been summarized in reference 723. In
the CBA strain, adult animals experience a dose-related
increase of the frequency of thyroid tumours following
x-ray exposures (500, 1000 and 1500 R) and 131 I
administrations (1.5, 3.0 and 4.5 µCi). Within this dose
range the induction curve is probably biphasic, with ashallow slope at very low doses and an increased slope athigher ones (724). For very high doses, the carcinogenic
effect probably passes through a maximum (389, 159).
It seems likely that thyroid carcinogenesis may beinitiated by radiation and promoted by hormonallystimulated epithelial hyperplasia (725, 104) and that theinitial shape of the dose-incidence curve may be theresult of the interplay of these factors. The anatomicaland functional processes related with ageing of the
thyroid gland in CBA mice were described by Walinder
et al. (727). Other data on mouse thyroid carcinogenesis
can be found in Upton et al. (688, 692).
137. In the rat, thyroid tumours have been described by
Doniach (155, 156, 157, 162) and by Lindsay's group(390, 391, 215, 546). These papers deal with thedose-effect relationships, fractionation effects andcomparative studies of x ray and 1 31 I-irradiation effects.
A comparison of the carcinogenic effects in rats of
1 31
I (3.2 to 125 µCL five administrations) and 1 2 5 I(administered activities four times larger) has beenreported by De Ruiter et al (150). Animals weresacrificed two years after injection for scoring of theeffects, but the ratio of the administered activities of thetwo isotopes was found to be too low. In fact, themaximum of lesions (hyperplasia. cysts and tumours)
was obtained in the 1 31 I group with the lowest activity
injected, while for the 125 I the peak induction was at
80 µCi. Some data on tumour induction in dogs
irradiated with x rays or 131 I were reported byMichaelson et al. (443).
138. Tumours of other organs. The incidence of these isusually extremely low. As there are few relevant reports
referring to varying irradiation conditions and animalstrains, and as the doses tested are very few, it is
impossible to derive dose-effect relationships for theseneoplasms. Often all the control and all the irradiatedanimals are grouped irrespective of dose in order toreach statistically significant numbers, and under these
conditions it is possible to observe in many cases anincreased incidence in the irradiated animals. However,
the actual significance of these changes is often
doubtful. Since reference to these data, howeverheterogeneous, is sometimes useful, the following list of
relevant papers which have been reviewed, subdivided
according to the various organs. is provided.

139. Tumours of the pituitary gland have been reported
by Upton et al. (694, 688. 692) and by Clapp et al.
(107); of the uterus by Upton et al. (692) and Clapp etal. (107), of the salivary glands by Glucksmann and
Cherry (214) and Takeichi (650); of the adrenal glands
by Upton et al. (694, 688, 692); of the prostate by
Hirose et al. (265); of the testis by Upton et al. (694,688). and of the brain (412, 423). Tumours of theharderian gland have been reported by Upton et al. (694,688, 692), by Darden et al. (145) and by Clapp et al.
(107). Most recently Fry et al (206) have reported aconsiderable increase of harderian gland tumours in
B6CF 1 mice with doses in the range of O to 788 rad of6
Co gamma rays and O tp 240 rad of fission neutrons insingle irradiations. The dose-effect relationships were of
the type described in paragraph 143. Analysis of total
solid tumour incidences at all sites. sometimes as afunction of dose but more often after one or a few
doses, may be found in the following publications:
Upton et al. (694, 692) Nowell and Cole (514), Lindop
and Rotblat (385), Cole and Nowell (119), Reineke etal. (560), Kohn and Guttman (350), Samuels et al.
(584), Castanera et al. (94), Hulse (286) and
Vesselinovich et al. (706).

°

3. Conclusions
140. It appears very difficult indeed to identify acommon trend of the incidence as a function of dose forall the tumour systems examined experimentally andreviewed in the present report. However, if the
discussion is confined to the most commonly observed
neoplasms, three major patterns of response have been
documented.
141. The first pattern refers to those tumours for which
the spontaneous incidence is not significantly changedby the radiation treatment in the low to mid-lethal dose
range. This is typically the case for myeloid leukaemia in
LAF 1 mice ( 688), for pulmonary and liver tumours in
SAS/4 (385), for mammary tumours in the B6CF 1 strain(206) and for mammary and liver tumours in RF female
mice ( 107). The lack of neoplastic response in this dose
range does not necessarily imply that these tumours
cannot be radiation-induced, but may simply mean insome cases that the dose applied was too low for
detectable induction. Actually, increasing the dose to
the lung in RF mice well over the mid-lethal range(which gives an uncertain or even a negative response)
results in the appearance of adenomas with a peak
incidence at 1500 rad of x rays (754) (fig. V). The
question remains open in such cases as to the real shapeof the dose-effect curve (threshold or quasi-thresholdtype) but such questions are only of theoreticalrelevance since for all practical purposes virtually notumours of this type will be induced at the low doses ofinterest.

142. In other cases. tumour incidences have been
described as having a negative slope in the dose-effectrelationship which sets in at the lowest doses and thengenerally proceeds up to the highest doses tested(700-900 rad). This pattern of response is found for the
reticulum cell sarcoma and the non-thymic lymphoma in
RF (694, 686, 681, 692, 145, 107) (fig. IV). LAF 1(688) and (C57BL X C3H)F 1 (438) (fig. IV), for591

pulmonary adenoma in RF (692, 145, 107) and LAF 1(515, 688) and for hepatoma and mammary sarcoma in
LAF 1 mice (688). A radiotherapeutic effect on the cells
which will eventually give rise to the tumours (in theabsence of any significant concomitant induction of new
tumours by radiation) is usually invoked to explain thenegative slope of the relationship (447, 671). This may
well be the case for systemic tumours, where such aninterpretation at the single-cell level is supported byancillary evidence concerning the slope of theinactivation curve of possible target cells (233, 438), but
cell inactivation data favouring a similar interpretation inother cases is lacking. A discussion on this point will befound in paragraph 151.
143. In the majority of cases,. the dose-effectrelationship is of a complex type and shows an initialrise at increasing radiation doses, a peak or a plateau atsome intermediate dose levels and in many cases, a final
decline of incidence of the type as shown in figure I(t).
The relationships for the induction of myeloid
leukaemia and thymic lymphoma in RF (694,671,684,
692, 145, 107), C57BL (330) and LAF1 mice (688)(figs. II and III), of ovarian tumours in LAF 1 (514, 688),
SAS/4 (385), RF (145, 692, 107) (fig. VI) and BALB/C
mice (750), of mammary carcinomas, fibromas andsarcomas in LAF 1 mice (688) and in Sprague-Dawley
rats (614,611,712) (fig.VII), of kidney tumours in
Wistar rats (422) (fig. VIII), of skin tumours in CBA(285) and Swiss mice (7) and in Sprague-Dawley (94)and CD rats (80) (fig. IX), of hepatomas in LAF 1 (688)and SAS/4 females (385), and of lung tumours in RFM(754) (fig. V) and in (C57BL X C3H)F 1 mice (135),
conform to this general pattern. Systemic andnon-systemic, benign and malignant neoplasms, mostly
with rather low spontaneous incidences are included inthis category. Although a large variability of this typical
pattern is observed according to the various systems
tested and to the quality of radiation, the doses at which
the initial rise becomes detectable and the shape of thisrise, the dose range where the peak incidence is observed
and the height of the peak, and the presence and slopeof the final negative part of the curve may usefully serveto characterize the various responses.
144. Regarding the shape of the incidence curves at low
doses, myeloid leukaemia has been tested down to thelevel of 25 rad of x rays in the RF mouse; if one
considers the observed points from that dose up to thepeak incidence, the shape may be described as
curvilinear ( 671) (possibly quadratic (233)) without
excluding a linear component (685). There are howeverquite substantial variations in x ray inducibility between
male and female RF mice (685), and neutron doses havenot been tested below 50 rad in the female, which is lessinducible (145), or below 130rad in the male (692).
Judging from these series, it would appear possible thatthe initial rise in incidence with dose may be more
prompt after neutron irradiation than after x or gamma
rays in both sexes. The dose-incidence curve for thymic
lymphoma, up to the peak incidence, may be described
as being of a curvilinear or possibly quasi-threshold type,but there appears to be considerable variation between
strains. with a faster rise between 300 and 500 rad of
x rays in the C57BL (330), a more gradual increase
between 25 and 300 rad of low-LET radiation in the RF(694, 686, 692, 107) and a very slow rise up to 700 rad
592

in LAF 1 mice (688). Where neutrons have been tested(688, 692, 145) (in these cases the observations do notextend below 50 rad) the curve might possibly bedescribed as becoming more linear.
145. The incidence of ovarian tumours is greatly
increased with respect to controls by a dose as low as
50 rad in RF mice, and for this reason it appears
difficult to attribute any shape to the response curve atlower doses (692, 108). In.the only instance where theeffect of 25-rad gamma radiation was estimated, thepoint did not appear significantly different, although
lower, than the control value (692) and a plateau wasalready apparent at 100 rad. Neutrons yielded conflicting results: 50 rad of 14-MeV neutrons produced asubstantial increase in incidence, but a beam of 5-MeV
neutrons seemed rather inefficient in producing ovarian
tumours in the same strain of animals.
146. The only instance in which a linear dose-effectrelationship has been reported in the interval of
17-250 rad is the early-appearing mammary neoplasia of
the Sprague-Dawley rat (611) although, even in thatcase, some departure from linearity was apparent at thelowest doses (575). In the same system, but on
late-appearing tumours, the hypothesis of linearity has
been questioned (714) at least for neutron irradiation
with doses as low as 5 rad. This observation does not
exclude, however, linearity of the response below thislimit, although it would indicate a much steeper rise of
the induction curve upon neutron treatment. In the caseof kidney, skin and lung tumours after local sparsely
ionizing irradiation (422, 285, 80, 7, 754), the responseat low doses would be termed in general to be of thecurvilinear type, while alpha-particle irradiation data
show less curvature than the electron irradiation curve inthe same system (80).
147. To the extent that simple biophysical models
could be applied to a biologically complex phenomenon
like tumour induction, the above conclusions would
appear to be in general agreement with the observations
made for variety of radiation effects on cellular andsubcellular structures, according to which the dose-effectdata at low doses (delivered at high dose rate) can be
fitted by power functions of the dose, with lower
exponents for high-LET radiation than for sparsely
ionizing radiation (13). They are also in agreement withthe arguments of Kellerer and Rossi (340), according towhich the interplay of primary biophysical events
produced by at least two low-LET particles is required
to initiate biological effects, whilst one single densely
ionizing particle might suffice to produce these effects.
Such a hypothesis implies predominant quadratic
kinetics as a function of dose in the case of low-LET
radiation and linear kinetics in the case of high-LET
radiation. Actually, an analysis of mammary tumour
induction in the Sprague-Dawley rat (575)-the only casewhere a linear relationship haS been claimed down tovery low dose levels of low-LET radiation-suggests thatlinearity, although consistent with the data points, may
be fortuitous and that more than one cell may be
involved in the origination of these tumours.

a148. In the most complete set of data reported fortransformation of hamster cells in vitro by x rays (57),the power function which would best fit theexperimental points in the interval 1-10 rad would havean exponent of less than one, although a linear
dependence of induction on dose would not fall outside
one standard deviation of the data. Thus, even at thisvery simple level, the expected quadratic shape of the
response to x rays cannot be confirmed, probably due toheterogeneity of the cell population to transformation(an inherent characteristic of the cell system used).
Population heterogeneity might also explain theparadoxical results of dose fractionation in this same
system (58), where dose splitting is shown to enhancerather than depress (hypothesis of a quadratic
relationship) or leave unaltered (hypothesis of linearity)
the transformation phenomenon. These data emphasize
the difficulties in the interpretatioa of the transformation effect even at the rather simple level of in vitro cells
and therefore indirectly point to the conclusion thatsimilar analyses in in vivo systems may at present be
unwarranted.
149. Concerning the doses at which the maximum
incidences in the dose-effect relationships of reticularsystemic tumours are found, the peak incidence for
myeloid leukaemia is generally observed at doses of200-300 rad with both high- and low-LET radiation in
the RF mouse; at higher doses, a declining incidence isusually observed. For thymic lymphomas the peak
appears at somewhat higher doses (300-700 rad) and asubsequent negative slope is rarely seen, probably
because of the post-irradiation bone-marrow syndrome
which can reduce substanstially the survival of theanimals at these high doses (694). The peak incidence
seems to occur generally at lower doses with densely
ionizing radiation. This feature is compatible with thetheory of dual radiation action and with the model of
two competing processes discussed in paragraphs 50 to
66. Peak incidences of between 40 and 60 per cent at
100-200 rad have been reported for ovarian tumours in
the most sensitive RF and BALB/c strains, and withineach strain there appears to be no special tendency forthe maximum to occur at lower doses with fast-neutronsor alpha particles than with x or gamma irradiation. Thisphenomenon seems, on the contrary, well documented
for mammary and skin tumours in the rat, in spite of thegreat diversity of the doses at which the peak incidence
occurs ( 400-500 rad and 3000 rad of low-LET radiation,
respectively). Maximum incidences in the dose range of
1500-1700 rad are found for lung and kidney tumour
induction by local x-ray treatment.
150. In conclusion, there appears to be no obviously
identifiable correlation between the susceptibility totumour induction and the character of the dose-effectrelationships resulting from low- or high-LET irradiation;neutrons and alpha-particles have a tendency to produce
peaks at lower doses than x or gamma rays in all
systems. The height of the peak is also not clearly
influenced by the radiation quality but may rather be
regarded as an intrinsic biological characteristic of theparticular system, having little correlation with radiation
quality.
151. The declining trend in tumour incidence at highdoses of radiation could be qualitatively explained bytaking into account two concomitant dose-dependent
phenomena: on the one hand. the effect oftransformation tending to increase with increasing doses
according to some linear or curvilinear function (seeparagraphs 144-146: and. on the other hand, theinactivation of the reproductive integrity of potentiallytransformed cells, which also increases with dose
following complex kinetics which in mammalian cells areusually described by a multi-target one-event type ofequation (170).
152. A quantitative analysis of this hypothesis was
carried out by Gray (233), who tested data on theincidence of myeloid leukaemia in RF mice (671) andmore recently by Mole (459) and by Mayneord and
Clarke ( 430). Gray found that at the low doses theinduction of tumours would proceed in this system withthe 2.28 power of the dose: the loss of reproductive
integrity of the transformed cells at high doses could
reasonably be described by a survival curve having an
extrapolation number of 2 and a D 0 of 120 rad.
153. However, a similar model fitted to the skin tumour
data of Hulse (285) by Hulse et aL (288) showed that adose-squared function would adequately describe theinitial rise, but the Do resulting for potentially tumorous
cells from the declining portion of the curve would be
20 times greater than the 135 rad reported by Withers(741) as the sensitivity of the clonogenic cells in
irradiated mouse skin. Fitting other linear or two-hit
kinetics to the induction process did not essentiallychange the conclusions of the analysis, nor could thehigh D 0 be explained on the basis of cell migration from
non-irradiated areas of the skin. Very similar arguments
have also been developed by Barendsen (25) for his
system of tumour induction in the skin and might also
be easily applied to other results on kidney
carcinogenesis ( 422). It might further be added that if
the negaiive slope at high doses does in any way reflect
the sensitivity to killing of the potentially transformed
cells, one should expect a steeper decline after high-LET
radiation than after x or gamma rays in the same system,
which is by no means an obvious or a consistent findingin all the data reviewed.
154. Finally. the data of Borek and Hall (57) indicatethat the plateau and the decline in incidence of thetransformed clones with dose is independent of thekilling of potentially transformed cells, since it isobserved also after correcting for loss of reproductive
integrity. This would imply, therefore, that transformed
cells have a higher sensitivity to radiation with respect tonormal cells in the same population. On the basis ofthese data (which are anyway of doubtful applicability
in vivo: see paragraphs 147 to 148) the hypothesis of abalance between transformation and killing ofpotentially tumorous cells should therefore beconsidered under a different perspective. Granted thattumours must by defmition arise from cells which haveretained their reproductive ability, the peculiar shape of
the induction curve would show that at the highest
carcinogeneic doses an excessive amount of damage may
render the transformed cells more sensitive than theirnormal counterparts to radiation-induced loss of mitotic
integrity. In this respect, the plateau and the declining
portion of the curve would not reflect the intrinsic
sensitivity to killing of the transformed cells, but rather
the differential sensitivity of these cells with respect tothe normal clonogenic population.
593

C. RADIATION QUALITY AND THE EFFECTS OFDOSE RATE AND DOSE FRACTIONATION IN
CARCINOGENESIS

I. The concept of RBE
155. In addition to absorbed dose, the quality ofradiation, sometimes specified as the linear energy
transfer (LET) of the charged particles (primary or
secondary) in the medium of interest, is also an
important physical factor in radiation carcinogenesis.
This factor was discussed in the 1972 report of theCommittee ( 670). In experimental work the concept ofrelative biological effectiveness (RBE) is commonly used
to characterize the quantitative differences of effectbrought about by different types and energies ofradiation. For this purpose, the RBE of one kind ofradiation compared to another is defined as the inverse
ratio of the doses of the two kinds of radiation that
produce the same biological effect (563), under the
stipulations that (a) the basis for comparison should be
the absorbed doses, and (b) other radiological or
biological factors known, or suspected, to influence theresponse of the irradiated system should be the same.
156. It is clear however that since the nature of thebiological effect, the nature and physiological conditionsof the irradiated system, the dose level, the distributionof the dose in time and within the irradiated systemaffect the RBE estimates, the strict definition given
above would imply a very detailed knowledge of the
exposure conditions and of the system and effect understudy before reference could be made to true RBE
values. Short of this knowledge, an "equal-effect ratio"
could be derived, defined as the ratio of two doses
producing equal responses, when undetermined factors,
other than the LET of the two radiations compared,
would affect the biological response (563).
157. Actually, the vast majority of the so-called RBE
values for tumour induction published in the literatureand reviewed in the present report fall into this latter
category of estimate, since only seldom have thephysical parameters of exposure and the biologicalcharacteristics of tumour system studied been
determined or reported with the necessary degree ofprecision. This observation refers especially to the use of
inappropriate end-points or of uncorrected estimates oftumour incidence for the calculation of the dose ratios
and to the lack of a systematic exploration of thedose-effect relationships within a large range of doses inmost of the systems studied. All this might largely
account for the scatter of the values reported. Chapter Iof this Annex discussed the appropriate methodology for
RBE studies. The influence of the shape of thedose-effect relationship on the RBE values, especially at
the low doses of interest in radiation protection, wasalready discussed in the 1972 report of the Committee(670), where the rationale for the interpretation of therelevant RBE changes was reviewed. Although additional
experimental data have since become available. theseconcepts have not been sufficiently considered in generalterms (except in references 340 and 430) and needreview and systematization in the light of the mostrecent theoretical acquisitions.
594

2. Dose-RBE relationships
158. Figure X, taken from the I 972 report of theCommittee (670), illustrates schematically the influenceof the shape of the dose-effect relationships on thechange of RBE values with dose. It appears that whenthe effects brought about by the two radiations undercomparison follow simple linear (case a) or second-order(quadratic) polynomial kinetics
with different
second-order coefficients (case c), there is no reason why
the RBE should differ at different levels of dose and/or
effect. However, when the effect of the standard
radiation follows a curvilinear shape and the test
radiation produces a linear dose-effect relationship(case b ), the RBE will tend to increase at very low doses;
at higher doses the RBE would gradually decrease andmight in principle even become less than 1 above theintersection of the two curves. However, as was
mentioned in paragraphs 91 to 103. simple polynomial
approximations are only valid at the lower doses. A
similar increase of RBE values at low doses, but without
a tendency for inversion at high doses, will take placewhen the effect of the standard radiation follows asecond-order polynomial relationship and the test
radiation produces a dose-effect relationship with anappreciable first-order component in addition to thequadratic term (case a).
159. The most recent theoretical analysis of theconcept of RBE has been carried out in the context ofthe theory of dual radiation action (340) which leads torigorous mathematical formulations and, even forcomplex effects such as tumour induction, may accountfor the shape of the dose-RBE relationships. Concerning
the RBE changes as a function of dose rate, it iscustomary to explain the experimental data on theassumption that high- and low-LET radiation canoperatethroughsingle-track
andmulti-trackmechanisms, with a very high probability of multi-track
phenoma in the case of the low-LET radiation. As thedose rate decreases, the probability of simultaneous ornear simultaneous multi-track events for sparsely
ioruzmg radiation also decreases and only thesingle-track component remains effective. The RBE
would then tend to a high limiting value which is thesame as the limiting value of the ratio of the initialslopes of the dose-effect curves (563). The loss of
efficiency at very low dose rate is comparatively smaller
for the high-LET than for the low-LET radiation, andtherefore the RBE increases towards a limiting value thatwould correspond to the RBE at low doses.
160. The mathematical formalism for the dependenceof effect on dose and on RBE in the presence ofinter-track phenomena, as a function of the irradiation
time and of the recovery time of the irradiated system,has been recently worked out on the basis of the theoryof dual radiation action (340). The relations holding forconstant irradiation times and for constant dose rates are
given, and the pitfalls in interpreting RBE values atconstant low dose rates as being due exclusively tosingle-event mechanisms are also discussed. Data on RBEof different radiations in various tumour model systems
are examined in the following paragraphs. The values of
RBE pertaining to high and low dose rate will beconsidered separately for those systems where sufficient
data are available.

