SOURCES AND EFFECTS
OF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
UNSCEAR 1993 Report to the General Assembly,
with Scientific Annexes

UNITED NATIONSNew York, 1993

NOTE
The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Forty-eighth Session, Supplement No. 46 (N48/46).
ll1e designation employed and the presentation of material in this publication do not imply
tl1e expression of any opinion whatsoever on the part of tlie Secretariat of the United Nations
concerning the legal status of any country, territory, city or area, or of its authorities, or concerning
tl1e delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those tliat were in use at thetime the data were collected or the text prepared. In other cases, however, the names have been
updated, where tliis was possible and appropriate, to reflect political changes.

UNITED NATIONS PUBLICATION
Sales No. E.94.IX.2
ISBN 92-1-142200-0

ANNEX F
Influence of dose and dose rate on stochastic effects of radiation

CONTENTSINTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620

DOSE RESPONSE FROM RADIATION EXPOSURE. . . . . . . . . . . . . 624..................... 624.............................625
2. Multi-track effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626

A . THEORETICAL CONSIDERATIONS
1. Single-hit target theory

B.

.

C

D.

3. Low doses and low dose rates:
miaodosimetric considerations . . . . . . . . . . . . . . . . . . . . . . . 627
4. Radiation quality and relative biological effectiveness . . . . . . . . 629
5. Deviations from conventional expectations . . . . . . . . . . . . . . . 630
MULTI-STAGE MODELS OF CARCINOGENESIS . . . . . . . . . . . 630
1 Multi-stage models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .630
2. Thresholds in the dose-effect relationships . . . . . . . . . . . . . . . . 632
MECHANISMS OF DOSE-RATE EFFECTS
IN MAMMALIAN CELLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
1. Repair of DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
2. Effect of dose rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636.

. DOSE-RESPONSE RELATIONSHIPSI1

IN EXPERIMENTAL SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
A. TUMORIGENESIS IN EXPERIMENTAL ANIMALS .......... 639
1 Radiation-induced life shortening639
2 Tumour induction
647
B IN VITRO CELL TRANSFORMATION
662
1 Dose-response relationships .......................... 664
2. Dose rate and fractionation665
3 High-LET radiation
667
4
Summary
671
C MUTAGENESlS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
1 Somatic mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
2. Germ cell mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

.
.
.
.
.
.
.
.

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

UNSCEAR 1993 REPORT

620

111. DOSE AND DOSE-RATE EFFECTS IN HUMAN CANCER . . . . . . . . . 676
A. LEUKAEMIA AND ALL OTHER CANCERS . . . . . . . . . . . . . . . 676
1. Survivors of thc atomic bombings ill Japan . . . . . . . . . . . . . . . 676
2. Workers in the nuclear induslry . . . . . . . . . . . . . . . . . . . . . . . 677
B. TllYROlD CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .678
C. BREAST CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
D. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
IV. DESIGNATION O F LOW DOSES AND LOW DOSE RATES . . . . . . . 680
A. PHYSICAL FACTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
B. BIOLOGICAL FACTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
C. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682

Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715

INTRODUCTION
1.

Radiation-induced malignant disease is thc mainlate sonlatic effect in human populations cxposcd toionizing radiation and the only statistically detectablecause of radiation-induced life shortening at intermediate to low doses. In this dose range the incidenceof radiation-induced canccr appears to increase withincreasing dosc, and the probabilistic nature of therelationship between dose and risk of the disease has
led to the use of the tern1 "stochastic" for this type ofeffect. Quantitative information on the risk of cancer
in human populations exposcd to ionizing radiation atpresent comes largely from infornlation available from
populations that have been exposcd at intermediate tohigh doses and dose rates. In general, however, forassessing the consequences of environmental andoccupational exposure to radiation, risks need to be
known for exposures to low doscs delivered at low
dose rates. Some information is now starting tobccomc available from epidemiological studics on
occupationally exposed groups, although at present theresults of such studies havc si~bstantial statisticaluncertair~tiesassociated with tl~cm.It is likely that for
the immediate future quantitative risk cstimatcs willcontinue to be based on the higher dosc/dose-ratestudies, although increasingly low-dose studies will
provide support for these values.

which both total dose and dosc rate influcr~cecancer
induction in exposed individuals. The two features ofthe dose response that are most important for evaluation of the risk at low doscs arc the possible presenceof a lhrcshold dose, below which the cffccts could notoccur, and the shape of the dose response. Both thesefactors have been considered in earlier reports of theCommittee.