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2.0
2.0

20

1.6

2.0

100

0

100

C

80

2.66

2.74

60

80

60

2.80

2.24

2.86

40

40

2.98

2.24
2.24

d

2.70

2.24

2.24

20

2.2
0

2.24

40

20

3.16

20

3.62

2.24
0

0
100

200

300

400

500

100

600

200

300

400

500

SOO

DOSE (rad)Standard radiation, second-order (quadratic) polynomial;
test radiation, first-order polynomial(a)First-order (linear) polynomial curves with the sameintercept but with different slopes

(b)

(c)

Second-order polynomial curves defined by only two terms,
the intercept a (which in this case equals 0) and thesecond-order term cx 2 , but with different second-ordercoefficients c(d) Standard radiation, second-order polynomial defined byonly the intercept and the second-order term; test
radiation, second-order polynomial defined by the intercept, and the first- and second-order terms,y =a+ bx+ cx 2

Figure X. Influence of character of dose-effect curves on RBE (670)161. Concerning the induction of tumours of thereticular tissues, when myeloid leukaemia was induced in
RF mice, the RBE of fast neutrons (1, 5 and 14 Me V)
compared with x and gamma rays was shown to varywith dose and dose rate. For acute exposure in the dose
range of 25-450 rad. the neutron RBE was estimated to
be not appreciably different from 1 (145, 693, 692),
while at low dose rates an unequivocal increased relative
effectiveness of the neutron treatment (perhaps by afactor of 10) was reported. owing to the greatly reduced
yield of tumours in the animal groups irradiated withsparsely ionizing radiations ( 692). Treatment of thesame strain of mouse with 60-MeV protons appearedslightly less effective than irradiation with 300-kV x raysin the interval of 50-200 rad, but at higher doses theeffectiveness of the two radiations was very similar(107).
162. Thymic lymphoma incidence was also examined in
the course of the same experimental series (145,692. 107). At the highest dose rates, the RBE ofneutrons of all energies was not significantly greater than

1 at all doses tested, but 60-MeV protons tended to beless effective than x rays at doses of 300 and 400 rad. At
low dose rates the efficiency of the low-LET radiation
treatments decreased by two to three times and acorresponding increase of the neutron RBE was observed(692). As already pointed out (see paragraph 142), otherreticular tissue neoplasms such as non-thymic lymphoma
and reticulum cell sarcoma show an inverse relationshipof incidence with dose, with x, gamma, neutron andproton irradiation. ln view of the inhibitory effect of theradiation treatment and due to very pronounced
variability introduced by biological factors (seeparagraphs 80-82) the RBE calculation would be here oflimited interest.
163. The different shape of the dose-incidence curves
for the various classes of leukaemia seen in the rodent.
the different times at which the leukaernic syndromes
occur, the distortions introduced on the final incidence
estimates of the late-appearing leukaemic syndromes by
the early-appearing ones, and the frequent lack ofappropriately corrected incidence data account for the595difficulties in generalizing meaningful RBE values for all
leukaemias considered together. In cases where suchcomprehensive analyses have been attempted, 60-MeV
protons appeared slightly but consistently less effective{0.80-0.65) than 300-kV x rays in the interval
100-400 rad, but microdosimetric and biologicalconsiderations could not account for this difference andwould not permit in any case extrapolation of such data
to larger animals (107).
164. Observations on the mortality and pathology atdeath were carried out on hybrid mice irradiated with
200-kVp x rays {0-200 rad) or with 400-MeV neutrons(0-84 rad) at comparable dose rates. No differences wereobserved in the longevity, which would suggest an upper
limit to the RBE for life-span shortening ofapproximately 2.5. Similar conclusions were also drawn
with respect to the induction of all types of leukaemias
and of other solid tumours {136). Preliminary data on alarge RBE experiment on C57BL mice have been
published by Mewissen and Rust (442). The dose range
was between 3.2 and 47.2 rad of reactor fast neutronsand between 18 and 141 rad of 6 ° Co gamma rays. A
spontaneous spectrum of tumours including a major
proportion of reticular tissue was established in control
animals and modulation of this spectrum by theradiation treatment was observed, particularly in thereticular tumours. Dose-effect relationships for tumour
appearance were non-linear and the radiation-inducedchanges in tumour spectra seemed to be related more todifferent intercompetitive processes, rather than toprobabilistic random events. No numerical RBE factors
were however provided. In conclusion therefore, as far as
neutrons are concerned, their RBE appears to be about 1
in the range of a few tens to a few hundred rad at highdose rates; at low dose rates the tendency is towards anincrease of the RBE by a factor of 2-10, according to theparticular type of leukaemia and the particular dose rate
examined.
165. In RF mice, the incidence of lung adenomas has anegative trend with dose which is not appreciably
different in groups irradiated with 300-kVp x rays or
60-MeV protons (107): fast neutrons at various doses
and dose rates caused a greater reduction in incidence of
these neoplasms than gamma rays (692).
166. The RBE for the induction of ovarian tumours byneutrons in the RF strain cannot be established withcertainty: in one series (145) 14-MeV neutrons appeared
no less effective than x or gamma rays, whilst in otherexperiments (693) lower energy neutrons appeared to bevery inefficient for the induction of ovarian neoplasia. In
a more recent report by the same group of workers(692), RBE was studied as a function of dose and doserate, and similar results were found, with the exceptionthat tumours appeared in a significantly increased
number after only 2 rad of neutron irradiation deliveredat the dose rate of 0.004 rad/day. If this observation is aspurious one, then the RBE for neutron carcinogenesisof the ovary could be low: but if it were confirmed. it
might imply that the absence of tumours at higher doses
and dose rates (neutrons) could be due to excessive
injury or life-span shortening due to the treatment. The
latter would be then in favour of a very high RBE value
for ovarian carcinogenesis by 1-MeV and 5-MeV
neutrons. The RBE for x rays and fast protons for this596

same effect was rather similar at all doses tested. with apossible higher efficiency between 100 and 400 rad for
protons. However, for both radiations the maximum
incidence was seen already at 50 rad, suggesting that
down to this dose level the efficiency of the tworadiations under comparison is not appreciably different
from unity.
167. The RBE for the induction of mammary neoplasia
in the rat following acute irradiation has been the objectof considerable attention. The 1972 report of theCommittee (670), in examining the older RBE data forthis tumour, commented on their technicalheterogeneity. Actually, although the same animal strain
was used in all the experiments, the most extensive
results on low-LET irradiation were obtained in one
laboratory on 40-day-old rats by scoring the neoplastic
response at about one year post-irradiation (for acomprehensive analysis of the low-LET data see
Shellabarger {611 )). The neutron irradiations, on theother hand. were performed in another laboratory on
animals 2-3 months old. with lifelong observations (708,712). The differences in the scoring technique accountfor the fact that the background incidence of mammary
neoplasia in non-irradiated rats is negligible in the firstcase and approaches 50 per cent in the other. In
addition, the use of data uncorrected for competingrisks, probably did not alter greatly the final estimates oftumour induction in the first case, since only 4 per centof the rats had died at all doses within the observation
time of one year (611), while in the neutron series it
seems likely that the calculation of appropriate final
incidence values might have changed the conclusions tosome extent.
168. There is no doubt that if one considers the data
produced by the 6 °Co gamma treatment, which arereported as being linear in the interval of 16-250 rad(611 ), and the data of the fission neutron series (where adose as low as 5 rad produced a near-maximum effect(714), and one calculates the ratio of doses producing
the same neoplastic effect, one finds very high values of
the RBE. However, comparing the results of 5 rad offission neutrons and 100 or 300 rad of x rays by thesame lifelong technique of scoring shows that at all times
from irradiation to death the curve describing thepercentage of rats bearing tumours for theneutron-irradiated group is intermediate between the
curves following 100 and 300 rad ofx rays (714). Thus,
RBE values of between 20 and 60 could be applicable tothe data.
l 69. The problem of RBE for breast tumour inductionin the rat was discussed recently at the Symposium on
Biological Effects of Neutron Irradiation ( 43), where theresults of the two groups of scientists active in the field
were updated and compared. Long-term observations on
animals irradiated with neutron doses of about 2 radwere matched by the results of 100 rad of x rays.
implying an RBE of about SO. A non-linear "stepfunction" of the neutron dose-effect relationshipbetween 2 and 20 rad was also reported, the explanationof which, except for the possibility of statisticalfluctuations, seems rather obscure (709), especially sinceno such trend was found by the second group of workers
in an experimental series extending down to 0.1 rad ofneutrons {613).

170. These latter data were thoroughly analyzed bymeans of dose-effect relationships based on thetime-integral of the tumour incidence rate P(t) (seeparagraph 103) for the two radiations under comparison(0.43-MeV neutrons and 250-kVp x rays). In good
agreement with previous analyses (575), the neutron
dose-effect relationship showed an effect proportional toa dose power of less than 1, an observation interpreted
to imply that the induction of neoplasia in thisparticular animal system might be due to the interactionof a number of cells, rather than to the transformationof an individual cell developing into a tumorous clone.
The RBE approached values of 100 at the lowest
neutron dose of 0.1 rad and of about 10 at the highest
dose used, 6.4 rad. Thus, the earlier discrepancies foundin the analysis of the breast tumour system by the twolaboratories were apparently reconciled, at least to theextent that at the very low neutron doses the RBE
would attain extremely high values, as the theory of dual
radiation action (340) would predict.
171. However, the biological peculiarity of this tumour
system should be emphasized, since radiation acts in thiscase essentially through an acceleration of tumour
appearance, rather than by the induction of newneoplasms. There seems to be agreement about
increasing values of the RBE with decreasing doses, butwhether the above conclusions would also apply
quantitatively to all other tumour systems remains to beestablished by new experimental evidence. An equal
effect ratio of 1.5 between 6 ° Co gamma rays and2 .2-GeV protons for the induction of breast neoplasia has
also been reported (620), following a pattern qualitatively similar to the induction of this tumour by otherlow-LET radiations and well within a range of RBE
values reported for different cellular and functional
end-points. Finally, the RBE of 3 H administeredinternally as compared to gamma rays from 1 3 7 Cs given
externally at similar dose rates was found to be around
1.8 for the yield of mammary tumours in rats between
13 and 19 months after exposure (475).
172. No data are available for the breast tumour systemon the changes of RBE as a function of the dose rate,
except for the facts that after gamma irradiation at
exposure rates of 10 R/min or of 0.03 R/min there is no
sparing effect of the low dose rate in the incidence of
mammary fibroadenoma, but a lower incidence ofadeno-carcinoma. The total breast tumour response ishowever unaffected ( 612). Thus, since at the relatively
high doses used the overall low-LET radiation effect is
not changed, one should not expect consistent changes
in the RBE because the predominantly linear component
in the neutron dose-effect relationship would not be
expected to change with dose protraction. Similarly, atthe very low dose rates, for which, according to thetheory (340), the inter-track interaction is negligible bycomparison with the intra-track effects. one should not
expect the RBE values to exceed those which apply forthe acutely delivered very low doses.
173. Another tumour system where there appears to beenough data for some analysis of RBE is the skintumour. Scattered information on the induction of thisneoplasia by neutrons and x rays in the rat has beenreported by Jones et al. (312) and in the mouse by

Lippincott et al. (394) after proton and alpha-particle
irradiation, but this information is unsuitable forderiving RBE values. A fairly complete dose series in the
rat has, however, been reported (80) following
irradiation with cyclotron-accelerated helium nuclei orwith monoenergetic electrons, which allows someestimate of
RBE for skin tumour induction. If the
RBE is calculated in this system (see figure IX) according to
the displacement of the rising portion of the two curves,then a value of 2.9 is obtained. Since there is thesuggestion that the initial slope of the alpha-particle
curve is greater than that of the electrons, at very low
tumour incidences of between 0.1 and 0.2 tumour/rat
appreciably higher values (possibly about 5) might becalculated. The authors themselves point out, however,that the significance of the experimental points at these
low levels of induction is questionable in view of thevery low number of tumours involved. A range of RBE
values dependent on dose and dose rate can be estimatedfrom the data of Fry et al. (206) on harderian gland
tumours. By comparing the irradiations with fission
neutrons and 6 °Co gamma rays, an RBE value of about
12 may be inferred.

an174. A number of values have been obtained from otherimproperly called RBE studies in various animals andtumour systems, and they are reported here mainly forthe sake of completeness. It should be pointed out,
however, that in these cases the effectiveness ratio of theradiation is often obtained by dividing the level of effectinduced by similar doses, instead of dividing the doses
for equal effect. In addition, these data refer mainly tosingle acutely delivered doses in the range of some
hundreds of rads and therefore they do not allow any
generalization relating to the changes of RBE with doseand dose rate.
175. In the mouse, RBEs of between 2 and 3 wereobtained between 250-kVp x rays and fission-spectrum
neutrons for the induction of kidney tumours (118),
gastro-intestinal carcinoma (514) and hepatomas (118).
Mean after-survival and tumour incidence were the samefor BAF 1 mice irradiated with acute whole-body dosesof 250, 135 and 80-kVp x rays (229). In the rat, acomparison between fission neutrons and x rays yieldeda ratio of about 2 for skin tumour induction (312). In
the rabbit, 2.5-MeV gamma rays and 0.7-MeV neutrons
gave a ratio of effectiveness of about 3 for the
production osteosarcomas, fibrosarcomas and basal-cellcarcinomas (286).
3. Conclusions
176. The number of tumour systems for which analysesof the RBE of different radiation can be performed withany degree of accuracy is still rather scanty, in spite of
the repeatedly pointed out need for such data inradiation protection (563, 670, 564). From thefragmentary information available it appears that theefficiency of high-LET radiation is greater than that of
low-LET radiation for the induction of tumours of.
various kinds. In those systems where complete
dose-effect relationships for both types of radiation areavailable, the RBE appears to change with the dose,
according to patterns dictated by the shapes of. thedose-incidence curves. At high sublethal dose levels, RBE
597

values as low as I may be found, but for various tumours
the pattern is that of an increasing RBE toward thelower doses. Values of up to I O have been reported atdoses of 25-100 rad, according to the various tumour
systems studied.

177. When doses of the order of 0.1 rad of neutrons
were tested in the rat breast-tumour system, RBE values
approaching 100 were reported. Although such highvalues conform to the theory of dual radiation action(207) and have previously been reported for acute anddelayed somatic effects in irradiated plants and animals,
they remain unique in the field of tumour induction.
Even though such high RBEs "cannot be used to predictthe radiation induction of other tumours in othersystems" ( 613) they certainly require further confirmatory work in other appropriately selected tumour-model
systems.

178. An increase of the RBE is generally to be expectedalso at low dose rates, mainly due to a decreased
efficiency of low-LET radiation. Data in this respect
however are even more fragmentary and do not allow
precise quantitative evaluation, except perhaps in thecase of mouse leukaemia where chronic, as compared toacute, treatment could decrease the efficacy of the
low-LET radiation by factors of 2-10, with acorresponding increase in the RBE of the high-LET
radiation.

4. Effects of temporal distribution ofirradiation

179. A physical variable of great relevance in radiation
carcinogenesis is the dose rate. The most recent
theoretical treatment of the dose-rate effect has beenpresented within the framework of the theory of dual
radiation action (340, 574). According to the generalfoundations of this theory, a wide range of radiobiological effects in higher organisms (including the induction oftumours) may be visualized as the end-result of
elementary lesions taking place in the cells at thesubnuclear level.
180. The relationship of these effects with dose may beconsidered as the sum of two components, a linear and aquadratic one. The former predominates in the case of
densely ionizing radiation and is essentially independentof the dose rate since it is associated with the interactionof the lesions produced by one single-particle track. The
quadratic component is more clear for low-LET
radiation: it is very dependent on the dose rate because
it reflects the interaction of lesions produced bydifferent charged particles. Lowering the dose rate inirradiation with sparsely ionizing particles causes a
reduction of the inter-track effects because of the
spontaneous recovery processes of the elementarylesions and consequently reduces the probability ofeffects resulting from the interaction of lesions produced
by different tracks. In very general terms, the reductionof the inter-track effect will depend on the ratio
between the characteristic recovery time of the systemand the exposure time; therefore when the latterbecomes long compared to the recovery time (i.e. at
progressively lower dose rates) the final effect of a given598

dose will decrease through a reduction of the quadraticcomponent. The case of dose fractionation may beanalyzed in a manner which is qualitatively similar tothat of continuous irradiation.

181. A further consequence of the postulated model isthat correct dose-effect relationship determinations at
different dose rates require the use of dose rates
proportional to the total dose (constant irradiation tin1e)
in order that equal recovery apply at ·all dose levels. This
technique appears to have been followed only rarely inthe work reviewed, since the vast majority of theexperiments have been performed at constant dose rates
for different dose levels, a procedure which makes theanalysis of the data very complicated, due to the need ofapplying to the effect reduction factors inversely
proportional to the total dose.
182. It should be pointed out in addition that thepreceding theoretical analysis, although valid in principle
for any biological effect including carcinogenesis. isbased essentially on arguments stemming from thetheory of dual radiation action which are applicable onlyat the subnuclear level; the extrapolation of such formal
treatments to the level of cell population, tissues or thewhole animal is subject to the methodological difficulties
discussed in chapter I and is further complicated byintercellular and physiological effects not easily
amenable to generalization. Among these effects one
should consider the kinetics of target-cell population for
the induction of any particular tumour type (compartment size, cell turnover rates and intercompartment
transit times), the phenomena of cellular inactivation,
intracellular recovery and compartment repopulationinduced by the radiation treatment (which have variable
dependencies on the dose rate) and also the modifying
factors discussed in chapter II . and the biologicalvariables to be considered in chapter IV.
183. All these factors have different relevance in thevarious tumour systems considered and, although
included in the overall carcinogenic response of thesystem, make it impossible to derive a true quantitative
analysis of the dose-rate effect. Hug (283) has analyzed
several dose-effect relationships in several animals fortumour induction by external whole-body exposure andinternal irradiation. He has attempted to link the effectsof dose and dose rate on tumour induction with theincidence and latency time of the spontaneous
neoplasms, with the purpose of extrapolating theestimates of malignancy induction to man.
5. Dose-rate effects
184. In agreement with the theoretical interpretation
given previously, the reviewers who have considered atvarious times the effect of dose rate on tumour
induction have all confirmed the reduction of the yieldof tumours with decreasing dose rate and the relatively
lower dependence on dose rate of the effect of densely,
as compared to sparsely, ionizing radiation (671, 672.
676, 454, 230, 670). The evidence available up to thepresent on chronic and protracted exposures will bereconsidered in the following paragraphs in view ofattempting general qualitative conclusions referring to alltumour systems examined and of providing. whenpossible, quantitative parameters to the effect of dose
rate. Experiments on fractionated and protracted
exposures will also be considered. On the other hand,the cases of lifelong exposure and of split-dose
irradiation will be discussed separately for their
methodological and/or theoretical peculiarity.
185. Concerning the tumours of the haemolymphopoietic system (446, 325, 674, 675, 676, 678,670), summaries of the state of knowledge have been
published on various occasions. The changes of
induction of myeloid leukaemia appear to have beenstudied mainly in the RF mouse. Dose rates of
0.01 rad/min and 0.004 rad/min of 6 °Co gamma rays
induce considerably less of the disease as compared toacute irradiation and also change the characteristic shapeof the dose-effect relationship found with acute doses(which has a maximum at about 300 rad) into a flat
dose-effect curve with a maximum incidence of about
5 per cent. The ratio of the peak incidences appears to
be about 5. Irradiation by neutrons of about 5 MeV
mean energy, at a dose rate of 0.0004-0.004 rad/min,compared to irradiation by cyclotron neutrons (meanenergy about 1 MeV) at 100 rad/min, had somewhat lessleukaemogenic efficiency, probably by a factor of 2-3, atthe same peak incidence of 300 rad. If, alternatively, thereduction of the initial slope of the dose-effectrelationship is taken as a measure of the reduced
effectiveness at low dose rates, it may be estimated thatin the case of low-LET radiation the efficiency ispossiqly reduced by a factor of 2 at the low dose rates.
No difference in slope is seen in the case of neutrons(693).
186. In another series of experiments male RF mice
were subjected to daily 6 °Co gamma-ray exposures at
0.007-0.07 R/min and showed a peak incidence of
myeloid leukaemia of about 12 per cent at doses of
250 rad, compared to an approximate incidence of
40 per cent after single high-intensity x or gamma ray
exposure. A further reduction of the exposure rate from0.008 to 0.004 R/min resulted in a still lower incidenceof less than 5 per cent at the peak ( 685).
187. Finally, in an exhaustive report, the influence ofdose and dose rate on the induction of myeloid
leukaemia was tested in male and female RF micewhole-body exposed as young adults to neutrons of 1
and 5 MeV, or to 6 °Co gamma rays or 250-kVp x rays atdose rates varying from 10-6 to 102 rad/min (554. 691,
692). For a given total dose of neutrons. chronic
irradiation was found to be as effective as acuteirradiation, but with x or gamma rays the reduced dose
rate led to a considerably decreased incidence of thedisease, so that no leukaemogenic effect above thecontrol level was observed at dose rates of 0.056 to
0.0038 rad/min for total doses of 200-300 rad, whereas
the incidence was up to 40 per cent in animals irradiatedat 80 rad/min. The loss of effectiveness induced by the
low dose rate of gamma rays was about 1/20 andconsequently the RBE values for neutrons at low dose
rates might be estimated to be of the order of 10-20( 692). A reduced effectiveness of the low dose rate istherefore consistently found in the case of myeloid
leukaemia induced by sparsely ionizing radiation. The

magnitude of the reduction factor is difficult to evaluate
in view of the changes introduced by the low-rate
treatment in the character of the dose-effect relationships. Neutron induction appears to be less sensitive tothe decrease of the dose rate.
188. The pattern of response of thymic lymphoma to
low dose rates appears definitely less uniform. A gradedsequence of whole-body x-ray doses in 2, 4, 8 equal
fractions at intervals of 1, 4, 8 and 16 days given to
C57BL mice of both sexes produced a gradual increasein lymphoma incidence as a function of dose. For agiven total dose the induction of tumours did not seemto be affected by daily fractionation, but fractionation
at intervals of 4 and 8 days resulted in a higher incidenceof tumours appearing at shorter latency times. A further
increase of the fractionation interval to 16 days resulted
however in a decreased incidence (330). These resultsappear to be in contrast with those obtained for otherimmediate effects of irradiation and for the induction ofmany types of neoplasia, indicating that different
pathogenetic mechanisms are involved in the inductionof thyrnic lymphoma. According to Kaplan and Brown(330), the presence of optimal rythms of fractionation
for lymphoma production is to be related to the optimal
sequence of the pathogenetic mechaniSil]S (bone-marrow
injury, viremia, thyrnic regeneration, immunodepression)leading to the transformation of the thymic cells (seeparagraphs 46 to 48).
189. An enhanced effect of dose-fractionation atintervals of 5 to 8 days has also been confirmed after
neutron irradiation of the RF mouse (689). On thecontrary, a change in the dose rate of 6 °Co gamma raysfrom 7 to 0.004 rad/min results in a rather shallower
slope of the induction curve, while the yield of
neutron-induced lymphomas appears to be unchangedby the decreasing dose rate (693). These results wereconfirmed and enlarged in a subsequent series showingthat with decreasing dose rate of neutrons no change in
the induction of lymphoma takes place, while chronic
daily exposure to gamma rays consistently reduces theeffectiveness of the treatment to such an extent that there
is no detectable tumourogenic effect on the thymus atdose rates of 0.0038 rad/min (692). In CFl femal micewith doses of 60 rad of fission neutrons or 300 rads ofgamma rays administered at the average rate ofl rad/min in weekly irradiations given in 1, 3 or 6 equal
fractions per week, the incidence of thymic lymphoma
increased as the number of weekly fractions increased
from I to 6, whilst at 3 fraction/week a decreased
incidence was noted (688).
190. In conclusio~, while a difference of behaviour
among different strains cannot be excluded, it appears
that dose-rate reduction by continuous or by fractionated exposure acts in the case of thymic lymphoma
through quite different mechanisms. A decreased rate of
exposure rate on a continuous treatment leads to a
reduced tumour induction in the case of x or gamma
rays but not in the case of neutron irradiation. Dosefractionation, on the contrary, tends to enhance theincidence of tumours and the optimum weekly
fractionation schedules may be related to the pathogenetic mechanisms discussed in paragraphs 46 to 48.
599