3.
Proving or disproving a threshold on the basis of
epidcrniological studies or studies on tumour induction
in experimental animals is, for most tunlour types,
likely to be impossible due to statistical uncertainties
in both the spontaneous and induced incidences of thedisease. Therefore, on the assumption that cellulartargets can be altered by single ionizing events, thatsuch damage is u~~likely
to be error-free and that it
may ultiniatcly give rise to a tumour, it is normallyassumed that thcre is no thrcshold for the neoplastic
rcsponsc. This working hypothesis is consistent wiU~
many, but not all obscrvatior~sof induced callccr rates
found in anirnal experinlcnts as well as with obscrvations in cpidcn~iologicalstutlics and is considered insome detail in Anr~exE, "Mcchanisnls of radiation
OIICO~CI~CS~S".

Tumour induction resulting from exposures toionizing radiation has becn systematically examined instudies with various species and strains of animals and4.

2.
It has becn recognized by the Comrnittee forsome time that infon~ialionis needed on the extent toANN13 I.': INF1,UI~NCE 01: DOSE AND DOSE RA

for specific tunlour typcs. Pl~ysical f;~ctors such as
dosc, dose rate, dose fractioriatior~ and radiation
quality, as well as biological factors such as age,gender and species wliicli can modify the tunlour
yield, havc been considered. In the rnajority of cases,
tllc dose-cffcct rclatio~~sliipsobtained are complex,
showing first a rise with increasing radiation doses, apeak or plaicau at intcrnlcdiatc doses and in marlycascs a final decline in incidence at high doses. In a
few cascs the spontaneous iricidc~~ceof tumours changes very little with incrcasilig radiation dose, and insome studies where there is a high spontaneous incidence this has resulted in a negative correlation withincreasing dose at high doscs.

5.

The Committee noted in the UNSCEAR 1977
Report [U4] a considerable variability in the net
incidence of various tumour types at intermcdiate tohigh doses, bolh between different species and, within
species, between inbred strains. In many cases aparticular tumour could be induced by irradiation in
only one or two strains of a given species, raisingquestions as to whether such tuniours represented
adequatc models of the corresponding human diseases.
Similar doubts also applied to some observed forms of
dose-response relationships that differed from species
to species, although in other cases consistent patterns
were found. For thcse reasolls it was concluded thatthe absolute cxccss of radiation-induced tumours perunit of dose could not, as a general rule, be extrapolated between species.

6. Dcspite these reservations, a number of general
conclusions were drawn by the Committee in 1977
[U4] relating to the preponderance of tumour types&at show an increasing incidence with increasing dose
up to a maximum, with a subsequent decline at higher
doses. A number of common features in the doseresponse data obtained fro111 experimental animals
appeared to be consistent with radiobiological effects
occurring in single cells, such as cell killing, inductionof mutations and chron~osonieaberrations:
(a)

@)