191. The incidence of reticular tumours other thanthose previously discussed is also variable with the doserate, reflecting probably the heterogeneity of the
syndromes included in this class of malignancies. :Mice of
the CBA and C57BL strains given limited periods ofdaily x irradiation at an average dose rate of
81-1.3 rad/hour up to total doses of 900-1000 rad andthen followed for the rest of their lives, showed that thedegree of life-span shortening and of lymphoidleukaemia incidence (on which life-span shortening was
primarily dependent in these strains) were markedly
dose-rate dependent. The uncorrected incidence ofleukaemia in the highest dose-rate group was found to be
39 per cent (average between the two strains) and fell to
5 per cent in continuously irradiated animals. Thesefigures should be compared to a 2-per-cent incidence incontrol animals (448).
192. In contrast, fractionation of a dose of 690 rad of
x rays into 2, 4 and 8 equal fractions given in 8 weeks
resulted in an increased incidence of non-thymic
lymphoma in LAF 1 mice, with respect to animals
receiving a single dose of the same total magnitude(122). Fractionation of x irradiation has also beenreported to increase the incidence of leukaemia in CAF 1
mice (115). Finally, it has been reported that in RF micethe incidence of reticular tumours other than myeloid
leukaemia or thymic lymphoma has a negative trendwith single doses of both neutrons and x rays (seeparagraphs 117 and 118). With decreasing dose rates theinhibitory effect of the gamma rays decreases markedly,
and at a dose rate of 5 rad/day, there is an actual
increase of the incidence in males. Chronic irradiation
with neutrons has different effects depending on the sex(since in females no change is found with respect ofacute irradiation but in males a failure of the inhibitory
effect is found), resembling in this respect the patternseen with gamma rays (692).
193. In the RF mouse the induction of ovarian tumoursby 6 °Co gamma rays is decreased by a reduction of thedose rate from 7 to 0.04 rad/min. The dose-effectrelationship obtained after acutely delivered single doses
is also very different, the maximum incidence being
obtained at higher total doses; this difference makes itvery difficult to specify a numerical value for the
reduction factor. In the case of neutrons a very shallow
dose-effect relationship is seen at all doses with a veryslight increase at low dose rates (about 5 per cent) overthe spontaneous incidence (about I per cent). For
comparison, the maximum incidence obtained in therange of 100 rad/min is of the order of 15 per cent(693).
194. In a more recent report the effectiveness of
gamma-ray irradiation decreased with smaller dose rate,even though tumour induction was evident down to dose
rates of 10-4 -10- 5 rad/min. Neutrons at 0.004 rad/day
significantly increased the induction of ovarian tumours
after a total dose of only 2 rad. but no such effect wasseen at higher dose-rates. This result clearly needs
further confirmation to verify whether the low incidence
at higher dose rates could be attributable to excess ofdamage (692). In sharp contrast with the above data, theincidence of ovarian adenoma was increased to 80 per
cent after 618-1335 rad of 6 °Co gamma rays at
600

1.45 rad/hour in the LAF'i mouse (515) starting from abackground incidence of about 6 per cent. Animals
irradiated previously with comparable doses at 2830 rad/min had shown an incidence of ovarian neoplasiaof 35 per cent (514).
195. A detailed quantitative analysis of ovarian tumour
induction in Balb/C mice as a function of dose rate has
also been reported recently (750). Animals were exposed
to graded doses of 1 3 7 Cs gamma rays in the range of
49-392 rad at dose rates from 1. 7 5 to 112 rad/ day, andit was shown that the incidence of neoplasms was adecreasing function of the exposure time. At yariable
dose rate, i.e. at constant exposure time, the incidenceof ovarian turmours appeared to follow a squarefunction of dose, and when the exposure time wasvariable, the incidence seemed to be inversely related to
the 0.69 power of the exposure time. It was found, in
addition, that about one third of this exposure-time
factor could be accounted for by an age-related loss of
sensitivity of the tumour system, while the rest was
attributable to recovery phenomena at the intra- orintercellular level. In summary, therefore, the mostcomplete studies available have confirmed on two
different strains the presence of a significant dose-rate
effect for the induction of ovarian tumours by x and. gamma rays. The neutron data are, on the contrary,inconclusive.
196. Some experiments are available concerning theeffect of dose rate and fractionation on the mammary
tumour system of the Sprague-Dawley female rats. A
dose of 500 rad given in one single exposure at 40 daysof age, or divided into 4 equal fractions given over 2
weeks or 8 fractions in 4 weeks, or 16 or 32 fractions fora total treatment time of 8 or 16 weeks, respectively, did
not appreciably change either the percentage oftumour-bearing rats or the total number of tumours
observed over the entire life span. The susceptibility ofthe system to tumour induction by a single dose
remained constant during. the time the experiment was
performed. As regards the histological type of tumours,
a decreased yield of adenofibromas and a relatively
increased yield of adeno-carcinomas was found in theirradiated animals: in this strain adeno-carcinoma isobserved particularly in old age and appears to be shifted
forward in time after all fractionation schedules (618).
197. The results of the change in dose rate were
somewhat similar, in that an inversion of the time of
appearance of the two histotypes seemed to be
operating. Animals given 6 ° Co gamma irradiation at
0.03 rad/min or at 10 rad/min and followed for about
one year had an overall tumour incidence of 37 per centand 40 per cent after 88 rad given at the lower andhigher dose rate, respectively. After 265 rad the total
incidence of tumours was 57 per cent at 0.03 R/min and
60 per cent at 10 R/min. However, while the adenocarcinomas showed a reduced incidence at low dose rate.
the fibroadenomas were not reduced (612). Considering
the peculiarity of the mammary tumour system, theseresults are not incompatible with the data obtained inmany other tumour systems. In fact, the decrease indose rate and the dose fractionation act by reducing theyield of the tumour type which is actually induced.

which is the adeno-carcinoma, and the effect is
manifested through a relative increase of the induction
time by comparison with the acute irradiation.

•,

,,

i

I
i

i

198. In the case of lung tumours the data on the effectof dose rate and fractionation are few and uncertain. It
has been reported that in male LAF 1 mice, urethane
alone in appropriate doses produces 16 per cent tumour
incidence within 25-26 weeks, while a dose of 300 rad of
x rays results in 12.5-per-cent incidence: the twotreatments combined give 50 per cent animals withtumours. Fractionation of the x-ray dose into 6 equal
fractions of 50 rad daily followed by urethane elicits ahigher tumour response than observed in several
appropriate groups of control animals (116). In RF micewhole-body irradiated with mid-lethal doses of radiation,
the neoplastic response of the lung shows in general adecreased trend with dose, but. paradoxically, gamma
rays at a low dose rate cause an increased incidence. To
explain these data, it has been postulated that atumourogenic effect on the lung may result at all dose
rates, but may be masked at high dose rates by life-span
shortening caused by other forms of injury. Neutrons,
for any given dose, generally yield a greater reduction
than gamma rays at all dose rates ( 692).
199. In the B6CF 1 mouse the incidence of mammary
tumours is around 1 per cent and shows little increase
with either single or fractionated exposures to 6 Co andfission neutrons (206). Ainsworth et al. (3) reported agreater life-span shortening in hybrid in B6CF I micewith fractionated doses than with single doses (80 or
240 rad of neutrons in a single dose or in 24 doses given
over 23 weeks), associated in part with the appearanceof pulmonary tumours. Less killing of potentiallyneoplastic cells because of fractionation, the possibility
that acceleration rather than true induction could be
operating and changes in age-dependent susceptibility
during irradiation are explanations that have been
invoked to account for these findings.

°

200. Some results are also available on dose-fractionation effects on skin tumour induction by beta particles.
A sparing effect of fractionation has been reported in
the rat by Henshaw et al. (262) and by Zackhaim et al.
(755). CBA mice irradiated with 6 OOO or 12 OOO rad of204
TI beta particles in 4, 12 or 20 doses over a
maximum fractionation time of three months showed
little evidence of change in skin tumour incidence withrespect to animals receiving single exposures to the same
total doses. However, the yield of epidermal and dermal
tumours after extreme fractionation and protraction(20 fractions in 25 days) was reduced to 50 per centwith respect to other groups receiving fractions of bigger
size. It was noted that this relative insensitivity to
fractionation is in sharp contrast with the great
dependence of the acute and chronic skin damage on thefractionation regime, which would indicate that theinduction of skin tumours has little correlation withacute skin damage (287, 25).
201. Vanderlaan et al. (696) reported a model toaccount for dose and dose-rate effects on skincarcinogenesis in rats. The model assumes that tumours
can arise as a result of either one or two dose-dependent
events and predicts that the one-step mode of tumour

induction is very small, if at all present. For the two-stepmechanism, the first step is visualized as reversible with arecovery time constant estimated to be of the order of
0.17 hour- 1.
202. In contrast with what would be predicted by thestudy of chromosomal damage in partially hepatectomized mice ( 142), an increased incidence of hepatoma(32 per cent) has been reported in LAF 1 mice irradiatedwith 6 Co at 1.45 rad/h ( 515) with respect to animals
irradiated with x rays at 30 rad/min (2 per cent) (514).
Control incidence of hepatoma in this strain is of theorder of 6 per cent.

°203. The incidence of gastro-intestinal carcinoma is also
increased above control level in LAF 1 mice bywhole-body irradiation with 690 rad of x rays. Fractionation of this dose into 2, 4 and 8 fractions over a
total time of eight weeks resulted in a definitely reduced
incidence. It has been pointed out that the effect is notdependent on life-span shortening since comparisons
between the same age groups show a similar reduction( 122). Scattered observations on the effect of dose rate,
fractionation and protraction on miscellaneous tumours
can also be found in Reineke et al. (558), Bustad et al.
(85), Upton, Randolph and Conklin (692), Vesselinovitch et al. (706) and Ainsworth et al. (2).
204. Tumours of the thyroid have also been reported
after chronic administrations of 1 3 1 I. Jomo andZapolskaya (316) have treated mongrel rats withactivities of 0.015-0.0015 µCi 131 I/day for cumulative
thyroid doses up to 4500 rad for the highest dose group.
The incidence of neoplasia in these animals was about
10 per cent in the two years after the treatment. No
tumours were found in the low-dose group. In anotherpaper (84) a significant increase of malignant (up to
20 per cent) and non-malignant (41-44 per cent)tumours of the thyroid was reported following chronic
intake of 1 31 I in drinking water at 0.07 µCi/day for 180
days. However, short-term (IO days up to an activity of
0.1 µCi/rat) versus long-term (6 months up to
1.6 µCi/rat) administration of 1 3 1 1 produced similar
carcinogenic effects in the thyroid (15-18 per centtumour incidence) and the yield of tumours was in bothcases higher than in controls (8 per cent) (702).
Morphological and ultrastructural data were also
reported in the same publication in the thyroid of131
I-treated animals.

6. Lifetime irradiation
205. A number of experiments have been reported on
the effect of dose rate on animals irradiatedcontinuously during their lifetimes. They should beconsidered separately as a rather uniform group,interpretation of which is very difficult, both conceptually and because of problems of technique. It has,in fact, been pointed out ( 445) that the radiation
received during the last part of a duration-of-life
exposure is less effective than that received earlier. The
difference in efficiency per unit dose between ashort-term and a lifelong exposure has been referred toas ''wasted radiation" that is. radiation given in excess ofthat required to elicit the effect. In the present context,601.
the concept of wasted radiation applies to the dose inexcess of that strictly required to induce a tumour,
namely, the dose received during the tumour latency
time plus that received between the clinical appearanceof the tumour and the death of the animal. When dealing
with an effect characterized by its late manifestation intime, not allowing for wasted radiation may lead to very
important alterations of the determined dose-effectrelationship.
206. Groups of LAF 1 mice of both sexes were
submitted to lifelong 6 Co gamma irradiation starting at
100 days of age with daily exposures from 2 10-s to
5 R. The survival data were analyzed in terms ofaccumulated lethality per unit daily dose, and four
distinct phases of early lethality corresponding todifferent types of damage were thus identified.
Coefficients of life-span shortening for after-survival inexcess of 60 days were also worked out (582). The
induction of tumours as a function of daily dose, age
and sex at dose rates below 56 rad/day were reported ina subsequent publication (370), and tumour incidence
data were obtained both after serial sacrifice and after
lifelong observation.

°

207. Concerning thymic lymphoma, the slope of the
cumulative incidence curves increased with daily dose up
to 32 rad/day and remained constant thereafter. There
was no evidence that lymphoma incidence was higher
than control in the 5-rad/day group, but 12 rad/day gave
rise to an abrupt increase in incidence in both sexes andto a marked shortening of the latency time. Pulmonary
tumours were above control values only in females
irradiated at 5 rad/day but otherwise declined withincreasing dose in all other dose groups; above
12 rad/day there was a shift forward in the time of
appearance of these neoplasms. Hepatomas were only
found in the control and in the irradiated groups withlong survival times: radiation had little effect on theirincidence in both sexes. The incidence of ovarian
tumours rose sharply in the irradiated groups but rapidly
decreased above 12 rad/day, suggesting that the mosteffective carcinogenic dose for this organ is to be set atsome dose rate below this limit.
208. Comparison of these data with the tumour
incidences reported for the same strain with single
terminated exposures led to the conclusion that the
duration-of-life exposure is considerably less carcinogenic per unit of accumulated dose. The duration-of-life
experiment was later extended to mice of six different
genotypes. Evidence at dose rates below 6 rad/day,where life-span shortening is less than 15 per cent,indicated that all of this life-span shortening could be
associated with neoplastic diseases (227. 228). The
pattern of age-specific mortality rate for reticular tissue
tumours indicated a maximum in the incidence-rate
curve at daily doses from 6 to 43 rad/ day, with total
accumulated doses of about 3000 rad. Pulmonary
tumours, hepatomas and ovarian tumours showed, on
the contrary. a modest increase in incidence at 6 rad/day
or less. followed by a sharp decline at higher daily
dosages. A possible model accounting for the observed
life-span shortening due to causes other than reticular
tissue tumour has been also proposed (583). Lifetime
periodic gamma-ray exposure experiments have also602

been reported in other mouse strains, with special regard
to leukaemia and life-span shortening on five successive
generations (735) and in the guinea-pig (581 ).
209. Yakovleva (744) reported data on tumour
development in 150 dogs exposed for six years tochronic (21, 63 and 125 rad/year at dose rates of 0.06,
0.17 and 0.34 rad/day) or to combined chronic andacute gamma irradiation. Various types of benign andmalignant tumours of various organs were seen at
autopsy and the majority of them were seen in animals
exposed chronically at the highest dose rate and at thehighest total dose.
210. Of special interest is an experiment being
performed on beagles irradiated continuously in a 6 Co
field at daily doses varying from 5 to 300 rad. delivered
over 22 hours (205). In this experiment the causes ofdeath appear to be related to the dose rate and total
accumulated doses; septicaemia, anaemia and myeloproliferative disorders usually under the form of myeloid
leukaemia appear to be the haemopoietic syndromes
most common in these animals (204, 203). At
35 rad/day or higher the dogs die with septicaemia, but
not at 10 rad/day or less. At 17 rad/day all three
syndromes appear: at 10 and 5 rad/day only anaemia
and leukaemia are seen, the latter at longer exposure
times. Two out of 13 animals dying at 17 rad/day
developed leukaemia after 1038 days: 6 of 13 at
10 rad/day after 719 days. and 4 of 6 at 5 rad hadleukaemia at an average time of 1063 days. Thus, lower
dose rates produced leukaemia in equal or shorter
exposure times, so that the optimum rate of exposurefor leukaemia induction would appear to be around
10 rad/day, and higher rates might be inhibitory (205).

°

7. Split-dose irradiation
211. Attempts to utilize the split-dose methodology(170) to evaluate the time-course and the extent ofrecovery processes in the case of tumour induction havebeen reported. The data are extremely few and scatteredso far, although our knowledge of the kinetics and of thenature of the recovery from late damage could beconsiderably expanded by the use of such methodology,
which has proven to be very fruitful in the case of
short-term radiation effects. Split doses of radiation
given at various intervals from 4 to 48 hours haveresulted in increased long-term mouse survival following
a kinetics which is reminiscent of the recovery curves forthe survival of single cells (628). The pathologicalobservations performed on these animals were not verysatisfactory but showed clear evidence of a decreased
tumour incidence even at such short fractionationintervals (439).
212. Split-dose experiments with a 24-hour interval in
the mouse lung-tumour system were reported by Yuhas(7 51 ), showing significant recovery when the total dose
was well in the curvilinear part of the dose-effectrelationship (1500 rad), while no recovery was apparent
when the total dose fell on the linear portion of theinduction curve (750 rad). The split-dose method applied
to the mammary tumour system of the Sprague-Dawley
rat yielded negative results (605). These latter findings
might be explained on account of the linearity of thedose-effect relationship in this particular experimental
model. Recovery with respect to skin tumour inductionin the rat was measured by split-dose methodology at a
fixed 31-day fractionation interval after a conditioning
dose of 750 rad (surface dose of fast electrons) (81). The
difference in dose between the fractionated and thenon-fractionated treatment to obtain the same level ofskin tumour induction was found to be about 650 rad,in good agreement with the 600-rad value found for hairfollicle atrophy. More recently the same group (82)reported on the tumour incidence and the lethality ofhair follicles in rat skin following several single doses offast electrons (1000-4000 rad) and split doses (1000 and
1000-4000 rad) with a 24-hour interval. The number oftumours per rat 70 weeks after single doses showed theusual peak at 2000 rad (fig. IX) followed by a decline at
higher doses. With split radiation the peak was displacedby at least 70 per cent of the initial conditioning dose.
Since the interval of 24 hours is too short for any
significant cell repopulation. it was concluded that theeffect could be best explained by a rapid process ofrecovery, similar to the intracellular recovery describedby Elkind ( 170).

radiation, or it may even be absent. Departures from thisvery general pattern are found in special cases (thelymphoma, for example); rather than exceptions to thefundamental radiobiological mechanisms they may be
regarded as special cases due to· the pathogenetic
mechanisms of these tumour systems. There are wellfounded theories accounting for the decrease in effect oflow dose rate and fractionation. which may beconceptually ascribed to repair of the elementarybiophysical lesions responsible for tumour induction. It
seems reasonable to postulate. in addition, that intraand intercellular mechanisms of recovery may be
operating in this case as in the case of short-term
radiobiological effects. But the kinetics and the natureof these repair phenomena are still essentially unknown
and urgently require elucidation.

IV. CARCINOGENESIS BY INTERNALEMITTERS
A. GENERAL

213. Split-dose data are, in conclusion, very incomplete
and inadequate to resolve between the intracellularcomponent. of the recovery and the component due tocell repopulation: the approach ~ems, however, wellfounded and should be pursued in the future in view ofthe essential need for information on recovery fromneoplastic damage. In this context, in vitro techniques ofcell transformation could also be very valuable for theinterpretation of experiments on in vivo systems.
Experiments in vitro have already been reported at a
5-hour fractionation time (58) and they deserve further
attention since they have shown an increased yield oftransformed clones by fractionation, which would
appear to be the exception, rather than the rule, in all
the in vivo systems examined.

8. Conclusions
214. The following conclusions may be drawn from ananalysis of the effects of dose rate and fractionation on
the induction of tumours in various animal systems.
When methodological and technical difficulties areconveniently accounted for. a decrease in the dose rateof low-LET irradiation results in general in a decrease oftumourogenic effect, followµ,g some inverse function of
the exposure time. The form of the dose-effectrelationship applicable to acute irradiation is often
greatly altered by the change in the dose rate, andtherefore precise values of the reduction factor have so
far been estimated only for very few tumour-model
systems. Reduction factors of 2-20 have been reported
between the highest and the lowest dose rates tested(102 -10- 6 rad/min) and between single and extremely
fractionated and protracted doses, for various systems
and different end-points.
215. In the few cases where high-LET radiation has
been tested for tumourogenic effects (essentially the
haemo-lymphoreticular neoplasms of the rodent) the
reduced effectiveness of the low dose rate appears to bequantitatively less important than that induced by acorresponding decrease of dose rate of x or gamma

216. In reviewing the data on tumour induction byincorporated radionuclides each nuclide will be dealt
with separately in this report, the specific distribution ofa nuclide being by far the most significant variable. The
general problems posed by internal irradiation are inprinciple the same as for external irradiation, though thepresentation by nuclide requires a different format thanthat used in chapter III. One special aspect referred to in
the 1972 report of the Committee ( 670) is theinhomogeneity of the dose in relation to space and timein the case of internally administered nuclides. The
physical and chemical characteristics of the nuclides andthe anatomo-physiological characteristics of the target
tissues in different animal species give rise to widelydifferent patterns of deposition, retention and excretion.
The route and schedule of administration and also
biological variables related to the genetic make-up, thesex, the age of the animals, add to the complexity of themain problem, which is the establishment of reliable
dose estimates for evaluation of the neoplastic effects.
217. Any meaningful comparison of effects and risks
between various animal species requires in fact that thedose delivered by the nuclides to the cells at risk be
known with reasonable certainty. In spite of the efforts
that have been made to refine the dose estimates (forreviews on dosimetry. see (634) and (635) for beta
particles and (704) for alpha particles), there are still
considerable uncertainties which render any comparison
between nuclides and between species at best semiquantitative. Data for interspecies comparisons may befound in a monograph edited by Moskalev (469). The
criterion for comparison used in many studies ofbone-seeking radionuclides, namely the ··mean accumulated skeletal dose" is calculated differently by different
authors, which increases the uncertainties of thecomparisons. Since the object of the present report is to
discuss specifically the neoplastic response, the reader isreferred to more specialized publications for the above
problems (431, 703). There are, however, someproblems that must be dealt with and that appear to be603

relevant for all nuclides; they refer specifically to theestablishment of dose-effect relationships and to theconcept of RBE in internal radiation carcinogenesis.
218. In regard to dose-effect relationships for internal
irradiation, it should be realized that the effect of dosecannot be readily tested independently from the effectof the rate at which it is delivered, that the dose rate ischanging in the course of the exposure period, and thatinternal irradiation is often extended until the death of
the animal and therefore the concept of "wasted
radiation" (445, 185, 46) is intrinsic to the analysis of
the dose-effect relationships. It is possible to take thisfactor into account by computing the dose accumulatedby the tissues at risk up to the time of first appearanceof the tumour or to some such extrapolated time (185,433, 434). Secondly, although in external radiation
carcinogenesis the concept of RBE may be reasonably
defined, at least operationally (see paragraphs l SS-157, inthe case of internal emitters it is difficult to compare
nuclides which, in addition to LET differences, havevery peculiar types of distribution, retention andtranslocation to various tissues. These concepts are
mentioned in order to stress the need of extreme caution
in interpreting statements abstracted from the context
of the reviewed experiments.
219. It is customary to divide the bone-seeking nuclides
into volume and surface seekers ( 426). The volume
seekers include the alkaline earths, calcium, strontium
and radium, the atoms of which can occupy the samesites in bone mineral. They are initially deposited in highconcentrations on the surface of the mineral bone andslowly migrate into deeper sites by chemical exchange.
This process plus the continuous apposition of newly
formed bone mineral eventually buries most of theradioactivity within the mineralized structures of theskeleton. Other radionuclides like plutonium, thorium
and americium are surface seekers and deposit on the
periosteal and endosteal surfaces in the immediate
vicinity of the capillary vessels, after which they may beremoved by bone resorption or buried by the appositionof new bone. Added to the physical characteristics oftheir radioactive decay, this different behaviour has ofcourse the most direct consequences on the distributionof dose to the target cells. Volume seekers with shorthalf-lives (like, for example, 224 Ra having a half-life of
3.64 days) represent special cases since they decay
almost entirely on the bone surfaces before being buriedin the mineral part of the bone.

B. BONE-SEEKING BETA EMITTERS
1. Bone tumours
220. Strontium-90 has a half-life of 28 years: it decays
to 90 Y by beta emission with maximum energy of
0.54 MeV. The 90 Y has in tum a half-life of 64 hours
and decays to stable zirconium by beta emission with amaximum energy of 2.27 Me V. The range of soft tissuesof the 90 Sr + 90 Y beta radiation is about 10 mm.
Strontium-89 has a half-life of 51 days and abeta-particle maximum energy of l.46 MeV with a 7-rnm
range in soft tissue. Strontium nuclides are volume
seekers. The data avail~ble· on single administration of604

90

Sr are more of theoretical than of practical interest,
but have been reported in a number of animal species.
Small rodents are particularly suitable to this type ofexperimentation, since they may be treated in large
numbers, thus providing better statistics. Their body size
however is very small and therefore not particularly
appropriate to mimic the geometrical conditions of
exposure of man, without adequate corrections.
221. The data on the incidence of bone tumours
obtained in CFI female mice injected with 90 Sr at
70 days of age by Finkel and Biskis (183) (nine doselevels between 1.3 and 2200 µCi/kg), have been updated,
re-evaluated and statistically analyzed by Mays and
Lloyd ( 434). When the average skeletal doses, calculated
up to the estimated start of tumour growth and ranging
in this experiment between O and 12 OOO rad, wereplotted against the percentage incidence of osteosar·
comas, the dose-effect relationship was found to behighly non-linear. Furthermore, a decrease in incidence
from 91 per cent to 73 per cent was seen after anaccumulated dose between 6630 and 12 OOO rad. The
incidences found at low doses appeared consistently lessthan those which would be predicted from an assumed
linear dose response extraP.olated to the control
incidence value and fitting the data up to the peak
incidence. Median life spans decreased rather regularly
from the lowest (1.3 µCi/kg) to the highest (2200 µCi/kg) dose injected.
222. Dose-related data on radiostrontium intoxicationof CBA X C57BL female mice injected at two levels (0.2
and 1.0 µCi/g) were also reported by Van Putten (699)and Van Putten and De Vries (700). Incidences of bonesarcoma of I 9 per cent and 82 per cent were foundrespectively in the two groups, to be compared with a 0
per cent incidence of the control mice. In another series,
two malignant bone tumours were found in 102 RF
male animals injected once with 0.2 µCi/g and one in 75
animals receiving 0.04 µCi/g. No tumours occurred incontrols or in animals given 0.51 µCi/g (128). In a more
recent series of papers, Nilsson (497. 499, 502), re~orted
dose-related data for CBA mice injected with 9 Sr atlevels of 1.6, 0.8, 0.4 and 0.2 µCi/g. The spontaneous
incidence of osteosarcoma was low in these mice. Bonetumours were found in all groups but the highest
number (292 tumours in 120 mice) was observed in the
0.8 µCi/g group. A tendency to multiple tumours was
also found, except in the 0.2 µCi/g group. The
dose-effect relationship has been analyzed by Mays and
Lloyd (434) and found to be non-linear. latency time ofbone sarcoma was shorter (from 485 days to 268 days)
as the dose increased.
223. Single dose experiments with 90 Sr were carriedout by Moskalev, Streltsova and Buldakov (470) on
Wistar rats injected intraperitoneal (IP) at three monthsof age with activities ranging from 0.005 to 500 µCi/kg.
The dose to the bone at 170 days before death were
calculated by Mays and Lloyd (434) to range between
0.2 and 5760 rad. The incidence of osteosarcoma inthese animals was up to 51 per cent in the two highest
dose ranges and the average time from injection to deathtended to lengthen as the dose decreased. The
dose-effect relationship found did not appear to support
a linear non-threshold hypothesis.

224. Brooks et al. (64) reported data on hamsters
injected with 9 0 Sr (0.2 to 5.0 µCi/g. given IP). An
activity-related shortening of life-span was observed. No
animal survived within the first two weeks with 3.0 and
5.0 µCi/g. The 50 per cent survival times ranged from90 days with 2.0 µCi/g to 1100 days at 0.2 µCi/g.
With 1.0 µCi/g, an activity known to produce a highincidence of bone tumours in mice, only a few
osteosarcomas were observed. Myeloproliferative diseases were, on the contrary, very common in thecontrols and in injected animals. 9 0 Sr was also injected
into rabbits of various ages (from 2 days to 165 weeks).
Osteosarcoma was found in animals receiving 500 µCi/kg
at 6 weeks of age and occasional bone tumours were also
found at 50-200 µCi/kg (705). Two bone sarcomas wereobserved in 15 miniature pigs with single injections of
64 µCi/kg (281 ).
225. The latest published data (April 1970) on the Utah
experiment on beagle dogs given at 1.4 years of age
single IP injections of 0.57 to 97 µCi 9 0 Sr/kg (corresponding to doses of 105-9100 rad at one year before death)
were reported by Mays and Lloyd (434). Eight out of 14(57 per cent) dogs that died at the highest dose level hadbone sarcoma. Two of 12 dogs injected with
63.6 µCi/kg, which died, had osteoscarcoma. No bonetumours have yet been observed in the lower dosegroups. Data are far from complete and no firm
dose-effect relationship can yet be established, but theresults so far would not support a linear response. Other
interim data on 9 0 Sr toxicity in dogs ( the Argonne
Study), in relation to age effects and dose pattern, werereported by Finkel, Biskis. Greco et al. ( 188). Finally,
acute inhalation studies with 9 0 SrC1 2 were also
performed and reported by Beecher et al. ( 49) and by
McLellan et al. ( 414). Seventy-two dogs were exposed toaerosols which resulted in long-term body burdens of
1-120 µCi/kg. In the animals already dead, hemangiosarcomas, osteosarcomas and chondrosarcomas wereobserved.
226. Another volume seeker is 4 5 Ca, a beta emitterwith a half-life of 165 days decaying to stable Sc. The
radiation emitted is weaker than that of 9 0 Sr and has amaximum energy of 0.254 MeV and a maximum range
in soft tissue of- 0.7 mm. A dose-effect relationship for
single injections of 4 5 Ca in 70-day-old female CFl micehas been reported by Finkel and Biskis (183), and thesedata have been reanalyzed by Mays and Lloyd ( 434).
The activity range extended from 16 to 49 600 µCi/kg,
corresponding to average skeletal doses from 63 to
111 OOO rad. The highest incidence of bone sarcoma (96per cent) occurred at 26 400 rad, after which a
pronounced decrease in incidence was observed. Mediansurvival time from injection to death decreased regularly
with dose. Seven cases of bone sarcoma were observed in
the dose interval 63-4700 rad, while a linear model
would have predicted 26 cases. The chance that thelinear extrapolation would actually be valid in the lowdose region, appears to be less than one in 10 5 • Kuzma
and Zander (361) have also carried out a comparison of
the neoplastic effects of 8 9 Sr and 4 5 Ca in rats and haveestablished that the carcinogenic effect of calcium perunit activity administered is lower. A number of benign
osteomas were found after its administration. Histologic

and histochemical studies were also reported on
Ca-induced autochtonous and transplanted osteosarcomas in Donryu rats (257).

450227. A single treatment with 9 Sr results in an uneven
distribution of the dose both as a function of time andwithin the bone. The dose rate is bound to be very highat the time of injection, after which dose willaccumulate at a progressively slower rate. In addition.
the nuclide will be deposited initially only in those bonezones which are actively laying down bone mineral at
the time of treatment, thus producing a non-uniform
irradiation of the osteogenic and haemopoietic tissues.
Repeated administration, on the contrary, is likely to. result in a more even distribution of the dose within thebone tissue. Also, by injecting the nuclide in different
fractions or by continuous administration, it is possible
to deliver the same dose at various average dose rates,
which may give indications about the role of thetemporal distribution of dose in internal irradiation.
Following this idea (185), experiments on fractional andon continuous exposure to 9 0 Sr have been carried out invarious animal species.
228. Seventy-day-old female mice of the CFI strain
were injected with three different activities of 9 0 Sr
(250, 500 and 1000 µCi/kg), once or five times in 5
weeks or 20 times in 4 weeks. It was found that for thesame total dose the tumourogenic response (both as
tumour incidence or as tumour expectancy) was highest
when the nuclide was delivered in one injection andlowest when the dose was divided into twenty fractions.
This experiment shows that the distribution in time ofthe same dose reduces its carcinogenic effect and that
immediate high dose rate is more important for bonetumour production than the dose from the isotope
retained in the skeleton (194). Similar data with 4 5 Cagave a maximum yield of tumours at five injections infive weeks and lower responses at I or 20 injections. The
data were explained on the basis of the lower energy andof the non-uniformity of deposition of 4 5 Ca withrespect to 9 0 Sr (I 85).
229. 9 0 Sr was also incorporated into food, and female
CFl mice were kept on this contaminated diet fromthree days before mating until death, together with theiroffspring. A 9 0 Sr level of 15 µCi/ g of stable calcium
produced bone tumours in adult females, but at lower
levels the tumour expectancy was within control limits.
Females on 9 0 Sr diet since conception had osteogenic
tumours at dietary levels of 9 0 Sr from 15 to 5 µCi/g ofcalcium. but not at lower levels. Males, on the other hand,developed three times fewer tumours than the female
siblings. A careful analysis of body burdens in theseanimals and comparisons with the results of single
injections, suggested that the activity accumulated in theskeleton was a valid indicator of the absorbed radiation
responsible for oncogenesis (185). Preliminary data on
the dose-rate effect following continuous ingestion of89
Sr in Balb/C, C57BL and RFM mice have beenreported for both haemopoietic and osteogenic tumours(742). It has also been shown that the incidence of90
Sr-induced malignancies in CBA mice decreased after
gestation and lactation, by comparison with unmatedcontrols ( 495). and that this effect results from adecreased dose rate to the bones of the lactating females
owing to a higher excretion rate of the nuclide (503).
605

230. In the rat, data on short-term administration (from10 to 30 days) of 90 Sr in the drinking water werereported by Casarett et al. (93) and reanalyzed by
Sundaram (746). Myeloid leukaemias, angiosarcomas
and osteosarcomas were observed at total activities of
90 Sr of 330.464 µCi. There was an indication that at
low dose levels the primary effect might be leukaemia
and that at high levels osteosarcoma might be prevailing.
718 miniature swine representing three generations were
kept on a continuous 9 0 Sr diet at levels from l to
3100 µCi/day; some animals were also sacrificed for
dosimetric and histological studies. The experiments arestill in progress and the data have been reviewed invarious reports (280, 110, 281, 278, 109). Tumours of
the bone (giant cell tumours, osteosarcomas) have beenfound at bone doses of 6300 rad ( 434), corresponding toan intake of 125 µCi/day of the nuclide. The chance thata linear non-threshold model for bone-tumour induction
may correctly apply to these data has been estimated to
be about 16 per cent (434). However, the highcompeting risk of leukaemia and other proliferative
disorders and the non-completion of the study renderthese calculations very uncertain.
231. A study on chronic feeding of 9 0 Sr has been set
up at the Davis campus of the University of California
on several hundred beagle dogs treated from midgestation (onset of foetal ossification) up to 1.5 years ofage with the purpose of labelling uniformly the skeletonof these animals. Average levels of ingestion range from0.03 to 12 µCi/ day. Metabolic and dosimetric parameters are evaluated in parallel experiments (217, 218)
as well as non-neoplastic skeletal changes like endostealor periosteal sclerosis, fractures, osteolytic lesions andtrabecular coarsening (462). Up to 1972, osteosarcomas
and other tumours were seen at the highest intakes of 12
and 4 µCi/day, after accumulated doses to the skeletonof 8000. l l OOO rad (166, 543, 87). In a most recent
report of these experiments (463), the delay period
between exposure and bone sarcoma incidence wasestimated to be 1.5, 5 .1 and 9 .4 years with activities of36, 12, and 4 µCi respectively, starting from birth. Theinterplay of dose, dose rate and age were analyzed in thisexperiment in order to attempt extrapolation to low
doses. Other data on dogs given fractional injections of90
Sr during one year have been reported by Finkel,
Biskis and Greco (188). Malignant bone tumours
occurred in this case at 150 µCi/kg but none was seen
after 10-100 µCi/kg.
232. Chronic feeding studies with 9 0 Sr in dogs werealso reported by Burykina (83) at levels of 0.2 to
0.0004 µCi/kg per day, yielding average skeletal dose rates
from 0.4 to 0.004 rad/day. Treatment lasted from 2 to
4 years. The tumours observed' were mainly in the soft
tissues (16 cases out of 51 dogs in all treatment groups)
but 1 out of 15 and 2 out of 15 dogs at the highest doselevels developed osteosarcoma and leukaemia. respectively. The latency period of all tumours decreased withincreasing dose. The data show that marrow andsoft-tissue neoplasms are more readily induced thantumours of the bone for chronic irradiation.
233. A detailed statistical analysis of the dose-effectrelationship for bone sarcoma induction. in 9 0 Sr and45
Ca treated animals of various species, has been made606

by Mays and Lloyd (434), and it seems relevant here toreport the main conclusions. They have normalized thedata analyzed to a common quantity, the '·averageskeletal dose" (i.e., the dose from the time of treatment
initiation to the time of initial tumour growth), which
has been estimated differently in the various animal
species. They have found that in all analysed cases thenumber of bone tumours appearing at low doses is
considerably lower than the number that would be
predicted from a linear model of the dose-induction
relationship. The probability that a linear dose-induction
relationship might adequately fit the data, ranges from
10-13 in the case of 90 Sr-injected rats (470) to
1.6 10- 1 in the case of continuously treated swine(281). In their opinion, the data at low doses would
strongly support a "practical threshold" model withextremely low incidences below a few hundred to
I OOO rad spread over the lifetime. At very low doses thismodel would not be distinguishable from a ·'sigmoid"model where the dose-incidence curve would first bevery shallow, then would rise steeply and eventuallywould reach the plateau or bend down at extremely highdoses. Mays and Lloyd have ascribed the sigmoid trendof the data to the efficient recovery from low-LET
radiation damage at sufficiently low dose rates.
234. Extrapolating from the analysed data, the authors
have inferred estimates for the SO-year risk from90
Sr-induced bone sarcoma in man, which are (1 ± 1)
10-6 tumour per man rad for average skeletal doses
below 1000 rad, according to a linear model, and (4 ± 4)
10-1 0 tumour per man rad 2 for average doses below
l OOO rad according to the dose-squared model. Thesefigures should be compared with the natural incidence ofbone tumours, which is of the order of 5 10-4. Vaughan(703) has however pointed out some of the difficulties
in accepting these conclusions, which extrapolate
single-injection arid continous-treatment data between
species, while it is clear (see paragraphs 236 to 240) thatdifferent types of neoplasia may be relevant under thetwo exposure conditions. In addition, the dose estimatesshould be treated with caution in view of the differences
in bone structure in various species.
235. It is of some interest to report, for comparative
purposes, that the lowest estimated average skeletal
doses proven to induce bone sarcomas in various animal
species after intravenous (IV), IP and oral administrationof 90 Sr range, according to Mays and Lloyd (434), from
2500 to 6300 rad. Concerning the effect of dose rate,
the data available suggest a reduction of bone sarcoma
incidence at low dose rates. Dynamic studies of thegrowth of osteosarcomas produced in beagle dogs by
various IV-injectod nuclides have been reported {662)
together with comparative studies on the skeletal
location of naturally occurring or radiation-induced
tumours in the dog and in man (544, 663).
2. Myeloproliferative diseases andother tumours
236. Tumours of the bone are not the only form ofneoplasia found after radiostrontium intoxication.
Another important neoplastic disease is leukaemia. The
general problems concerning the induction of thisdisease in animals and in man after 11 uSr contamination
have been discussed by Loutit (404), especially in
relation to the risk of osteosarcoma. Concerning theexperience with laboratory animals, a high incidence ofreticular tumours by comparison with the controls wasnoted by Finkel (182) in the mouse (CFl) given 90 Sr in
a single injection or in fractionated administration. In
another report, an activity of 0.2 µCi/g in intact or
splenectomized RF male animals increased the incidenceof thymic lymphoma; other forms of leukaemia andnon-thymic lyphoma also increased in number andoccurred earlier (128).
237. Continuing reforted experiments on the effects ofvarious levels of OSr on the haemopoietic system(marrow, spleen, thymus) of four groups of mice at the
0.2-1.6 µCi/g level (498), Nilsson reported more recently(501) on a complete series in which 1430 CBA mice
were administered graded activities of 9 0 Sr (0.21.2 µCi/g), in order to investigate the site of origin, thedevelopment and the dose-effect relationship ofleukaemia induction. The significance of the bonemarrow in the thoracic vertebrae as the site of origin of
the leukaemia and the relations among marrow, spleen
and thymus in leukaemogenesis were also studied. The
highest frequency of leukaemia developed among
animals in the 0.2-µCi/g group and the incidence of thedisease decreased with activities of the nuclide. The
latency time did not vary greatly among the different
groups. In a comparative study of the leukaemogenic
action of x rays and 90 Sr in mice it was found that
680 rad of fractionated x rays produced 77.3 per cent of
mostly thymic leukaemia. while 1.0 µCi/g of 90 Sr gave
61.8 per cent of lymphoblastic, reticulum cell or stem
cell leukaemia. Thymectomy inhibited the developmentof the x-ray-induced but not of the 9 0 Sr-induced disease(298).
238. In a recent and yet incomplete study, CBA mice ofa low-tumour strain were given from 6.7 to 20.0 µCi per
mouse. The predominant tumours found were notosteosarcomas but haemangial and lymphoreticularsarcomas, presumably arising in the bone marrow. In thiscase also, the highest incidence was more likely to be at
the lowest dose (405). The effect of 9 0 Sr (0.4 or
0.8 µCi/g) and of combined 90 Sr (0.2 µCi/g) andfractionated x irradiation on the thymus and otherhaemopoietic tissues of CBA mice were also studied by
Jarplid (305, 306) with serial sacrifice and long-term
studies. Following the 9 0 Sr irradiation changes of theweight and cellularity of the thymus, spleen and marrow
were reported. In the case of combined irradiation, theadministration of 9 0 Sr delays the haemopoietic
regeneration that takes place after an x irradiation,
resulting in an increased incidence of thymic lymphoma.
The induction of non-thymic lymphomas by 90 Sr was
also enhanced by small doses of external x rays.

,,,
I

I

239. In the rat, myeloid leukaemias were reported after
chronic administration of 90 Sr in drinking water.
suggesting that at low dose levels the primary effectmight be leukaemia and not bone tumours (93, 646). An
incidence of 6.1 per cent of leukaemia (reticulosis,
haemocytoblastosis and myeloid) was noted in 82 rats
given 10 µCi/kg, corresponding to a marrow dose of
530 rad. These data should be compared with aspontaneous incidence in the controls of 1.7 per cent(470). Marrow changes, but no leukaemia. were also
reported in rabbits given 600 µCi of 9 0 Sr per kg (703).
In miniature swine fed on a 9 0 Sr diet ( 1 to3100 µCi/day) for three generations a large number of
myeloproliferative disorders were described. including
myeloid, lymphoid and stem cell leukaemia. theincidence of which seemed to be in general relationshipwith dose and to have latent periods shorter than thoseof bone sarcoma (280,110,277,278,109,551).
240. Haemopoietic changes (leukocyte depression,
erythrokinetic disturbance, formation of ectopic haemopoietic centers) were described in beagle dogs chronically fed 9 0 Sr at dose levels of 12 and 4 µCi/kg (86). At
later times, myeloproliferative disorders became apparent (166, 218, 165, 543). In these animals there was acontinuous spectrum of diseases ranging from myeloid
metaplasia to neoplastic proliferation of the granulocytic
series. The main feature of these lesions consisted of an
infiltration of the haemopoietic sites by mixtures ofstem cells and granulocytes in various stages ofdevelopment, rather than an increased blood leucocytosis. Infiltrations of the· subendothelial and perivascularspaces of various organs (liver, lung, etc.) were also
found. Finally, lymphosarcomas, myeloid leukaemias
and reticulum cell sarcomas were also observed in the
Argonne dog experiment (188). Other tumour types
found in various mammalian species with single orcontinuous treatment with 90 Sr included haemangioendoteliomas and angiosarcomas of the bone marrow (195,431, 49, 498, 499, 405), carcinomas of the mucous
membranes of the head (496, 652), squamous cell
carcinomas of the external ear or of the skin (705. 500,
502. 474), epidermoid carcinomas of the oral cavity(195, 652) and tumours of the mammary gland ( 474). In
most of these cases (including leukaemia) the observations were too few to allow the derivation of complete
dose-effect relationships.