(c)

a decrease in the dose rate of low-LET radiation
leads, in general, to a decrease of tumour yield,
following some inverse function of the exposuretime;high-LET radiation is generally more efficientthan low-LET radiation for tumour induction,and h e tumour yield often shows little
dependence on dosc protraction and dose
fractiona lion;
the relative biological effective~~ess(RBE) ofhigh-LET compared with low-LET radiation
changes with the dosc, reflecting the patterns of
the dose-response curves for low- and high-LET
radiation. At high sublethal doscs (>I Gy) RBE
values as low as 1 havc been found, but for various tumour types the RBE generally increases

with decreasing dosc, approaching a m a x i n ~ u n ~at low doses.
These patterns or dosc rcspoi~scfor low- and highLET radiation are illustrated in Figurc 1.
It was gcricrally co~rcludcdin the UNSCEAR
7.
1977 Report ([U4], Ar111cxG, paragraph 31 1) that therisk per unit dosc of low-LET radiation at low doscs
and/or dosc ratcs was unlikely to be higher but could
be subsrantially lower than tlic values dcrivcd bylinear extrapolatio~~to the range of a few tens of niilligray from observations niadc abovc 1 Gy. Reduction
factors froni 2 to 20 were reported between the highcst
and lowest dosc rates tested (1 to lo4 Gy min") andbetween single and extremely fractionated and protracted doscs for various animal strains and tumour types.
It was specifically noted by the Committee that8.
the Life Span Study of the survivors of the atomic
bombings in Japan followed to 1972 gave a risk ofleukaemia of 3.5
G ~ - at
' a mean kcrma of 3.3 Gy' a mean kerma of 1 Gy, suggestand 1.8 loJ G ~ - ating a reduction factor of 2 for thc risk coefficient at
the lower dose as compared with that at the higher
dose ([U4], Annex G, paragraphs 317 and 318). The
Committee in its final estimate of risk adopted a
reduction factor of 2.5 for estimating risks at low
doses and low dosc ratcs when extrapolating fromehigh dose and dose-rate studies. The C o ~ n n ~ i t t ealso
emphasized that this reductio~~factor was derived
essentially from mortalities induced at doses of theorder of 1 Gy and that larger reduction factors niay beappropriate for assessing risks from occupational orenvironmental exposure.
9.
On the basis of thcse conclusions by theCommittee [U4], the International Commission on
Radiological Protection in 1977 [ I l l adopted a reduction factor of 2 for assessing the risk of fatalities fromradiation-induced leukaernia and solid cancers forradiological protection purposes from high dose andhigh dose rate studies.
10. In the UNSCEAR 1982 Report [U3] theComminee reviewed information on causes of death in
exposed human and animal populations. It concluded
that the overwhelming body of cvide~iceshowed thatat intermcdiate and low doscs. abovc about 1 Gy (lowLET) life shortening was essentially caused by anincreased incidence of tumours. When the contribution
to life sliorteni~ig by thcsc cxccss tulnours was
subtracted from total life shortening, there was nocvidencc of odler non-specific niecha~~ismsbeingc d effect of
involved. The Cornniittcc also c x a r l ~ i ~ ~theradiation quality, as well as dose and dosc rate, on
life-span shortenillg and reported some conflicting
results. For a given total dosc, the chronic exposure ofmice to both x and gamma rays was less effective than

622

UNSCEARacute cxposurc in causing life shortcning, suggestinga dosc-rate cffcct on tumour induction. In niicc givens i ~ ~ gacutcl c doscs of low-LET radiation, howcvcr, thc
dosc rcsponsc found in diffcrcnt studies varicd widely.
By pooliag m:11ry series ofstudics, an al~parc~rtlyli~rcarrclatioasl~ipwas obtained, whiclr might iniply no doserate dcpcndcnce. In practice, howcvcr, the data could
also be fitted with a lincar-quadratic relationship,
which would bc consistent with thc obscrvation of adosc-ratc cffcct.
11. In the case of neutron cxposurc, somc studies
reported that fractionated or protracted exposures ofanimals rcsultcd in reduced life shortcning comparedwith single exposures; other studies reported the
rcvcrse. Thc Committee concluded h a t such variationsin rcsponsc could be due to diffcrcnccs in dosc-cffcct
rclationships for different tuniours in various strains
and specics. Thus, although life shortcniag following
cxposurc to high-LET radiation appcarcd to be fully
explained by a higher incidence of tuniours, the cffcct
of dose rate on tumour induction as a cause of death
was not clear. Further investigations inlo thc eflccts of
dosc and dosc rate on life shortcning in animals
cxposcd to high-LET radiation were needed.

1 2 In the UNSCEAR 1986 Report [U2], the Comm i ~ t e ereviewed evidence at the subccllular and cellular levels rclcvant to assessing the possible nature of
the dose-response relationships for cancer initiation byradiation. It also examined how the initiation ofcancerous clones and their progression to clinicaltuniours may affect the shape of the dose-response
relationship. Finally, it examined various models ofcanccr induction and tested them for compatibility
with cpidcn~iologicaland experimen~alfindings. This
provided the basis for somc gcncral conclusions on the
shape of the dose response and on the uncertainties
involved in the assessment of risks at low doses.
13. Threc basic non-threshold models of the effect ofradiation as a function of dose were considered withrcspcct to both cellular effects and to cancer induc~ion:thc linear, the linear-quadratic and the pure quadraticmodels. Notwithstanding some exceptions, thcse relationships provided a general framework for a varictyof end-points at the cellular level as wcll as fortumour induction in experimental animals and humanpopulations. The Committee concluded that the vast
majority of dose-response curves for induction of point
r~iutatiorrsand chromosomal aberrations by low-LET
radialion could be represented by a linear-quadralicmodel at low to intermediate doses; for high-LET
radiation, aftcr correction for ccll killing, a linear
rr~odelusually applied. Linearity of thc dosc rcsponse
for somatic niutations and termi~ralchroniosomal deletions in sonie ccll lines was notcd even for low-LET
radiation, although such firrdings were relatively
infrequent.

14. Ccll transfor~nationin virro can be rcgardcd as asimplified nrodcl of ccrtain stages of radiation carcinogcncsis. Cclls exposed in virro to low-LET radiationllrc day aftcr srcdi~rg in culture are trarisfornicd
according to conil)lcx kirictics that cannot always be
fitted to l~iodclsused for otllcr cellular cffccts sucli ascell killil~gand the irrduction of chromosome abcrrations. Morcovcr, dosc fractionation (at total doscs<1.5 Gy) in soltic cases enhances transfonriation frcquency, which is inconsistent with a linear-quadratic
dcpcndcnce unlcss the dose-squared coefficient isnegative. In reviewing this material for the UNSCEAR
1986 Report [U2], the Committee felt that further
research was nccdcd to elucidate such phenomena, but
it was gcncrally co~rsidcrcdthat these in vifro systems
gave anomalous rcsulk owing to atypical conditions ofcellular growth during the early periods aftcr cstablishment of the culture. Irradiation of non-dividing cells,
conditions of growth, whichor cells under cxpo~~c~rtial
may be niore typical of asynchronously dividing ccll
populations in vivo, produces results that are nioreconsistent with those obtained for other cellulareffects. For example, high-dose-rate gamma-inadiation
had resulted in a greater transformation frequency perunit dose than low dose-rate exposure. The Committee
also notcd that in some studies transformation
following dose fractionation or dose protraction ofhigh-LET ncutron cxposure was enhanced at low tointermediate doscs, compared with high doscs arid
high dose rates [U2]. In view of the limited extent ofsuch data and the unccrtaintics regarding the mechanisms involved, further work was needed before thesestudics could be properly interpreted.