3. Conclusions
241. The general picture drawn from the reviewed datacannot yet be very detailed and systematic, but appears
in any case sufficient to support some inferences. It will
have of course to be refined in the future by other data.
either becoming already available or in progress,
concerning the deposition, excretion and dosimetry of90
Sr in the many species tested, for the various routes
and schedules of administration. A detailed discussion of
all these problems is clearly not within the scope of thepresent report and more specialized publications havedealt with them extensively (703).
242. Even if qualified by the uncertainties mentioned
above, some important conclusions seem to emerge fromthe reviewed data. Firstly, the incidence of bonetumours, especially osteosarcoma, increases with dose in
all the experiments examined. the form of thedose-effect relationship is probably sigmoid. and adose-rate effect can be found if adequately looked for.
Secondly, in most animal species tumours of thehaemopoietic tissues are also found, sometimes in fairly
high numbers. Thirdly. bone tumours predominate athigh total doses and dose rates, while the incidence of607

haemopoietic neoplasms follows in general grosshaematological ·disturbances and is particularly high at
low doses or with continuous exposure (415, 703).
Fourthly, it seems possible that the neoplastic syndromethat will kill the animal may be determined by thedifferent latency periods of the various forms ofleukaemia and of bone tumours which are speciesspecific. and which depend on the dose and dose ratedelivered by the nuclide. These variables, however, have
not yet been incorporated into a comprehensive model.
Finally, vascular and epithelial tumours may appear insome cases.
C. BONE-SEEKING ALPHA EMITTERS
1. Radium isotopes
243. Radium-226 has a half-life of 1620 years anddecays to 2 2 2 Rn with the emission of alpha particles of
4.6 MeV having ranges in soft tissue of 31-70 µm.
Radon-222 is in turn, as are several of its decay
products, an alpha emitter, with a half-life of 3.82 days.
Since radon is an inert gas, it does not become fixed intissues and tends to escape at a rate that is different indifferent species and depends on the tissue characteristics. Radium-226 follows the metabolism of calcium andis therefore a volume-seeking isotope. Since information
on 22 6 Ra is available in man ( 578), it is regarded as thestandard bone-seeking nuclide and a basis for deriving
estimates of risks for other bone-seeking nuclides in man
by comparing radium and these other nuclides in theexperimental animal ( 185). Earlier animal studies with226
Ra have been summarized by Chiacchierini et al.
(I 01).
244. In a report compnsmg 3210 femal CFl mice(191), 70-day-old animals were injected singly with 14
different amounts of the nuclide, ranging from 0.05 to
120 µCi/kg. In these experiments, bone sarcoma wasfound to be the most sensitive indicator of damage, since
it was induced even at dose levels where histologicalevidence of damage was not apparent. When the averagetumour expectancy (the number of tumours still toappear divided by the number of animals still alive) was
plotted against dose, the effect was shown to increaselinearly between the control and the 2.5-µCi/kg level. At
higher activities, up to 20 µCi/kg, another linear
response having a lower slope was obtained; still higher
activities produced no further increase in tumour
response. According to the authors, the change in slope
at around 20 µCi/kg would reflect severe damage andpossibly the interplay of several carcinogenic factors, therelative importance of which would change at thatturning point. Tumour expectancy is an unusual
end-point in carcinogenesis and one rarely to be found in
the analysis of dose-effect relationships; the above data
are therefore not directly comparable with otherexperimental series.
245. Actually, when a more conventional end-pointsuch as the (uncorrected) percentage incidence oftumours was employed, a different dose-effect relationship could be generated (433), and the incidence ofradiation-induced bone tumours was shown to increaselinearly with the average skeletal dose up to about
6081000 rad. In the low-dose region (below 300 rad), thecases of bone sarcoma observed were in good agreementwith those predicted by a linear dose-effect relationship.
Other tumours, such as osteomas, hemangioendoteliomas and reticular tissue neoplasms, were also
observed, in no obvious relation with dos.e (191).
Radium-226-induced osteosarcomas were also reported
in H strain mice (511) and ( 648).
246. Two still incomplete experiments on dogs injectedwith 226 Ra are also available. In the Utah study (163)beagles were given single injections of the nuclide at 9
levels from 0.0074 to 10.4 µCi/kg, corresponding tocumulative average skeletal doses at one year before
death of up to 10 900 rad. Osteosarcomas were found(433) down to the 0. 166-µCi/kg level ( 458 rad). At thethree highest dose levels (1.07-10.4 µCi/kg), 32 of 35
animals died with osteosarcoma. At 0.339 µCi/kg andat 0.166 µCi/kg respectively, 5 out of 13 and 1 out of 9 ofthe dogs that died had osteosarcoma. No bone tumours
were found in 13 out of 22 animals dead at the lower
levels or in the 12 out of 22 animals dead in the control
group. A progressive decrease of the survival time of theanimals who died with bone tumours was noticeablewith increasing dose. Some more recent data from thisexperiment were analyzed in terms of dose effect by
Mays and Lloyd (433), and it was observed that a linear
relationship fitted through the data would predict 0.7
sarcoma cases at a dose level of 147 rad, while up to thattime no case had been observed. It was also noticed thatthe slope of the linear dose-effect relationship (0.043 percent incidence per rad) is remarkably similar to the slope
found for the previously considered experiment on mice(191 ).
247. In the Davis study (218), 226 Ra was administered
to beagles in 8 injections at 14-day intervals. Retention
and distribution studies were carefully performed (461).
The data on late effects are still incomplete, but
osteosarcomas have appeared, the number being roughly
related to dose. Acute haemopoietic effects (leukopenia
and ensuing anaemia) have been described in theseanimals, but no myleoproliferative disorder has yet beenfound. Eye melanomas were also reported in the dog( 651 ). A comparison of the toxicity of 9 0 Sr and 2 2 6 Ra,on the basis of injected activities causing bone cancer inequal times, has been performed by Blair (47) showingthat the ratio of 2 2 6 Ra to 9 0 Sr is about 40 to 1.
248. Radium-228 is a beta emitter that decays (half-life
5.7 years) to radiothorium or 228 Th, an alpha emitter(energy 5.4-8.8 MeV, particle tissue range 39-88 µm)
with a half-life of 1.9 years. Thorium-228 concentrates
on the endosteal surfaces and is therefore to beconsidered a surface seeker. With this nuclide,experiments have been carried out on dogs given a single
IV injection (163). It appears from the results (433),
that at 8.49 µCi/kg, 1 of 4 dogs had died with bonetumours: at the 2.62-µCi/kg level, 4 of 5 dogs; and at the
0.973-µCi/kg level, 3 of 9 dogs had developed
osteosarcomas. There appeared to be a shorter induction
period at increasing doses. A relative carcinogenic
potency of about 2.5 for 22 8 Ra compared to 22 6 Ra has
been computed for the average skeletal doses accumulated to the mean time of death with bone tumours. Thishigh figure has been ascribed to the longer alpha-particle

-range of the 2 2 8 Th daughter and to the re deposition of
228
22sRa.
To and 224 Ra (163). The dose-effectrelationship up to the peak incidence (corresponding to
an average skeletal dose of 485 rad calculated at one
year before death), has been reanalysed by Mays and
Lloyd ( 433), and it appears that many functions could
be fitted to such data. However. a linear function passing
through the origin would predict at least one case ofbone sarcoma among the four dogs that had died alreadyat an average skeletal dose of 226 rad. Six dogs at thatdose level were still alive and it cannot be excluded thatbone sarcomas might develop among them. Until theconclusion of the experiments, therefore, no firm
statement can be made.

J
I

249. Radium-224 (thorium X) has a half-life of 3.64
days. The decay scheme of the isotope is complex, butessentially it is an alpha emitter with energies of
5.4-8.8 MeV. Radium-224 is not a surface seeker, but its
short half-life results in its decaying almost entirely on
the bone surface. When IP-injected into Neuherberg miceof both sexes 20-30 days old in single administrations of
5-200 µCi/kg at weekly intervals, it induced bonetumours very efficiently (284). Even at 5 µCi/kg, about
13 per cent of the females developed osteosarcoma and afurther in<;rease up to 50 µCi/kg did not result in ahigher incidence. At still higher levels, the incidence
decreases owing to a high acute-mortality. Differences in
induction be!ween males and females were conspicuous.
The monthly tumour rates and the integral of tumour
rates in males increased with increasing doses up to
100 µCi/kg. Tumours of other tissues and organs werealso observed but, with one exception, not in higher
incidences than controls. The microscopic distributionof the 2 24 Ra and its relationship to tumour induction invarious bones were reported on by Hendringer and
Gassner (261 ).
250. The observations on sarcoma induction in theseanimals were also reported by Gl5ssner et al. {222) and,supplemented by further data, provided the basis of ananalysis of the dose-effect relationship for the inductionof osteogenic tumours at low doses. carried out by Mays
and Lloyd (433). In the femat"e, a mean skeletal dose of
150 rad (5 µCi/kg) already produced a peak incidence of
17 per cent; in the male, 1500 rad ( 50 µCi/kg) wereneeded for an incidence of 7.6 per cent. Spontaneous
incidence was zero in 259 males and 1.3 per cent among
460 females. The experimental points agreed better withthe hypothesis of linearity than with the thresholdmodel. On a ·'per rad" basis, females would appear to be
15-20 times more sensitive to the induction of bonesarcoma than males. Whether this phenomenon is related
to the higher spontaneous incidence of bone tumours infemales or to other reasons, such as more active bone
remodelling by oestrogen stimulation in the female ·(507), it would, in the opinion of Mays and Lloyd (433),
give cause to question the hypothesis of Mole ( 456) thatradiosensitivity to tumour induction by alpha and beta
emitters is the same in all species.
25 l. In more recent work, single injections of 2 2 4 Ra
(1- 100 µCi/kg. corresponding to skeletal doses of70-3000 rad) produced incidences of osteosarcomasfrom 7 per cent to 22 per cent in female mice. In
contrast with other data with beta emitters (185), dose

protraction by fractionation (twice weekly up to
36 weeks) resulted in increasing incidence (up to 90 percent) of osteosarcoma with protraction time and total
dose. This phenomenon might be related to cell kinetics
or disturbed cell turnover (478. 479. 223). Similar
experiments in rats (5-40 µCi/kg) produced an incidenceof osteosarcoma of about 19 per cent. The radionuclide
appeared to be slightly more effective than in mice. forthe same activity injected. A comparison between 2 2 6 Ra
and 224 Ra data in mice on a µCi-to-µCi basis showedthat 2 2 4 Ra might be 1O times less effective in the low
and medium dose range, taking the life-span shortening
effect of the two nuclides as the basis for comparison(284).

2. Thorium isotopes
252. Another series of beagles was injected in the Utah
experiment with 22 8 Th in single IV injections of amonomeric solution (163). From the latest publisheddata it would appear that the peak incidence (83 percent of animals with bone sarcoma) occurs already at the
0.0302-µCi/kg level (corresponding to an average skeletaldose of 249 rad accumulated until one year before
death). There is, as in other cases, a good inverse
relationship between the dose and the time to deathwith osteosarcoma. At lower levels some departure fromlinearity is observed, in that one case of sarcoma would
have been predicted by a linear model among the six
dogs dead without tumours at doses of 16 and 47 rad.
However, the experiment is not yet complete and morethan 20 animals are still alive at the lowest doses.
Thorium-228 was evaluated to be 9 times more
carcinogenic than 2 2 6 Ra on the basis of the average time
to death with osteosarcoma ( 163). On the basis ofincidence per unit dose (433) the efficiency would seemto be 6-7 times that of 2 2 6 Ra.
253. Thorium-232 has received attention because
colloidal thorium dioxide has been used as a contrast
medium in radiological practice. The content of 2 3 2 Th
in Thorotrast {the commercial name of the medium) is
about 25 nCi/ml. Thorium-232 has a half-life of
1.4 10 1 0 years and emits alpha particles with an energyof about 4 MeV. Upon IV injection it is taken up by thereticulo-endothelial cells and becomes encapsulated infibrotic lesions of the liver and spleen, from where somedaughter products, 224 Ra, 2211 Ra and 228 Th, may
escape to reach bone. However. the characteristic lesionsof Thorotrast in the human are liver tumours andmyeloproliferative diseases. Information on the distribution, retention and late effects of Thorotrast is to befound in 151 and an up-to-date collection of papers,
mainly on human Thorotrast cases, has recently become
available (549). Studies in animals are relatively few.
Guimaraes and Lamerton (240) found concentration of
Thorotrast in the liver, spleen and lung of injected mice.
Bensted (31) described late-occurring vascular spleentumours, anaemias and a high incidence of leukaemias inmice injected with Thorotrast, but questioned ·its
carcinogenic activity as being due to the radioactivity of
the injected compound. Nodular adenomatous hyperplasia, adenomas and parenchymal cell carcinomas of theliver have been observed, and a dose-effect curve for lungtumour induction in the rat has been obtained (231,609

232). Spindle cell sarcoma of the cheek pouch and liver
cholangiosarcomas were also reported in Syrian hamsters(465).

mainly with plutonium and other actinides was also
obtained by the Committee (477). Additional data will
also be found in a chapter by Buldakov et al in (72).

254. Thorium-227 has a half-life of 18.7 days, decaying
to a relatively long-lived nuclide (2 2 3 Ra) that can enter
mineral bone. Dose-effect curves for the induction ofbone sarcoma in mice were reported for single
administrations of this nuclide (410, 411, 223) in therange 0.1-50 µCi/kg, corresponding to average skeletal
doses of 20-10 OOO rad. A peak incidence of osteosar·
comas (60 per cent) was observed with 5 µCi/kg, with a
median time for appearance of these tumours of about
17 months. Some differences in the anatomical locationof the tumours with low and high activities of thenuclide and with similar activities of 2 2 7 Th and 2 2 4 Ra
were also reported. Metabolic and dosimetric studies
were performed by Muller et al. (480) with rats inhaling
solutions of 2 2 7 Th in nitrate form. These authors
showed that an initial deposition of 100 nCi in the lung
resulted in alpha-ray doses of 150 rad in this organ,
76 rad in bone, 2 rad in the kidney and 0.1 rad in theliver.

257. The available experimental studies concerning theinduction of bone and bone-marrow tumours show that
CFl female mice of about 70 days of afe given a single
IV injection of (probably) polymeric 2 3 Pu in the range
0.04-15.6 µCi/kg developed a number of osteosarcomas(184, 185). As in other cases reported by the sameauthors, the carcinogenic effect was analyzed in terms oftumour expectancy, and it was found that this variable
was reasonably linear with dose. A reanalysis of thesedata by Mays and Lloyd (433) shows that the highest
percentage incidence of bone tumours (77 per cent)occurs at 3.1 µCi/kg, corresponding to an averageskeletal dose of 560 rad at 140 days before death. Nobone tumours were found in 195 mice injected with
0.04 and 0.08 µCi/kg, while a linear relationship ofpercentage incidence to dose including all points up to
the peak would have predicted about 3 Pu-induced
tumours in this range, in addition to about 2
spontaneous tumours. The probability of obser,ing notumour against the predicted 5 would be about 0.5. In
these same mice. the low-dose groups had an incidenceof lung tumours up to 68 per cent, and the decreased
incidence at higher doses was attributed to life-span
shortening. The frequency of tumours of the reticular
tissues was highest at 0.16 µCi/kg and decreased
thereafter, probably owing to the same cause. Liverchanges (mainly degeneration and a few hepatomas)
were also noted in a number of cases, but theirsignificance could not be attributed with certainty to thenuclide, in view of the poor state of health of the colony(184). Monomeric 239 Pu (0.0058-0.025 µCi) and polymeric 239 Pu (0.0087 and 0.015 µCi) in solution was
injected intravenously into other CF I female mice.
When the induction of bone sarcoma was compared on
the basis of equal amounts of the nuclide in bone, mice
given the monomeric solution appeared to develop twice
as many tumours with a shorter induction time. The
higher concentration of the monomeric nuclide on bone
surfaces was primarily responsible for the difference(572).

3. Plutonium
255. Although there are many isotopes of plutonium,
Pu and 2 3 9 Pu are the most widely used inradiobiological research. They are both alpha emitters,with half-lives of 87.8 and 24 390 years, respectively.
Plutonium may exist in many valency states, but
tetravalent Pu is the most important for biology.
Plutonium tends to form complexes very easily and it§
deposition and toxicology are greatly influenced by thechemical form in which it is injected: monomericplutonium is taken up preferentially by the skeleton,
polymeric plutonium by the liver. Long-term exchanges
between liver, skeleton and other deposition sites takeplace. Uptake through wounds and by inhalation are themost frequent routes of contamination in occupationally
exposed workers. Animal experiments (292) suggest thatbone and lung tumours are likely to be the mostimportant risks of uptake by these routes. In theskeleton, Pu concentrates characteristically on theendosteal surfaces: it may however be found in the
marrow, especially when administered in the polymeric
form.
238

256. A thorough comparative discussion of the
distribution. excretion and effects of Pu as a bone seeker
has been published by Vaughan et al (704). Updated
reviews on the uptake, clearance, translocation andexcretion of inhaled Pu can be found in Sanders (585)
and Bair et al. (21). The deposition, retention andmetabolism in the liver of various animal species has
been reviewed by Lindenbaum and Rosenthal (381). The
concentration of plutonium in gonads of five mamma. lian species and man was investigated by Richmond andThomas (565). References and details on the radiation
biology and radiotoxicology of Pu and other transuranium elements can be found in the extensive reviews by
Stover and Jee (645), Hodge et al (269), Medical
Research Council (436), Bair (20) and Thompson (661).
A review of experimental data obtained by investigatorsin the Union of Soviet Socialist Republics in 1971-1975
on the carcinogenic action of radiation and dealing

610

258. In a small study of the toxicity of 2 3 9 Pu
(2.95 µCi/kg) injected into (Marshall X August)F 1 rats
6-8 weeks old, Bensted et al. (33) reported theoccurrence of osteogenic tumours and myelogenous
leukaemia. Fractionation of the radionuclide into 5
injections given at two-week intervals seemed to increase
the leukaemia incidence. In the same strain of rats.
fractionation of the administration did not significantly
alter the incidence of bone tumours but shortened thelatency interval (177). Plutonium-239 citrate administered intraperitoneally to three-month-old rats (in therange 0.65-5.0 µCi/kg corresponding to an estimatedaccumulated bone dose of 700-4300 rad) (460) produced a high incidence of bone tumours: the time frominjection to tumour death decreased with increasing
doses. The incidence data were said to be inconsistent
with a linear non-threshold hypothesis. As reported in
the same publication, 2 3 9 Pu was also administeredorally in daily fractions that gave an estimated dose to
the bone of 33-57 rad. Osteosarcomas. leukaemia andother soft-tissue tumours appeared in a relatively highpercentage of rats.

r,
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1

259. Buldakov and Lubchansky (73) studied theinduction of bone tumours in Wistar-derived rats by
2 3 9 Pu administered in various chemical forms (citrate,
nitrate. ammonium pentacarbonate), various routes ofadministration (inhalation. intratracheal, oral, intracutaneous. subcutaneous, intraperitoneal) and at various
concentrations. All these data were analysed by Mays
and Lloyd (381) by plotting computed (non-corrected)
average skeletal doses against the percentage tumour
incidence. Within the large scatter of the experimental
points (to be expected from such a heterogeneous .set ofdata) a linear function was fitted, corresponding to an
induction rate of 0.06 per cent per rad. This value might
increase to 0.1 per cent per rad if dose corrections for
wasted radiation were applied.

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260. Chronic oral administration of 2 3 9 Pu citrate inactivities of 0.1 to 1.0 µCi per rat (average skeletal doseof 1-10 rad) also resulted in an increased incidence ofosteosarcoma, leukaemia and marrow aplasia. Life-spanchanges were minimal in the treated animals (74).
Malignant and non-malignant tumours of the skin and of
subcutaneous tissues were also described by Buldakov etal (75) after intracutaneous and subcutaneous injectionof 2 3 9 Pu in various chemical forms. Finally, albino rats
injected IP with 2.8 µCi submicron-sized 239 Pu0 2
particles developed mesotheliomas and sarcomas of theomentum in great number (591). Other data on
239
Pu-induced sarcomas of the skeleton in rats were
given by James (300) and by Pestemikov andBukhtoyarova (531).
261. The Utah study on beagle dogs injected intravenously at 1.4 years of age with monomeric 2 3 9 Pu
citrate has been summarized by Mays and Lloyd in 1972
(433, 432), and more definitive data on the completed
injection groups were recently presented by Stover (644)and by Jee et al (308). Plutonium-239 levels ranged
from 0.016 to 2.9 µCi/kg. The dose-effect relationshipfor bone sarcoma induction up to the peak level of
69 per cent at 0.048 µCi/kg (corresponding to an
estimated average skeletal dose of 191 rad at one year
before death) was analysed in one of the papers (433).
The two low-dose points (0.0157 and 0.0477 µCi/kg)
and the control point fitted a straight line reasonably
well. Five further injection levels (between 0.00064 and0.016 µCi/kg) were added to this experiment in 1973
but no data are yet available. In terms of injected
activity the carcinogeneic potency of 2 3 9 Pu in dogs wasevaluated by Hems and Mole (260) to be 10-20 times
that of 22 6 Ra. The efficiency of 2 3 9 Pu relative to
22 6
Ra for life-span shortening was estimated to be 6: 1
( 163). On a "per rad" basis of average skeletal dose, andfor the induction of bone tumo\.)rs in beagles, this ratio
would appear to be of the order of 9: 1 (433). It has
however been pointed out (397) that the relative
toxicity of 2 3 9 Pu to 2 2 6 Ra in adult man may be
expected to be higher than in dogs.