15. The Committee considered that experimental
findings on radiation-induced tumoun in animals,
mainly rats and mice, published since the UNSCEAR
1977 Report [U4] generally supported the view that
dose-response relationships for low-LET radiation
tended to be curvilinear and concave upward at low
dosc rilles, allllough for llianlmary turnours in rats alinear dosc response with little dose-fractionation anddose-rate depcndcrice had been obtained. For tumour
induction in aninials following neutron-irradiation, theresponse oftcn gave a nearly linear response at low
doscs, with little dcpendence on dose rate. In soniecases e~rharrccmcrrt upon dose fractionation (andpossibly dose protraction) had been notcd, and at
doscs above about 0.1 Gy or so the dose-response
curve for acutc cxposurc tended to become concave
downward. Ulrdcr such conditions a lincar extrapolation to risks at low doses from information at intcrmediate or high doses arid dose rates would undcrestimate the risk of tumour induction to a variable degrce.
16. Review of dose-response relationships forradiation-induccd tumours in man indicated that for
low-LET radiation in some cases (leukaemia andANNIX I: INFLUENCE OF DOSE AND DOSE M E ON STOClLASnC E F E C l X OF RADIATION

cancer of the thyroid, lung and breast), the data
available were consistcat with linear or linear-quadratic models. For breast canccr, linearity was conwas little
sidered niorc probable as the i~~cidcncc
affected by dosc fractionation, Froni this review [U2],
the Commitlcc concluded lhiit for low-LET radiation
linear extrapolation downwards from cffccls measured
at doses of about 2 Gy would not ovcrcs~iniatcthe riskof breast cancer and, possibly, thyroid cancer andwould slightly ovcrcsti~natcthe risk of leukacmia.
There were ir~sufficicntdata on lung cancer to permit
any assessment of the effect of dose rate on tuniour
induction. On the basis of data on the incidence ofbone sarcomas in cxperiniental animals after intakes ofbeta-emitting radionuclides, it was considered thatlincar extrapolation could ovcrcstimate the risk of theiroccurrence at low doses. Dose-response curves forradionuclides with long effective half-times do, however, present great difficulty in interpretation [N9].

623

necessary for assessing risks at low doses and low
dose rates. The Conimittcc indicated that this was a
topic that it would considcr in iLs future programme ofwork.
20. A number of othcr organizations have considered
the effect of dose and dosc rate on turnour induction.
These include the United States National Council on
Radiation Protection and Mcasurcnler~ts(NCRP), theCommittcc on Biological Effects of Ionizing Radiation(BEIR) of the National Research Council of theUnited States, the United States Nuclear Regulatory
Commission (NRC), the International Commission on
Radiological Protection (ICRP) and the National
Radiological Protection Board (NRPB) of the United
Kingdom. Their estimates of reduction factors forcalculating cancer risks at low doses and low dose
rates arc given in Table 1.

18. For high-LET radiation, human information forlung cancer and bone sarcoma induction was reviewed[U2]. Although the data were limited, they suggested
that for lung cancer induction in miners exposed toradon and its decay products, the response was linear
initially; at high cxposurcs, however, because offlattening of the response, linear extrapolation could
underestimate h e risk. The incidence of bonesarcomas after internal contamination by radiumisotopes was interpreted as being distorted by apronounced inverse relationship between accuniulated
dose and latent period.

21. In 1980, the NCRP reviewed the influence ofdose and its distribution in time on dose-response
relationships for tunlour induction resulting fromexposure to low-LET radiation. It was concluded,
largely on the basis of animal studies, that the numberof cancers induced at low doscs and low dose rates arelikely to be lower than they are at high doses and highdose rates by a reduction factor in the range 2-10
[Nl]. The BEIR V Committee reached sinlilar conclusions on values for the reduction factor that could beobtained from animal studies [Cl]. The NCRP [Nl]used at that time the term "dose-rate effectivenessfactor @REF)" for this rcduction factor, which has
also been referred to as "linear extrapolation
overestimation factor (LEOF)" and a "low dose extrapolation factor (LDEF)" [P2, P3). The NCRP [ N l ]also concluded that human data were insufficient toallow the shape of the dose-response curve to beestablished or to provide a basis for confident judgements about any diminution in health risks at low
doses and dose rates. In view of the complexity andwide spectrum of tumorigenic responses to radiation
found in experimental animals, as well as the lack of
information on the detailed mcchanisms of such
responscs in animals or man, more specific reduction
factors for either individual tumour types or total
tumour incidence were not given.

19. On h e basis of epidemiological studies andexperimental invcstigations it was recon~niendedin the
UNSCEAR 1988 Report [ U l ] that a reduction factor
was needed to modify the risks of cancer calculated
from exposures to low-LET radiation at high doscs
and high dose rates for application to low doses andlow dose rates, suggesting that an appropriate value
for most cancers would lie in Ihc range 2-10, althoughno specific values were recommended ([Ul], Annex F,
paragraph 607). For exposure to high-LET radiation,
no dose or dose-rate reduction factor was considered

22. In its 1990 rcconimendations 1121, the ICRP
drew attention to the fact that theoretical considerations, experimental results in animals and otherbiological organisms, and even somc limited humanexperience suggested that canccr induction per unit
dose at low doses and low dose rates of low-LET
radiation should be less than that observed aftcr highdoses and high dose ratcs. In making a dctcrnlinationof the appropriate value of a reduction factor to be
used for radiation protection purposes, thc lCRP
considered the following:

17. For radiation-induced cancers of most otherorgans, only data from experimental animals wereavailable on dose-response relationships. For low-LET
radiation, linear-quadratic dose-response relationships
are commonly found, with pronounced dose-rate anddose-fractionation effects at intermediate doses. The
Committee concluded in the UNSCEAR 1986 Report[U2] that if similar curves applied to cancers in man,a linear extrapolation of risk coefficients from acutedoscs in Ihe intermediate dosc region to low doses andlow dose rates would very likely overestimate the realrisk, suggesting that a reduction factor of up to 5
might apply.

624

(a)

@)

(c)

(d)

UNSCEAR 1993 REPORT

the wide range of reduction factors obtained in(2-lo), which may have been
animal experinicr~~sobtained lor a broader range of doses thanhuman data ant1 tl~erefore m y include higher
values than are relcviinl;
the results of slatisticill nrlalyses of the data on
survivors of the atomic bombings in Japan,
which do not seem to allow for a reduction
factor of much more tllan about 2:
the human evidence tl~atshows little effect ofdose fractionation for some tumour typcs, withothers indicating possible effects of up to 3 or 4
at most;reduction factors adopted by other organizations
for risk estimation at low doses and low dose
rates.

23. Based on thcsc considerations, the ICRP adopted
in its 1990 recomniendations a reduction factor of 2,"recognizing that the choice is soniewhat arbitrary andmay be conservative". It was recognized that thisrecommendation on the reduclion factor "can be
expected to change if new, more definitive information
becomes available in the future". In theserecommendations the ICRP called this reduction factor
the dose and dose-rate effectiveness factor (DDREF).

24. The Committee has identified the need to keep
under review information relevant to the assessment ofrisks at low doses and low dose rates. This Annex
reviews data on dose arid dose-rate effects for both
high- and low-LET radiation with the aim of
improving the basis for estimating risks at low doses
and low dose rates. It considers first the role ofbiophysical models in understanding the response ofcells to radiation of different qualities and theirapplication in assessing the effect of dose and dose
rate on cellular responses. Experimental data on theeffect of dose rate in both expcrimcntal animals andcells in culture are then reviewed, with emphasis on
studies of the effects of low-LET radiation. Relevant
epidemiological data are also summarized.
25. Previous UNSCEAR reports have proposed bothdoses and dose rates at which reduction factors would
be expected to apply. Thus in the UNSCEAR 1986

Report [U2] low doses were taken to be tl~oseup to
0.2 Gy of low-LET radiation, while those above 2 Gy
were regarded as high doses, will1 intcnncdiate doses
lying between tllese values. Low and high dose rates
were taken to be <0.05 mGy niin'l and >0.05 Gy
min-l, respectively, with intern~ediatcrates between
these two extrelnes. These 1lppcr limits on low doses
and low dose rates are substantially higher than those
lfiat might be expected to prevail in most cases ofhuman exposure. Thus, the ICRP in 1990
recomniended an average annual dose limit forworkers of 20 mGy (low-LET) [I2]. The averageannual dose limit recomniended for members of the
public is 1 mGy (low-LET) in addition to exposures tonatural background radiation [12].