4. Other actinides
262. Some data on the distribution and carcinogenic
effects of other actinides have also been reported. An
indexed bibliography of works up to July 1976 includes

most of this information (661). In the present context
only the most significant data on tumour induction will
be briefly reviewed for each nuclide tested.
(alphaemitter;half-life,
263. Neptunium-237
2.14 106 years). This nuclide was injected IV as nitrate
and oxalate into rats in doses ranging from 0.017 to
2.0 µCi/kg. Osteosarcomas were produced with incidences ranging from 9 to 58 per cent after average skeletal
doses from 5 to 520 rad, respectively (373). In otherexperiments (371) 237 Np oxalate was given IV in
activities of 0.00083 to 0.0021 µCi/kg, yielding
corresponding bone doses of 110 and 270 rad.
Osteosarcomas were seen in 23 per cent of the animals
rece1vmg
thehighestdose.
Activities
of0.0001-0.005 µCi/g ( 100-3100 rad average skeletal dose)of 2 3 7 Np citrate were also injected into rats by the sameroute. Tumour incidence was highest in the animals
receiving the highest doses. but results were notconsidered statistically significant when compared with
control tumour incidence (472). At injected activities
resulting in average skeletal doses higher than 100 rad amore frequent occurrence of soft-tissue tumours has
been reported, together with an accelerated ageing.
Leukaemia and malignant tumours of the liver andkidney are also consequences of single and chronic
administration (372).
264. Americium-241 (alpha emitter: half-life, 458
years). The distribution and retention of this nuclide
were studied in adult mice by autoradiography after asingle IV injection of 1 µCi of the nitrate compound(242), and in the developing teeth of rats after IP
injection of the same activity (243). The isotope
accumulates mainly in the bone and liver tissues. In rats,
30 µCi/kg of monomeric 241 Am citrate injected IV
produced some impairment of the metaphyseal bone
resorption, manifested as abnormal trabeculation (538).
In experiments by Filippova et al (18 l) on rats, the IP
administration of 2 41 Am nitrate in doses of
26-13 330 µCi/kg (7-2099 rad to the skeleton) the
incidence of osteosarcoma was increased with amaximum (9.3 per cent) at the average skeletal dose of
376 rad. A somewhat different picture with a maximum(24.5 per cent) at doses around 1660 rad was obtainedwith the citrate of the same isotope ( 493). Renal andliver tumours were also reported by Moskalev et al(4 73) in rats injected with 2 4 1 Am.
265. The liver and the skeleton were confirmed to be
the principal deposition sites also in beagle dogs injected
IV with 0.00179-4.49 µCi/kg of the citrate. Some
concentration of the nuclide in the thyroid gland and in
kidney glomeruli was also noted (398). In the skeleton,
americium deposits on bone surfaces more uniformly
than plutonium. The endosteal and trabecular deposits of
the isotope are 1.5-2 times greater than the periosteal
deposits, while for plutonium this ratio varies from 2 to
4 (402). At the University of Utah the carcinogenic
effects of 2 41 Am in beagles are being studied with eightactivity levels ranging from 0.0018 to 2.8 µCi/kg. Twodogs at the 2.8-µCi/kg level have died with extreme liver
degeneration after estimated doses of 5500 and 7600 rad
in the organ. At 0.19 µCi/kg, 6 of 10 animals that died
had developed osteosarcomas and had damage of theliver, kidney and thyroid. Osteosarcomas have been611

l

observed with activities down to 0.096 µCi/kg, but moredefinite results are not expected to be available for many
years (644). Americium-241 cl1loride injected IV in dogs
at 1 µCi/kg ( corresponding to an average skeletal dose of1660 rad) was reported to induce osteosarcoma in
50 per cent of the treated animals (4 76).
266. Curium-244 and 243 (alpha emitters with half-livesof 17.9 and 28 years, respectively). Only data on
excretion. retention and distribution of injected curium
citrate have been reported, showing that although theliver and skeleton are the major deposition sites, othertissues, particularly thyroid, have significant concentra·
tions of the nuclide (400).

various routes and in various amounts, they observed
linear responses with dose in some cases and threshold or
sigmoid relationships in others. These conclusions are in
sharp contrast with the results of parallel studies withbeta emitters (434), where the relationship appears to be
in all cases non-linear. The higher probability of linearity
in the case of the alpha emitters has been ascribed tolower efficiency, or even the lack of repair processes
after high-LET irradiation. An alternative explanation isprovided by the theory of dual radiation action. Under
the assumption of linearity it would of course be
impossible to identify the lowest dose for which
osteosarcoma can be demonstrated, as is the case withthe "practical threshold" models of the beta emitters.

267. Californium-249 and 252 (alpha emitters withhalf-lives of 352 and 2.63 years respectively). In the rat
the distribution and biological effects of 2 5 2 Cf nitrate
were studied with eight administered activities from
0.0005 to 0.064 µCi/g. One to two days after IV
injection, about 70 per cent of the nuclide was found in
the liver and about 30 per cent in the skeleton. The
LDs o/IS was estimated to be 0.032 µCi/g, and theLDs o/3o.0.012 µCi/g. With acute doses the animals
developed an agranulocytic syndrome. On the basis of
the LDs o, 2 5 2 Cf was shown to be 5 times more toxic
than 241 Am and 9 times more toxic than 244 Cm (757).
In the beagle, the excretion and retention of 249 Cfand252
Cf citrate were followed during 160 days after IV
injection. After one week about 20 per cent of theinjected californium was in the liver and about 60 per
cent in other tissues, mainly in the skeleton (399).

271. Comparisons of efficiencies among alpha emitters
could be justified, and if one accepts at face value thedose estimates (433), it might be concluded from theslope of the fitted relationships that 2 3 9 Pu and 2 2 8 Th
based on the mean skeletal dose might be about 10 times
more carcinogenic to bone than 2 2 6 Ra. and that 22 6 Ra
may be equally carcinogenic in mouse and dog. but anorder of magnitude less effective in man. Finally,
regarding the effect of dose rate. no clear demonstrationof a sparing effect of low dose rate has been provided,
and the best-documented case would even giveindications in the opposite direction. Information onother types of tumours induced by alpha emitters isdefinitely too fragmentary for any generalization.

268. Einsteinium-253 (alpha emitter; half-life, 20.5
days). A study in beagles covered the early retention,
excretion and distribution of 2 5 3 Es over 8 weeks
following IV injections of the citrate. The isotope
closely resembled californium in its behaviour andlocalized mainly in the skeleton, liver and thyroid (40 I).

272. In regard to the effects of inhaled alpha emitters,
important contributions in the field of lung pathology
and oncology are found in the books edited by Hanna etal (244) and Nettesheim et al (409). A detailed accountof all toxicological effects of inhaled plutonium is given ·by Bair et al (21 ). In regard to the induction oftumours, particularly of the lung, there are a number ofstudies in various species of animals. Mice (BAF 1
female)were
injected
intratracheallywith(dosesestimated
at0.003-0.16 µCi 239 Pu0 2
115-4000 rad to the lung) and developed pulmonary
fibrosarcomas and carcinomas with a maximum
incidence of 12 per cent at 0.06 µCi (657, 656).

5. Conclusions
269. The reviewed information on the incidence ofbone sarcoma by alpha-emitting nuclides should be
evaluated with great caution since the experimental data
available are in general fragmentary and heterogeneousand. in particular. the series on large animal species arestill incomplete. The relevant variables on which dose
estimates should be based have not yet been identified
and measured with any confidence (644); until such data
are available, any conclusion could well be regarded as
open to doubt. Moreover, even if accurate estimates ofthe dose and dose rate to osteogenic tissues could be
made, the lack of knowledge 'on the variability among
species and on the kinetics of normal and malignant cell
populations would still make any projection of the risk
to man (301) quite doubtful.
270. However, if some conclusion is to be drawn at thepresent time, the one arrived at by Mays and Lloyd(300) should probably be offered. Analysing thedose-effect relationships for the induction of bonesarcoma in 10 experimental series performed in man,dog, rat and mouse for a number of nuclides such as
224
Ra, 226 Ra, 228 Ra, 228 Th and 239 Pu injected by
612

D. INHALED ALPHA EMIITERS

273. Carcinomas
andbronchio-alveolar
adenocarcinomas were also reported, with a maximum
incidence of 25 per cent in three groups of female
Sfrague-Dawley rats inhaling 0.005-0.207 µCi of
2 8
Pu02 (9-375 rad to the lung). Lower incidences were
found at lower intakes down to 0.005 µCi deposited in
the lung. Tumours of other sites were also found in asignificantly higher percentage in Pu-treated animals(586). An increased incidence of mammary tumours inrats injected with 2 3 9 Pu0 2 was reported, although, in
general, the deposition of less than I µCi/kg of Pu did
not result in an increased incidence of tumours of thebreast, irrespective of the method of Pu administration
or of the solubility of the compounds (588). The uptake
in the lung and the effects of 2 3 9 Pu0 2 particles injected
intraperitoneally (589) or transthoracically in the lung(592) were also reported. Preliminary data on
pulmonary carcinogenesis in Wistar rats after inhalationof various transuranic compounds are also available, andthey show an influence of dose and dose distribution on
the type and the incidence of neoplasms (590). An
experimental study of the effects of inhaled alphaemitters {2 38 Pu, 239 Pu and 241 Arn given as oxide andnitrate) was reported recently (468). The accumulated
doses varied between 1 and 10 OOO rad, and the spatial
and temporal dose distributions depended on the
different physico-chernical forms used. Survival times
and tumour latency times and tumour frequencies,
locations and histotypes were analyzed as a function ofdose rate and dose distnbution. On the basis of thesedata a model relating dose and the acceleration oftumour appearance was developed.

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274. Two large•scale studies in the USSR are alsoavailable in this field. Yerokhin et al (745) carried out
an extensive study on 1097 male and female Wistar rats
administered intratracheally with 0.00042-1.0 µCi of
2 3 9 Pu nitrate or 1 µCi plutonyl acetate. The range ofdoses to the lung in the first study was 3-5855 rad, andin the second the pulmonary dose was 1870 rad. The
percentage tumour incidence varied rather regularly
from 2.5 per cent in the lowest intake group to 33 percent at 0.42 µCi. A decrease to 24 per cent was noticed
at 1 µCi, while this same activity of plutonyl acetate
gave rise to about 40 per cent lung tumours. The
histological types observed were squamous cell
carcinomas, adeno-carcinomas and hemangiosarcomas.
Koshurnikova et al (358) observed up to 27 per cent of
pulmonary tumours in rats inhaling 239 Pu citrate(0.008-1.030 µCi/g of pulmonary tissue) and up to 48
per cent of tumours after ammonium 2 3 9 Pu
pentacarbonate (0.004-1.46 µCi/g of lung). Squamouscell carcinomas. adeno-carcinomas and hemangiosarcomas were the most common pathological forms
found. In the same study, ammonium 2 3 9 Pu
pentacarbonate and 239 Pu nitrate in various amounts
produced up to 20 per cent malignant tumours in the
rabbit. The induction of lung tumours in rabbits
administered intratracheally 144 Ce (25 µCi per animal,
corresponding to 24 OOO rad to the lung) was also
described by Ivanov and Kurschakova (299).
Comparison of these data with other data on 2 3 9 Pu
(358) would give an RBE of 239 Pu as compared to144
Ce of about 12 at this dose level. Data on
interspecies comparisons of the efficiency with whichtumours are induced by intratracheally administeredplutonium in soluble form are reported by Moskalev etal (471).

sclerosis and carcinogenesis following intratracheal
administration of 2 3 7 Np and 241 Am, respectively. A
quantitative assay was recently developed by Nobbe etal (510) for the transplantation of lung fragments from
Pu-contaminated rats into immunodepressed mice or
genetically compatible rats. In the host animals
transplantation of lung tissue from old normal donors
resulted in differentiation resembling a tumorous
condition. Lung from contaminated rats showed anincreased frequency of these lesions with a complex
dose-effect relationship.
276. An analysis of the dose-effect relationship for lungcancer induction, derived from some of theseexperiments, was attempted by Bair et al (22). The plotof the data showed that in the rat, an accumulated doseto the lung of as low as l O rad might be carcinogenic.
The peak incidence in mice and rats probably occurs
between 200 and 1OOO rad and the few available resultsin dogs would show an even higher incidence. Special
consideration was given in this paper to the problem oftissue distribution of plutonium, and it was concluded
that the non-uniformity of the dose distribution does
not produce a higher hazard by the nuclide but that on
the contrary, a more homogeneous dispersion in the lungcan be more hazardous. A similar conclusion wasreached by Little et al (396), by Snipes and Brooks( 631) and in a recent report (487) by the National
Council on Radiation Protection (NCRP).
277. In another review, Baily concludes (155) thatradiation from either alpha or beta radioactive materials
is usually, but not invariably, more effective than
external irradiation for lung tumour induction. The
difference in effectiveness is not sufficiently large toabandon the presently accepted concept of average lungdose in evaluating the hazards from radioactive particles
in the lung. Lower efficiency for lung cancer inductionof inhaled beta-gamma emitters, by a factor of about I 0,
would confirm the higher RBE of the alpha irradiation
by about the same factor (22).

V: BIOLOGICAL VARIABLES IN RADIATIONCARCINOGENESIS
A. GENERAL

275. In the dog, Park and Bair (22) produced nearly 90
per cent ofbronchio-alveolar carcinomas after inhalationof 0.6 µCi of 239 Pu, corresponding to a lung dose of
2922 rad. At higher doses up to 4094 rad. the incidenceof tumours and survival time of the dogs decreased. The
acute and chronic toxicity of inhaled plutonium in dogs
was also described by Park (522), Park et al. (523, 525)
and Clarke et al (111). In experiments by Moskalev etal. (473) the inhalation of 241 Arn nitrate in dogs
(0.14-1.39 µCi/kg, or 344-3320 rad to the skeleton)
induced the appearance of osteosarcomas in all cases,
while there was no incidence of this tumour in control
animals at all. Park et al (524), Levdi.k et al. (373) andKoshurni.kova et al (357) reported co-carcinogenic
studies on Pu-induced pulmonary neoplasias, andFilippova and "Nifatov (I SOY ·published data on lung278. The object of the present chapter is to examine
the role of various biological factors in the induction oftumours by ionizing radiation. The most common
variables known to alter the neoplastic response ofirradiated animals, such as genetic constitution, sex andage, will be reviewed. and additionally a problem ofgreat relevance for radiation protection will beconsidered, namely the question of the cells and tissues
at risk. This question will be considered with the aim ofidentifying in the tissues susceptible to carcinogenesis,
the cellular compartments where tumours originallyarise; this identification might allow the quantificationof induction phenomena on a cellular basis, and would
thus establish a link between information and work invitro and in viva.
613

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B. GENETIC VARIABLES
1. Species

279. Few systematic comparative studies have been
made on the influence of the species on the neoplastic
response in mammals, and most of the data available
have been obtained in the rodent. This problem has been
discussed on the basis of the limited available
infonnation in previous reports of the Committee ( 669.
670) and also by various reviews (69, 672, 675, 678). It
should be emphasized that the question of species
susceptibility to radiation-induced neoplasia has far
reaching implications, both theoretical and practical. In
fact, it relates not only to the obvious need ofextrapolating from one species to another, not only the
carcinogenic effect, but also the relationships between
latency time and life-span of the species ( 69). It is also
relevant to the relationships between the spontaneous
incidence of certain tumour types in certain species
versus the radiation susceptibility of these animals to thesame tumours.
280. Concerning tumours arising after external
irradiation, it has often been pointed out (69, 670)
that the variation between species appears to beconsiderable and that in any case, it seems larger thanthat observed after internal irradiation (456). Although
it is true that virtually any type of tumour can be
induced in any species by the appropriate doses andadministration schedules (670), some species may
develop certain tumours after rather low doses, or withrelatively shorter latency times than others, so that the
spectrum of malignancies found after irradiation indifferent species is extremely variable.
281. There are numerous examples of such differential
effects. By comparison with other species, the mouse
ovary is an example of an exceptionally high sensitivity
to tumour induction. The rat is reputed to beconsiderably more susceptible to kidney tumour
induction by 500 rad whole-body x irradiation thanother species, in particular the mouse (36), but theapparent resistance of the mouse may be attributed tothe particularly long latency of these tumours or todifferent pathogenetic mechanisms operating in the two
species (422). Doses of 300-500 rad are definitely
carcinogenic for many species, but the burro after single
and total multiple doses of 320-545 rad develops animportant dose-related shortening of life, without
evidence of tumours ( 67). Lung cancer after 3000 or
4000 rad in the chest occurs in 43 per cent of rats but
only in 2 per cent of hamsters (239), and thisobservation is confirmed by continuous irradiation
experiments (734). Rats may' develop leukaemia after
irradiation, but in a less consistent pattern than mice(683), and so do guinea-pigs (581): Chinese hamsters, on
the other hand, appear to be strikingly resistant (450).
Da!a on the incidence of myeloproliferative disorders inarumals other than rodents have been reviewed byNielsen ( 491 ).
282. When five different species of rodents were
continuously exposed to 6 °Co radiation, more boneand, especially, lung tumours appeared in rats than in
hamsters; other differences in inducibility of lung and614

oesophageal cancer were also shown to exist between
various mouse strains {734). The differences between
species found in this latter irradiation experimentappeared, on the whole, to be smaller than the
differences in spontaneous tumours. This fact has beeninterpreted as evidence that radiation is so effectively
carcinogenic as to override minor variations insusceptibility (734). Data are still insufficient to draw acomprehensive picture, and it may be concluded that thegenetic character of the species is probably the main
factor in these variations. to which other physiologicaland environmental components could add secondary,but by no means unimportant, contnbutions.

2. Strain
283. The genetic variation of the susceptibility to
long-term effects of radiation has been explored,
particularly in inbred strains of mouse, and discussed.
for example, by Grahn (226, 225) and Grahn et al(227). Data on the spontaneous incidence of various
forms of leukaemia in several strains of mice and on
their susceptibility to radiation induction have been
repeatedly mentioned in this annex (see particularly
paragraphs 45 to 49) and will not be examined again.
The conclusions drawn by Upton and Cosgrove (683}and Upton (678) are still applicable since, in general,
strains having low spontaneous incidence of a particulardisease are prone to develop an increased incidence after
irradiation, while high-leukaemic strains are not as
susceptible. T}).e presence of a viral agent and its verticaltransmission may be seen, for some forms of leukaemia,
as a necessary condition for interspecies variations of thedisease, although the condition is not sufficient since it
may be modified to a large extent by the immunological,
hormonal and ambient factors discussed in chapter II ofthis Annex.

2&4. The analysis of chronic-radiation lethality datafrom many· different mouse strains suggests that all
genotypes respond to radiation according to a single
primary-injury parameter that can be expressed as
life-span shortening. Strain or genotype specificsensitivities to tumour induction are of a secondary
genetic nature and may be separated from the basic
injury under special conditions of exposure (224). Daily
irradiation experiments have indicated, for example, thatlife-span shortening at doses below 6 rad/day can beassociated with specific neoplastic disease, but at higher
dose rates a non-specific component of the damage is
detectable (227). Such observations agree with thegeneral view that at sufficiently high doses genetic
differences tend to disappear (670). Information
concerning sex differences in tumour induction by
external irradiation, can be found in paragraphs 68 and73.
3. Internal irradiation
285. Although it is commonly held that the neoplastic
response of different animal species is more unifonn
after internal than after external irradiation (69. 456,670), differences in the tun:iour susceptibility in theformer case are also quite apparent. For internal
exposures, in addition to the genetic factors discussed.

..

ranatomical and physiological factors could modify theneoplastic response through modifications of the dose
received by the relevant cells. For example, differenceswith species and age of the trabeculation pattern ofbones are quite substantial (544, 18), and they influence
the dose to the osteogenic or haemopoietic target cells in
the case of bone-seeking radionuclides. Metabolic
differences in the retention and excretion ofradionuclides between different animals have also beenshown, even for closely related chemical substances. andwhen operating over a long time they will result inappreciable differences of the accumulated dose in thetarget tissues (680). Thus, extrapolation to man of
metabolic patterns and of the ensuing neoplastic effects
only appears possible after careful consideration ofseveral animal species with different life spans.
Evaluation of the relative species sensitivity should
therefore be made after appropriate corrections for all
the factors mentioned above, and on the common basisof the estimated dose to the target cells.
286. Attempts to express sensitivity in terms of tumour
induction have been made in the case of certain
alpha-emitting radionuclides (433), and it has beenconcluded, for example, that the dog and the mouse arevery similar in their response to 2 2 6 Ra, but that man
appears to be less susceptible by an order of magnitude.
After appro.priate corrections, mice and dogs seem also
to be equally sensitive to the oncogenic effects of 9 0 Sr
{188) or 226 Ra {219) and, on the basis of the lowest
dose of 9 0 Sr proven to be carcinogenic for bone, mice,
rats and dogs. would also appear to be very similar in
their susceptibilities ( 434 ), while the hamster would be
more resistant (64). The cat. on the other hand, has beenreported as particularly sensitive to 8 9 Sr induction of
osteosarcoma ( 489).
287. Systematic comparisons between species andstrains are, however. rather few. In one of them,70-day-old CFI and CBA mice were given the sameactivity of 90 Sr and examined every week
radiographically for bone tumours. CF I animals
developed the first bone sarcoma at 98 days, and fromthen on tumour appearance followed a normal
distribution with the mode at 27 weeks. The averagetime from the first scoring of tumours to death was
39 days. In CBA mice. on the other hand, tumours
started to appear later and the peak incidence was at
35 weeks. The presence of inhibiting host factors, thehigher spontaneous incidence of osteosarcoma in CF I
animals and the different rates of tumour growth in thetwo strains might account for these effects ( 185). Morerecently, four inbred strains of hamster treated withmultiple intratracheal administrations of 210 Po
absorbed onto hematite particles were found to havevery different tolerances to the treatment and induction
times of the lung tumours. However, the final incidenceof the tumours was very similar in the four strains,varying between 33 per cent and 50 per cent (395).
288. Species differences in the response of dogs, rabbits
and rats to subcutaneous injections of 210 Po were also
reported ( 490). An important difference in susceptibility
to osteosarcoma induction by 2 2 4 Ra between male andfemale mice of the NMRI strain (284) has already been
discussed (paras. 250-252); this observation appears to
be in contradiction with what is found in humans (636).

Chameaud et al (98) have recently compared thesusceptibility to lung tumour induction by radon and its
daughters in man and in rat. They have shown that thetumour incidence plotted against the accumulated
exposure in working level months (Wu.I) is similar inexperimental studies with animals and in epidemiologicalsurveys in man. They concluded that the rat could be agood model system for analyzing this type of neoplasia.
In conclusion, until further progress in the specificationof anatomo-physiological characteristics of the various
species is made, and until assessments of the dose to therelevant tissues may be carried out with better
confidence. the scanty available data appear to beunsuitable for meaningful generalizations.
C. AGE EFFECTS
1. Post-natal irradiation

289. The relationship between age and susceptibility to
the induction of tumours has been explored byirradiating animals of different post-natal ages or, inother cases, by comparing animals irradiated in utero orafter birth. The two cases will be considered separately.
It has long been known that life-span shortening in miceand rats after single acutely delivered doses of radiation
is frequently associated with tumour induction, even at
relatively low doses. Life-span shortening changes
considerably with the age at irradiation: it is maximum
in juvenile animals, then decreases with increasing age
and can rise again in very old animals (383, 384, 385,
386, 387, 451, 349, 313, 130, 682). These variations
have been attributed in part to the long latency in theexpression of the life-span shortening effect {682) and inpart to an intrinsic age-dependent change of the animals'
susceptibility (313, 385).
290. Concerning specifically the induction of tumours,
only fragmentary data on age-dependent differences in
response are available. Mice of the RF strain given
whole-body doses of 100-300 rad at several ages frombirth to 180 days, showed that their susceptibility togranulocytic leukaemia is minimal shortly after birth,reaches a maximum at about 70 days of age and thenslowly declines thereafter. This trend occurs in both
sexes, although in the male peak incidence reaches 54
per cent after 300 rad of x rays, while in the female theincidence after the same dose at the same age is only 26
per cent (690). Susceptibility to the induction of thymic
lymphoma in the same strain is maximal shortly after
birth and declines later in life with natural thymic
involution {690). These observations are in good
agreement with data on strain A mice, where maximal
susceptibility to induction of lymphoid tumours after
1000 rad of x rays (given in 12 days) occurs at the age ofI month or earlier, with a sharp decrease at 2 months
and later (319). They are also in agreement with data on
the C57BL mouse given fractionated daily doses of
50 rad of x rays for 12 consecutive days, where theincreased incidence in early life is also associated with ashorter mean induction-time (320). and with data on. SAS/4 animals. where leukaemia incidence tends todecrease with increasing age at exposure (386).
291. Sensitivity to the induction of ovarian tumours in
RF females appears to be high (61 per cent after
615

300 rad) between 1 and 9 days of age and to decreaseprogressively up to 70 days (26 per cent for the samedose) (573). A very definite age variation is also found in
SAS/4 mice where a dose of 650 rad of 15-MeV x rays
produces about a 30 per cent incidence of ovarian
tumours at 10-20 weeks of age, whereas in younger andolder ages the incidence is smaller and may even be lessthan the 15-per-cent spontaneous incidence observed in
the non-irradiated control mice (386). In another report,
the spontaneous incidence of this neoplasia appeared tobe different in three different mouse strains {IC, XLII
and C3He/A), but a whole-body dose of 300 rad of
x rays produced in all strains a higher tumour incidencein mice irradiated at an age of 4-6 wee)(s than in mice
irradiated at an age of 4-6 montns (566). In LAF 1 micethe induction of ovarian tumours was likewise lower
after irradiation at 1 year than after irradiation at
10 weeks of age {130), but no differences with age,
between 5 months and 2 years, were found in CAF 1
mice (349). In Wistar rats, the induction of ovarian
tumours was significantly larger when x irradiation was
performed at 13 days of age with a single dose of
270 rad (560).
292. A lack of dependence of mammary tumour
development on age at the time of irradiation. between
40 and 160 days, was observed in Sprague-Dawley
females exposed to 500 R of 6 °Co gamma radiation(610). Pulmonary tumour induction tended to increase
with age in SAS/4 mice (386), but was unaffected in
LAF 1 mice between l O weeks and 1 year of age ( 130)and in CAF 1 mice between 5 months and 1 year (349).
In the rat the induction of these tumours was
significantly higher at 3 months than at 1 or 21 months(95). Kidney tumours were found more frequently inmice given 690 rad of x rays at birth than in animals
irradiated at 3 months of age {123). Other data on theincidence of miscellaneous tumours as a function of theage at exposure may also be found in Kohn andGuttman (349), Reineke et al (560), Jones, Osborn andKimeldorf (315), Jones (311) and Castanera, Jones andKimeldorf (95).
293. It may be concluded that there are quite definite
age-dependent changes in the susceptibility to the
induction of various types of tumours by external
irradiation. The best-documented case is that ofleukaemia (both thymic and granulocytic) where data on
four different strains of mouse have confirmed
the presence of a low susceptibility at birth, followed bya peak incidence in the young mouse and a final decreaseof induction with age. The sensitivity of the ovariantissue tends in general to decrease with post-natal age,while the susceptibility to pul!l.}onary tumours appears
to be variable in the different animals examined. Data onother neoplasms are insufficient to allow any conclusion.

2. Pre-natal irradiation
294. Data on the relative susceptibility to tumour
induction in animals irradiated before or after birth are
relatively scarce compared to the data on pre-natal
irradiation in humans. Up-to-date lists of references on
this subject have been published (562, 458).
616

295. When RF mice were irradiated in utero l-3 days
before birth with 300 rad of x rays, it was found thatthe incidence of granulocytic leukaemia was nil, but it
increased substantially when irradiation was performed
after birth to reach an incidence of 30-50 per cent at
70 days of age. Thymic lymphoma was similarly not
induced by irradiation in utero but was readily induced
after birth. Ovarian tumours were significantly lesscommon in mice irradiated i,r utero· than post-natally.
There are no data at lower doses, but it could beassumed that 300 rad is too large a dose for effective
induction of these tumours, because at doses of thismagnitude the dose-effect relationship observed in theadult could be already in the declining portion (seeparagraphs 151 to 154) (690). In a study carried out in RF
mice irradiated at various pre- and post-natal ages,
life-span shortening was found to be minimal in animals
exposed pre-natally except for males exposed to 300 rad
at 14~ days of gestation. where survival time was very
short. Mice exposed pre-natally showed stunting of body
growth, microcephaly and premature glomerulosclerosis
but no increases in incidence of leukaemia or solid
tumours were noted (682). These data appear to begenerally in agreement with data on CFl mice withdoses of I 00 rad of x rays, where the evidence for any
increment in neoplasia following embryonic or foetal
irradiation was equivocal. There was, however, muchevidence of reduced growth and pennanent stunting(580). It may thus be concluded from all these data thatthe long-term effects of pre-natal irradiation relate moreclearly to growth disturbances than to tumourogenesis.
296. From the available data in the rat (560), it would
appear that animals irradiated in utero with a single doseof 270 rad of x rays had a considerably higher
short-term mortality, and the survivors showed growth
retardation, microcephaly and micro-opthalmia. Genital
tumours in the female increased significantly only after
post-natal irradiation. and their relatively low incidence
in pre-natally irradiated rats was attributed to hypoplasiaof the genital organs. Other data on Wistar rats.
irradiated on the 18th day of gestation, have beenreported by Piontovski and Kalashnikova (535). The
beagle dog foetus responds to continuous irradiation inutero in a manner similar to that of the adult dog, but
no effects on tumour induction were reported. At a dose
rate of 17 rad/day or less of 6 °Co gamma rays, beagle
bitches irradiated continuously from conception delivered apparently normal litters. At 5 rad/day, all female
offspring were sterile, and at 10 rad/day, all male pups
were sterile (512).
297. From the fragmentary data available, which do notcover specific tumour types in many different strains
and species. it could be concluded that pre-natal
irradiation affects the growth and differentiation of
mammalian systems, rather than their malignant
transformation. There is no evidence that irradiation inutero of mice and rats may be more carcinogenic than
irradiation of young or adult animals.
3. Internal emitters298. Age-related differences in the susceptibility to the
induction of tumours by internal emitters have at times
been reported. In the case of radiostrontium intoxica-

tion, the mouse (3-20 weeks) (701), the rat (6-60 weeks)(646) and the dog (new-born to adult) (188) wereapparently more sensitive to bone sarcoma induction inyouth than in old age. However, when appropriate
dosimetric corrections to account for body size andhigher retention in the young animals were made, thesedifferences disappeared, showing that there is no major
age variation in the intrinsic susceptibility of the cells at
risk. Similarly, a larger susceptibility to bone tumours
was noted after injection of 144 Ce (but not after
treatment with 2 3 9 Pu) in weanling rats than in adults(417).
299. Comparisons of tumour induction between pre·and post-natal ages have been made by Finkel and her
rsoup using foetal and infant beagle dogs exposed to9
At the level of 1.33 µCi/kg in utero, 8 9 Sr was notacutely lethal, nor did it produce haematologic disorders
and bone sarcoma, however, extremely abnormal
skeletal growth was found (186). In a later report (188)
on 90 Sr, some tumours were seen at higher levels ofcontamination. Differences in retention were held
responsible for differences in tumour induction withrespect to post-natal exposures, but it was concluded, on
the whole, that pre-natal exposure was not more
carcinogenic than post-natal exposures at comparable
levels of dose. In the pig, exposure of the foetus to 9 0 Sr
ingested by the mother, plays an important role in thedevelopment of leukaemia (517). It has been reported
that the administration of 32 P to pregnant mice
produces a significant increase of the incidence ofleukaemia in female offspring (272). Finallr, the age
dependence of metabolism and effects of 3 9 Pu has
been studied in the rat by Sikov and Mahlum ( 626).

Sr.

300. The relative sensitivity of the thyroid gland to the
induction of tumours by · 13 1 I was investigated byWalinder and Sjoden (729) in mice exposed in utero orat the age of 3 months. They found 3 benign and 4
malignant neoplasms in 109 mice irradiated in utero to
7800 rad but no tumours at all after irradiation of 91
animals 3 months old to approximately similar doses. It
was therefore concluded that the foetal thyroid gland ismore susceptible than the adult thyroid. In analysingother evidence (160, 627), Pochin (537) concluded,
however. that the numbers involved are probably too
small for any conclusive statement about a higher
sensitivity of the foetal thyroid.

D. TISSUES AT RISK
1. General
301. As pointed out in a publication (291) of theInternational Commission on Radiological Protection{ICRP), no general criteria are available at present tomake reasonable predictions of the susceptibility ofvarious tissues to tumour induction by radiation on thebasis of known properties of the tissues themselves.
Tumour susceptibility is therefore an empirical concept
derived from the observed frequencies of cancer indifferent tissues or organs, following a given radiation
dose. In man such a relative scale of sensitivity totumour induction has been derived. with possible use inestablishing dose limits to individual parts of the body(291 ). An empirical procedure is perfectly adequate forpractical purposes such as setting dose limits, but fails to
identify and explain biologically the reasons why sometissues or organs are more prone to neoplastictransformation than others, in a manner which is
obviously quite independent of the number of cells they
contain or of the renewal rate of these cells.
302. In considering this problem, it has to be kept inmind that although the natural occurrence of tumours is
a rather common phenomenon in animal populations,the probability that a neoplastic clone would be inducedin cells exposed to radiation is quite low. Induced
neoplastic transformatio1' may therefore be regarded as arare phenomenon (70, 429, 459). There are generalhypotheses compatible with this fact and also with theextreme variability of cell susceptioility to tumour
induction; they have been discussed at some length inchapter II of this Annex. Other basic questions have notyet been discussed in detail, such as whether all the cells
in any one tissue or organ, irrespective of their state ofdifferentiation, are susceptible to the induction ofneoplasia or only some of them can be transformed, orwhether it is pOSS1ole to identify the cells in a population
having a higher risk of neoplastic transformation byradiation. These questions have already been consideredin the I 972 report of the Committee ( 670) with special
regard to bone and skin tumours.
303. In a recent publication (430), Mayneord and
Clarke have discussed the relevance and importance of the number of cells at risk in studies ofradiation carcinogenesis and have developed somebiomathematical concepts to relate the transformationof these cells to radiation dose under various conditionsof irradiation. Although the authors themselves recognize the limitations of such an approach in view of thecomplex reality of the biological mechanisms, theformulations proposed and the general consequences tobe drawn provide a stimulus for a better definition of
the relevant problems. In the following paragraphs thequestion of the cells at risk will be consideredsystematically in the light of available information, in an
attempt to elucidate the problem of the differential
susceptibility of cells to tumour induction and also toprovide a rational basis for possible extrapolation of data
between species.
304. Leukaemia. The comparative aspects of radiationinduced leukaemia in animals have been considered by
Upton (678) and Kaplan (328). It is quite apparent thatthe histological type, the time of onset and the organ
distribution of the reticular tissue disorders developingin the experimental animals are extremely variable. In
the mouse, which is the species most extensively studied.
the inducibility of leukaemia by external or internal
irradiation and its type depend primarily on the strain
and then on sex, age at irradiation, environmental
factors. radiation dose and type of fractionation. All
these factors have been considered at some length in thisAnnex. In this species the tumours of the reticular tissue
may frequently take the form of a lymphoma (in the
CS7BL strain typically) which appears to arise early inlife in the thymus and then to spread in some cases tothe thoracic lymph nodes or to other lymphatic andhaemopoietic districts (326). Alternatively (and more617

•rarely) a myelogenous granulocytic leukaemia may
occur, particularly in the RF strain. involving primarily
the marrow, spleen and liver and producing peripheral
blood leucocytosis (685).
305. In the mouse another form of non-thymic reticulartumour of complex and still uncertain classification has
also been observed, which generally arises late in life,
involving primarily the reticular cells of the spleen andof the abdominal lymph node and which may thenextend to other organs where reticular tissue is present{683). In addition to anatomo-pathological and epidemiological evidence, there are also radiobiological reasons
to keep these tumours separate from the others sinceradiation appears to depress, rather than enhance, theincidence of the diseases (see paragraphs 117 and 119). In
the rat the development of radiation-induced leukaemia isless well documented as to form and induction time andrate, but myeloid leukaemia, leucosarcoma and reticulardiseases have been reported ( 683, 161 ). In guinea-pigs,
leukaemias of a chronic lymphatic type (683) orlymphosarcomas (581) have been described. Swine
irradiated chronically with 9 0 Sr develop high incidencesof myeloproliferative disorders, including myeloid,
lymphatic and stem cell leukaemias (278), while beagle
dogs submitted to chronic irradiation by externalsources (205) or by 9 0 Sr feeding ( 166) show highly
proliferative infiltrating forms of myeloid leukaemia.
306. In view of the diversity of these syndromes and in
the absence of any indication as to whether and to what
extent any of them might be akin to the humanleukaemias, attempts to identify the nature and thenumber of the cells at risk on the basis of our present
knowledge may only be regarded as an "academic
pursuit" (459). For all practical purposes, in fact,
reliance must be placed mainly on the few observations
made in the cases of human leukaemia (562). The
virus-induced thymic lymphoma of the mouse, thecomplex pathogenesis of which has been sufficiently
well documented, may be a good example of the
difficulties involved in assessing the cells at risk.
307. As already discussed in paragraphs 46 to 48,
anatomo-pathological observations and the effects ofthymectomy and thymus reimplantation have shownthat thymus is the target organ for the action of thevirus. Further experimental evidence has identified theimmature lymphoid cells of the thymus as the target
cells in this tumour system. However, irradiation of thetarget organ is not sufficient, as such, to induce
lymphoma without irradiation of the haemopoietic
system and, in addition, other micro-environmental.
humoral, immunological and consitutional factors are
essential requirements for the expression of the disease.
The relative abundance and the susceptibility of thetarget cells to the virus are very dependent on their stateof differentiation and on the age and constitution of theanimal (326, 327). It is clear, however, that since a viral
agent is present at the origin of the disease, the problem
is primarily one of investigating quantitatively in vivo
the interactions between target cells and virus, sinceradiation acts primarily through a change in thehost-virus relationships. The evidence on this point has
been reviewed by Kaplan (327).
618

308. The same approach should probably be followedin the case of myeloid leukaemia, although definitely
fewer data are available. The anatomo-pathologicalevidence concerning the site. origin and histological typeof the disease, and the fact that it occurs after localized
irradiation of the skeleton by bone-seeking nuclides(particularly high-energy beta emitters) point to thebone marrow as the target tissue and, among the great
variety of cells of the marrow, to the more immature
myeloproliferative elements as the target cells. Since it is
now possible to titrate progenitor haemopoietic cells byin vivo and in vitro assays (629), it should also be
possible to study cell-virus interaction in the case of
myelogenous leukaemia.
309. Special consideration should be given to thehaematological neoplasms occurring in animals (swine
and dogs) submitted to chronic external irradiation or tointernal irradiation by beta-emitting bone seekers. The
character of these diseases is rather heterogenous whencompared to other forms of leukaemia in the rodent.
They are often preceded by profound disturbances of
haemopoiesis, including all the differentiative lines ofthe marrow. Considerable differences in the invasivenessof the diseases in different species are noticeable.
Although they are frequently referred to as myelogenous
leukaemias, morphologically all cell types, from themore differentiated ot the ''stem cell". are often
described. It seems reasonable, therefore, to conclude
that the identification of one type of progenitor
haemopoietic cell as a possible target and the assumptionof a common induction mechanism are probably notjustifiable, in view of pathological, epidemiological andclinical variety.
310. For other non-thymic lymphomas, for which thereis as yet no definite proof of a viral origin, preliminary
data on the relationships between dose and probabilityof cell transformation have been obtained in vivo, in amodel system where heavily irradiated animals have been
repopulated with a known number of isogenetic
bone-marrow cells, intact or irradiated (135, 437). A
dose-related excess of leukaemia has been documented
in the animals given irradiated marrow and, correcting
for radiation cell-killing. some estimates of theprobability of leukaemic transformation of the injectedbone-marrow stem cells have been obtained. Quite aside
from the absolute value of these estimates, which may or
may not be relevant, it was shown that the rate ofinduction per unit dose of leukaemia per surviving cell
was higher at 400 than at 200 rad: this would becompatible with the fact ·that the probability oftransformation in this system is not linear (concave) up
to the doses tested.

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311. It appears, in conclusion, that in order toinvestigate the relationships between dose and probabili·
ty of neoplastic transformation of target cells, in cases
where radiation is not simply directly acting on thetarget tissue but through indirect or systemic mechanisms. highly sophisticated techniques of quantitative
radiation biology and cellular virology must be
developed and applied in viva. Nevertheless, if the dataon radiation-induced cell transformation in vitro(paras. 53 to 58) should at some stage be applicable to in

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vivo systems and be useful not only for investigations ofmechanisms but also for practical applications (564),
suitable in vivo models ought to be developed to fill thegap. These models should have under better control thenumber and the functional characteristics of the cells
that appear to be the likely candidates for neoplastictransformation.

Ij.

312. Ovary. Irradiation of the ovary leads in general toa precocious reduction of the number of oocytes andovarian follicles (14). With the exception of these cells,
practically all the other cells forming the organ (lutein
and granulosa cells, mesothelial and endothelial cells)
appear susceptible to neoplastic transformation byradiation (675). Ovarian tumours are particularly
frequent in the mouse, ·where doses as low as 50-100 radof low-LET radiation may produce peak incidences oftumours ( 107). They appear to be responsive tohormonal mediation by the pituitary gonadotropins orby the controlateral non-irradiated ovary, in the case ofpartial-body irradiation (211). No special cell may be
identified as being characteristically at risk in the case ofovarian carcinogenesis.
313. Lung. The pulmonary tissue is very complex, bothmorphologically (633) and functionally (623). A
considerable spectrum of tumour types occur spontaneously (492) or are induced in domestic animals after
pulmonary deposition of radionuclides. Bronchio-alveolar
carcinomas have been reported in dogs (111), squamouscell carcinoma, adeno-carcinoma and hemangiosarcoma
in the rat (358, 741) and fibrosarcoma, squamous cell
carcinoma and bronchiolar carcinoma in the mouse(657). It is apparent, therefore, that all cells ofendodermal origin composing the lung may give rise toneoplasia. With succeeding degrees of anaplasia, the cells
may express any of the characteristics of the embryonicpulmonary endoderm (633). Connective and vascular
tissues are also capable of neoplastic transformation. The
role of non-specific fibrosis of the lung, preceding or
accompanying the lung neoplasia. has been discussed( 111) and it has been concluded that it may be an
important contributing factor when a specific carcinogenis present. Bronchiolar and alveolar proliferation into
scarred areas of the Jung gives rise to proliferative andmetaplastic cells, which are often the primary changes ofthe lung in the case of inhaled compounds (490).
Pulmonary adenomas are frequently found in mice bothspontaneously and following whole-body and partialbody irradiation (see paragraphs 119 and 120). They are
frequently of alveolar origin. with a variety ofhistological patterns (641,642, 65).
314. 1\Jammary gland. Most of the studies on the
mammary gland are confined to breast tumours of theSprague-Dawley rat. In this system, irradiation of othertissues except the target tissue is not required to elicit
the neoplastic effect (52, 616. 617. 606). The intact
function of the ovary is however required for maximum
expression of the neoplastic effect ( 138). By histologicaland biological criteria, the tumours produced aredescribed as mammary adeno-carcinomas, adenofibromas or fibroadenomas, according to the relative
abundance of fibrous and adenomatous tissue {611). No
information is available on which are the possible cells at
risk, although this system, which has good characteristics

for oncological studies (614), would appear to be open
to quantitative developments on a cellular basis. It is ofinterest to note that very recently an experimental
technique to quantify radiation effects on rat mammary
tissue has indeed been developed by Clifton et al (112 ).
315. Kidney. In the Sprague-Dawley and the FAFI rat.
radiation-induced kidney tumours appear to be tubular
in origin, while in mice they seem to arise from theglomerular capsule with secondary tubule involvement.
Nephrosclerosis and arteriosclerotic changes would
appear to play a major role in their pathogenesis (36). Ina thorough study of the histogenesis of kidney tumoursin rodents (422), Mald~gue has confirmed that in theabsence of radiolesions, leading to renal atrophy andnephrosclerosis, no tumours are found in Wistar rats andin mice of the strain XVII. Concerning the tumour types
found in the rat, cortical adenomas originating from cellsof the convoluted tubules, carcinomas with various
degrees of anaplasia and a few sarcomas were described.
In animals locally irradiated in the kidney and thenuninephrectornized controlaterally. it was found that
focal localized proliferation of the epithelial cells at thejunction between cortex and medulla (which areprobably the induced cells transformed to malignancy)
give rise very frequently to the neoplastic nodules.
Cortical adenoma, cortical carcinoma and transitional
cell carcinoma were also described in rats (569). In themouse, tubular adenomas and clear cell carcinomas.
similar to the tumours found in rats. were also seen(422). It may therefore be concluded that the available
evidence points particularly to the tubular cells as thecells susceptible to neoplastic transformation, but thattumours arise in other degenerative and sclerotic lesions.
The role of these pathological components is still
unclear.
316. Skin. The histopathogenesis of skin tumours after
irradiation with low-energy beta particles of the CBA/H
mouse has been described by Hulse (421 ). Epidermal(papilloma and squamous carcinomas), dermal (mainly
fibrosarcomas, but also fibromas and hemangioendotheliomas) and subdermal (fibrosarcomas) tumours
were found. In spite of the fact that early and lateeffects on skin and skin annexes were carefully followed
and described. it was not possible to fmd any correlation
between the degree of non-neoplastic skin damage(depigmentation, ulceration, scars) and the likelihood oftumour development. It was definitely stated however
that. contrary to other reported results, tumours seemed
to arise as a direct effect on irradiated cells and in areasof the skin which did not appear to have suffered grossradiation damage. In a later report on dose fractionation,
the lack of correlation between skin damage and tumour
formation was confirmed and the relative independenceof skin tumour production on the mode of exposure toradiation suggested, in the opinion of the authors, theexistence of a mechanism of tumour induction of apermanent and cumulative type, such as a somatic
mutation (287). It was further argued that the sensitivityof the transformed cells to radiation killing might be
exceptionally low compared to the values commonly
found in mammalian radiation biology (288). Other
results in the mouse are particularly interesting for a
discussion of the cells at risk (369). By skin irradiation
with helium ions of different energies it was found that619

the number of tumours increased with increasing
penetration of the beam, in agreement with other data
relating to the rat to be discussed below. The
dependence of tumour formation on acute skin damage
was in this case partially confirmed.

317. The situation in respect to skin tumour inductionin the rat appears to be quite different, in the sense thatin the skin of this rodent there is an association between
hair follicle damage and the magnitude of tumour
response. The incidence of atrophic follicles reaches apeak at about the same dose at which maximum tumour
yield is found, and also there is good correspondence
between the shape of the dose-effect relationships forthe two types of damage ( 6). In a study performed withelectrons of several energies it was established that, when
the dose delivered with all energies is normalized at a
depth of 0.27 mm, the dose-incidence curves coincide,
indicating that the cells located at this depth from thesurface (identified as the cells at the bottom of theresting hair follicle) are to be considered as the cells at
risk for this type of tumour in the rat. In recent
experiments (7), a comparison of the skin tumour
response of mice and rats showed that the markedly
lower susceptibility of the mouse was due to the failure
to develop adnexal tumours, which are the predominant
type of neoplasia in the rat. Marked differences in hairfollicle injury in the two species were noted. In
particular, the mouse develops relatively little follicularatrophy, and hair follicles appear to be either intact ordestroyed; in addition, the mouse hair follicle appears to
be more sensitive by a factor of about 2. The
susceptibility to the induction of connective-tissue
tumours, on the contrary, is roughly similar in the two
species.
318. Bone. Detailed descriptions of the histopathological changes observed in bone after irradiation bybone-seeking nuclides have been provided by Nilsson(499, 509, 647, 494) and Vaughan (703). It is doubtful,
however (459), whether the described microscopic
damages have any relation with tumour induction since
the occurrence of tumours has been shown to be themost sensitive parameter and indicator of radiation
damage to the bone (185, 703). Histopathologicalevidence points to the following cells as the mostimportant cells at risk in the case of internal irradiation
by bone-seeking nuclides: the osteogenic tissues of thebone surfaces giving rise to osteogenic and chondrogenic
sarcomas; the bone marrow for all haemopoietic,
lymphopoietic and myelopoietic disturbances, and theepithelial cells in close contact with the bone, giving rise
to epithelial tumours of the mucous membranes of thehead. The case of the marrow has already been discussed
in connection with leukaemia (paras. 304 to 311), and it
should be pointed out that in rare cases other cells thanthe' haemopoietic elements might be susceptible toneoplastic transformation, as for example in the case of
haemangial tumours.
319. Concerning osteogenic tissue tumours. chromosome-marker experiments on chimerized CBA mice havedefinitely proven that osteosarcomas developing after90
Sr treatment derive from the osteoprogenitive tissuesof bone and not from the pluripotent cells of marrow(26. 48). The cells at risk are therefore to be found620

among the progenitor cells of the bone-forming tissue,
namely the pre-osteoblasts and pre-osteoclasts. Thesecells lie within 10 µm of the endosteal and periosteal
surfaces (703) and therefore are at risk in cases ofirradiation by both alpha and beta emitters of allenergies deposited in bone. These cells are the ones
becoming malignant due to an abnormal proliferation
following irradiation while maintaining the functional
activity of the original progenitors (499, 4). The
particular location of these cells explains the observationthat bone tumours are more frequently of endosteal
than of periosteal origin. on account of the fact thatendosteal surfaces are far larger than periosteal. It also
accounts for the observation that surface seekers are
more effective than volume seekers for bone tumour
induction, since the dose delivered to the target cells ishigher in the first case.

2. Conclusions
320. It may be concluded that further refinements ofour knowledge about cells at risk for neoplastictransformation are of extreme importance, both forelucidation of mechanisms and for better systematization of data. The problem has been tackled so far (and insome cases qualitatively solved) only in those tumour
systems where indirect mechanisms of induction andpromotion are relatively less important, and for which
the direct action of radiation on the tissue at risk
appears to be the determining factor for tumour
induction. A more quantitative approach seems now
required. as well as the development of investigation
techniques aiming at the establishment of links between
observations in vivo and model systems of celltransformation in vitro.

VI. SUMMARY AND CONCLUSIONS
A. GENERAL

321. A selective review of experimental radiation
carcinogenesis has been carried out in order to set theold information and the newest acquisitions in the moregeneral framework of cancer induction as a biologicalphenomenon, and with the ultimate ain1 of identifying
mechanisms or regularities which might facilitate theinterpretation of human data. The reviewed information
is both qualitatively and quantitatively inadequate fornumerical prediction of tumour induction rates in man,even though projections between species may beconsidered as the main objective of animal experimentation. The experimental data are. however. invaluable forunderstanding mechanisms, for the formulation of useful,generalizations applicable to all species. and for thedevelopment of models to test specific hypotheses oftumour induction.

B. METHODOLOGY
322. Several methodological approaches have been
followed in the past, ranging from the large-scale
epidemiological-actuarial analysis to the morphologicalr

and pathological approach, and from biochemical andmolecular experimentation to the more recent analysis
of model systems of carcinogenesis, All of these haveadvantages for specific purposes, but each of themappears inadequate for comprehensive solutions ofgeneral validity. The long-term nature of the work invivo is such that it requires a careful choice ofexperimental animals, high standards of animal husbandry and maintenance, advance planning of the size ofthe experiment. selection of appropriate biologicalend-points, quantitative observations on the relation ofdose and time parameters with the carcinogenic effect.
and careful statistical evaluation of the age-specifictumour induction rates. Although continuous improvements on these points are evident in the work reviewed,
much could still be done in order to refine the technicalrequirements for reliable investigations and to standardize the working conditions on an international basis topermit a wider applicability of the individual observations.
C. MECHANISMS
323. The probability of radiation-induced changes inindividual cells leading to the appearance of tumours isvery low.· Neoplastic transformation is presently
visualized as the end-result of a complex chain of
etiological and pathogenetic events that confer upon thetumorous cell an irreversible and unlimited capacity for
proliferation outside the nonnal control mechanisms.
Unlike some chemical carcinogens, radiation can both
initiate and promote neoplasia; it may also interact withother physical, chemical or biological carcinogenic
agents with variable results under different circumstances.
324. The genetic foundation is common to thecurrently accepted hypotheses of radiation carcinogenesis. and the recent advances in molecular genetics
and virology are gradually closing the gap between theclassical "theories" of the ·'somatic mutation" and"viral'' induction of cancer. Vertically transmitted RNA
oncoviruses have definitely been shown to be at theorigin of some radiation-induced murine tumours, and in
the very few cases where the analysis of mechanisms has
been carried to a sufficient depth radiation has beenfound to act through a modification of the host-virus
relationships, in a complex interplay of physical. genetic,
micro-environmental, honnonal and immunologicalactions. Attempts to study cell transfonnation byradiation on cultured cells have been initiated andshould be pursued to investigate the mechanisms ofcancer induction in the absence of other interactions
operating at the whole-body level.
325. There are data to show that a transient
non-specific immunosuppression caused by fairly highdoses of radiation may have a promoting role in thedevelopment of radiation-induced tumours. Moreover,the viral infection per se, acting through very specificcellular mechanisms, can cause a depression of theimmune reaction in cases where tumour viruses are
implicated. Although these effects would only appear tohave a secondary role, the questions as to their actual
importance and their relevance at low doses and dose
rates remain unsolved. Similarly, no definite answer canbe given about the role and the mechanisms throughwhich honnones could alter the susceptibility of certain
radiation-induced tumour systems in vivo, although theanimal's hormonal balance may affect the carcinogenic
response of some systems. Cellular proliferation is
implicit in the notion of a promoting action and iscertainly required for tumour progression. Cell division
is however a non-specific type of tissue reaction toradiation-induced cell depletion, and it is very difficult
to attribute to such an action a primary or a secondaryrole in tumour induction. Other environmental conditions concerning the host microflora, physical conditions, chemical substances and biological treatments may
affect to various extent the neoplastic response toradiation.
326. In conclusion, a variety of biological mechanisms
through which radiation can induce tumours have been
identified and, in some cases, analysed. The evidenceshows that mechanisms that appear very important for aparticular tumour system may, under a given set ofexperimental conditions, be less important or even not
relevant for the induction of other neoplasms. Ourpresent knowledge of mechanisms therefore provides
partial answers. but it is still insufficient for conclusionsof general validity.
D. DOSE, DOSE RATE AND RBE
327. Among the physical parameters affecting tumour
induction, the dose, dose rate and quality of radiation
have been considered. Concerning the dose, three major
patterns of tumour response can be identified. The firstrefers to those tumours which do not seem to beeffectively induced in the usual range of low to
midlethal doses but may however be induced at higher
doses. The second refers to those tumours for which thedose-effect relationship has a negative trend. The third,
and probably the most common pattern. is more
complex, showing an initial rise at increasing doses, apeak or a plateau at some intennediate level and, inmany cases, a final decline of incidence at sufficiently
high doses.
328. The peculiarities of each tumour-model system
which have been pointed out repeatedly in this Annex
are such as to prevent undue generalizations, particularly
when they might apply to all systems. There are alsodifficulties in interpreting tumour induction curves in
the animal on the basis of simple mechanisms of action,in view of the complex interplay of primary andsecondary factors, also discussed at length in this Annex.
With few exceptions, the existing data come fromobservations at doses above SO rad, since lower doses
have generally failed to cause an increased tumour
incidence large enough to be quanitified in experimentsof the usual size involving no more than 100 animals per
dose-group. Even in those instances where the incidenceof a particular neoplasm has been observed to increase
with dose, the data usually do not suffice to define thedose-effect relationship unambiguously in the low- tb
intermediate-dose region.
329. With one exception, namely the rat mammary
tumour. the dose-incidence curves obtained at high dose
rates with low-LET radiation generally increase in slope
621

with increasing dose in the range from 50 to a few
hundred rad. The data are not incompatible therefore
with the notion that an appreciable dose-squared
component might be present in these curves, which
would imply that linear interpolation or extrapolationfrom the observed data would tend to overestimate therisks to be expected at low doses (less than 5 rad) and at
low dose rates (less than 10-3 rad/min). With high-LET
radiation, on the other hand, the dose-effect relation·
ships are more often compatible with a linear
non-threshold response, and· their slopes vary relatively
little with dose and dose rate. Those instances where thetumour induction curves are seen to decrease in slope athigh doses and dose rates may be interpreted to result
from two independent dose-related phenomena: neoplastic transformation of the susceptible cells, theprobability of which increases with increasing dose, andsurvival of the transformed cells, the probability ofwhich decreases as a function of dose.
330. Detailed analyses of the dependence of the RBE ofdifferent ionizing radiations on dose and dose rate are
only possible at present for very few experimental
tumours. It appears that the efficiency of high-LET
radiations for tumour induction is higher than that of
low-LET radiations, and the efficiency often changes atdifferent dose ranges. At doses of 100 rad or more theRBE is often about 1, and it shows a rather generaltendency to increase at low doses and dose rates. owing
probably to the form of the dose-induction relationships, where the linear component prevails in the case of
densely ionizing particles, while the quadratic component might prevail, at least at high doses and dose
rates, in the case of low-LET radiation. A noteworthy
example of this type of effect is seen in theacceleration of breast-tumour development of theSprague-Dawley female rat, where effects of fastneutrons are detectable at doses of 0.1 rad, withcorresponding high values of the RBE.
331. A spreading in time of the delivered dose througha decrease in the rate or through fractionation of thedose results in general in a decrease of the oncogenic
effect of radiation, following some inverse function of
the exposure time. It is however difficult to assign
precise values to this sparing effect, since the shape ofthe dose-induction relationships is often altered by thechange of dose rate. The magnitude of the reduction ofcarcinogenic effect at low dose rates is often found to besmaller with high-LET radiation. Departures from thisgeneral pattern have been documented in some tumour
systems but are attributed to the pathogenetic
mechanisms of the particular system and not regarded as
exceptions to some fundamental radiobiological mechan·isms. Recovery processes are responsible for the sparing
effect of fractionation and exposure rate; their natureand kinetics in the case of neoplastic induction remain
largely unknown.

E.

INTERNAL EMITTERS

332. Carcinogenesis by internal emitters has been
considered as a special case since. in addition to thegeneral problems of radiation carcinogenesis, it poses622

other problems related to the inhomogeneity of the dose
distribution in time, and also to the concentration of theradionuclides in some organs or tissues. In addition, thecomparison of effects of various nuclides is often madeuncertain by the difficulties of assessing the dose to thetarget tissues. because of the peculiar behaviour of
nuclides having different physical and chemical characteristics and, therefore. different rates of uptake,retention and tissue localization. The cases considered indetail cover the induction of bone tumours andmyeloproliferative diseases by beta- and alpha-emittingbone-seeking radionuclides and the induction of lungtumours following inhalation of alpha emitters in various
animal species where data are available. A discussion of
the probable form of the dose-induction relationship forthe various types of neoplasms has also been included.
333. When the special factors mentioned above aretaken into proper account, it appears that the qualitative
picture emerging from these data is compatible with theconcepts developed from the analysis of the effects ofexternal radiation. The general form of the doseinduction relationships, the fact that at low doses beta
emitters tend to produce curvilinear responses and alphaemitters linear ones, the higher efficiency of the alphaemitters, and the sparing effect of low dose rates ofsparsely ionizing radiations, are all phenomena that canbe documented in the case of internal irradiation. Thisstrongly suggests that, with appropriate corrections, thegeneral knowledge on tumour induction may safely beapplied to both irradiation conditions.

F. BIOLOGICAL VARIABLES
334. Among the biological variables influencing radiation carcinogenesis, the effects of species, strain, sex
and age at time of irradiation have been reviewed. Even
with the lack of systematic data. it is possible toconclude that the genetic character of the species and,within species, of a particular strain, represents a major
determinant of the carcinogenic response, to which
other physical, physiological and environmental para·
meters may contribute as secondary variables. Genetic
differences in susceptibility to tumour induction byradiation are especially manifest at low doses: withincreasing doses and dose rates they tend to becancelled. There are also quite definite changes in thesusceptibility to the induction of various types oftumours as a function of the post-natal age at whichanimals are irradiated. Irradiation of experimental
animals in utero would not appear, on the whole, to be
more carcinogenic than irradiation during post-natal life.
335. Finally, the existing data on the problem of thetissue and cells at risk for the induction of various
tumours have been reviewed. It appears that this subject
may have important implications for the elucidation of
mechanisms and for possible practical applications.
Existing data relate, however, only to those tumour
systems where the direct action of radiation on target
cells appears to be the determining factor for tumour
induction. A better quantitative defmition of these
problems by development of more sophisticatedtechniques of analysis at the cellular level is desirable.

VII. NEEDS FOR FURTHER RESEARCH
336. The. previous report of the Committee (670). as
well as other publications (563, 291, 564, 419), haveindicated some topics of special interest for future
research. Adequate selection of research topics isparticularly necessary in carcinogenesis studies becauseof their long-term nature and of the major organizationaland financial efforts they require. The Committee calls
attention to the role of the experiments on animals forthe eventual elucidation of the mechanisms involved andtherefore for the extrapolation of data to man.
Considerably more data would be required to extrapolate the few available data in humans to different
conditions of exposure. A systematic analysis of theeffects of the main radiobiological variables inexperimental systems could make possible the refinement of the risk estimates in man by a considerable
factor with.in the next decade (564).
337. Concerning the strategy of future experiments,
special emphasis should be placed on the development
and analysis of models of the carcinogenic action, rather
than on large-scale experiments. It seems likely thatsome elucidation of the many factors interacting incarcinogenesis could be obtained through the study indepth of conceptually simplified experiments. A
multidisciplinary effort of a quantitative, rather than adescriptive, nature seems to be called for. For example,
our present knowledge of some tumour systems in viva
makes it possible to select as an indicator the inductionof tumours in a definite cell line at risk, rather than the
gross appearance of any type of tumours in a populationof animals. The use of more relevant end-points may
provide a- rational basis for possible extrapolations fromone species to another.
338. It is generally recognized that the area of greatest
applied interest is. and will continue to be, that of theeffects of low doses and dose rates. It follows that theexperimental efforts should be concentrated in that area.
It should also be emphasized that experiments on
tumour induction as a function of dose and dose rate inselected animal model systems appear at present to be
the type of studies that might best contribute to further
advancement. Careful planning and design of theexperiments, refined statistical analysis of the data, andalso a better standardization of the techniques used indifferent laboratories would strengthen the validity ofthe observations.
339. The following are some specialized topics requiring
further elucidation, and for which currently available
techniques would justify increased efforts with reasonable hope of progress. The topics are given in the sameorder as they have been discussed in the main text of thereport, without any indication of priority.
( a) The somatic mutation hypothesis of tumour
induction and its possible relations with the viral
hypothesis could be investigated by means of studies ofthe damage and repair to DNA and genetic structures intransformed celJs following irradiation or viral infection.
An attempt should be made to clarify the relationships
between neoplastic transformation of the cell and its
capacity for further reproduction and other possible
damage to important cell structures.

(b) On the basis of the data reviewed, it seems
that different radiation-induced tumour systems do nothave the same etiopathogenetic mechanisms: on thecontrary, it seems that the relative importance of eachmechanism is different in different systems. By testing
this relative importance, better elucidation of the roleand relevance of the various inductive and promotive
factors in different experimental situations could
reasonably be expected. Further experiments of the roleof various co-carcinogenic factors with particular
relevance to the presence of potentiating effects inregard to tumour induction would also be desirable.
( c) Since viral agents are implicated in the
induction of at least seine radiation-induced tumours.
attempts to demonstrate the viral origin of othertumours should continue together with studies on virus
activation and on the immunological mechanisms
interacting in such cases.

(d) The development of models of cell transformation in vitro should actively be pursued to clarify
the kinetics of cell transfonnation and its relationship tocell inactivation. Several possible models have alreadybeen identified (564), and it is not unreasonable toexpect that some of the classical radiation-induced
tumour systems in viva could also be subjected to morequantitative in vitro analysis.

(e) For in vivo studies, the identification of thecells at risk would greatly help in identifying themechanisms and unifying the observations. Quantitative
analysis of the capacity for division and differentiationof these cells, in relation to the transformation events,
would provide important links between in viva and invitro studies. Furthermore, the period elapsing between
the initial transformation of the cell and the clinicalmanifestation of the tumour should be studied. together
with the influence of immunological, hormonal andother promotive factors.
(!)
More experimental data are required toestablish with precision the dose-effect relationshipbelow 10 rad for many tumour systems. Studies of therelative importance of the linear versus quadraticcomponents in dose-induction curves would be very
valuable in this context. Better knowledge of the natureof such relationships would considerably improve theconfidence in the estimation of the risks of tumour
induction in man at low doses and dose rates (seeAnnex G).The development of model systems in vitro
and the analysis of the data by means of refined
theoretical models could help identify the relevant
trends. It should be pointed out, however, that any
conclusion will have to be confirmed by data in viva,
which are extremely difficult to obtain, particularly inthe less susceptible species.
(g) The mechanisms involved in the deterrnina·
tion of the nature of the dose-effect relationships -at
medium to high doses are uncertain. It seems reasonable
to assume that the identification of such mechanisms
might indirectly help establish the possible shape at very
low doses.
(h) There are few studies of RBE for tumour
induction. More effort is needed in this direction,
particularly with the most sensitive systems which could
allow an assessment of the RBE at low doses and dose
rates. for which information is definitely insufficient.

623

(i)
The lower efficiency with which irradiation
at low dose rates induces tumours, which has been
qualitatively described for some systems in vivo, should
now be explored in other tumour systems and evaluatedquantitatively.

(j)
Although it seems reasonable to postulatethat repair phenomena with various time constants areoperating at various levels of the biological organization,
the nature and kinetics of such repair mechanisms in thecase of low dose-rate irradiation are still essentiallyunknown and require elucidation.

(k) Further comparative studies of tumour
induction in different species and strains would increase
our confidence in interspecies extrapolations. In thisrespect it would be desirable to test in other animals theconclusions reached in rodent experiments about theeffect of the main physical and biological variables.
However, no large-scale studies should be undertaken

624

without sufficient scientific justification, which could bebased on the relevance of the information to be gainedfor human assessments.
(/)
The importance of systematic studies oftumour induction in various animal species and inanimals of different size and age should be recognized.
These studies should attempt to correlate the inductionof neoplasia with the number and functional state of thetarget cells at risk of malignant transformation in any
particular tissue.
(m) The conclusion that irradiation in utero is
not more carcinogenic than in the young or in the adultanimal appears to be based on rather scanty data. A
more systematic search covering various tumour types indifferent strains and species and relating tumour
induction with the rate of maturation of the relevantorgans would considerably strengthen that preliminary
conclusion.

I

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