26. In practice, the majority of workers receive doses
much lower than the recomlilendcd dose limits, andactual exposure rates are low (see Annex D,"Occupational radiation exposurcs"). There will,
however, be sonic individuals (e.g. radiographers in
hospitals) exposed over short periods of the working
day to substantially higher dose rates than the average,
although total doses are low. Lifetime doses for a few
workers may also be high even thougl~dose rates arelow. Information is, therefore, needed on both total
doses and dose rates for which the application of areduction factor is appropriate. Chapter IV examines
the physical, experimental arid epidemiological basis
for the choice of doses and dose rates below which
reduction factors might be expected to apply. The
choice of the appropriate unit of time over which toassess dose rate is not straightforward. The experimental data reviewed in this Annex cover a wide
range of doses, dose rates and exposure conditions.
Cellular studies typically involve irradiation times ofminutes to hours, while animal studies can involve
exposures of days or weeks. The Committee considers
that for assessing the risks of stochastic effects inhuman populations exposure rates should, in general,
be averaged over about an hour, which is in line withthe repair time of DNA (deoxyribonucleic acid). However, for consistency and to facilitate the comparisonof experiments carried out under different exposure
conditions, dose rates are given in this Annex in termsof Gy min-' or niGy min" as far as is possible.

1. DOSE RESPONSE FROM RADIATION EXPOSURE
A. THEORETICAI, CONSIDERATIONS

27. Damage to DNA (deoxyribonucleic acid), whichcames the genetic infomiation in chromosonies in thecell nucleus, is considered to be the main initiating
event through which radiation causes cancer as well ashereditary disease. Present knowledge on tlie stages intumour dcvciopnicnt is described in Annex E,"Mechanisms of rsdi;ltion oncogenesis". Dilmage to
the DNA of cells has been directly observed experimentally at absorbed doses in excess of about 1 Gy.
The DNA niolecule has a double helix structure, andA N N W F: INFLUENCE OF DOSE AND DOSE IUE ON STOCI LASnC EFFECTS 01: RADIATION

damagc in many forrl~sis obscrvablc, including singlcand doublc-strand breaks and basc damage [C5, H26,
M4, T201. Damage may be dctcctcd, but with greatcr
difficulty, at lower doscs (0.05-0.1 Gy) [B13]. Daniagc
to cl~ro~nosornes
in hurl~an cclls can be obscrvcd,
cilhcr at nlctaphasc or intcrpllasc [C9, ClO], and has
been obscrvcd in t111rna11pcriphcral blood lyn~phocytcs
at doscs dowll to about 0.02 Gy [L13, L141.
28. The cfl'ccts of radiation on cellular components
arc thought to occur cithcr through thc dircct intcraction of ionizing particlcs with DNA molecules or
through the action of frcc radicals or othcr chemical
products produced by the intcraction of radiation withneighbouring molecules. Othcr more indirect mechanisms have also been proposed. Cells are able torepair both single- and doublc-strand breaks in DNA
over a pcriod of a few hours [B13, M4, M15], but
somctimcs misrcpair can occur. Such damagc isthought to be the cause of chromosomal aberrations
and may also be the origin of both mutational andcancerous transformations as well as death of the cell
[ G l , R1, U2, Y2]. Spontaneous single-strand damage
can also occur in thc abscnce of radiation or otheridentifiable insults [B41, L23, S39, V3, V9], but thisis unlikely to cxtcnd to the full range of types ofdouble-strand, clustered damage that radiation can
produce [G21, W9].
29. It is commonly prcsurncd that mutational cvcnts
in gcnn cclls arc due to singlc biological changes butthat carcinogcnesis is a multi-stage process in whichradiation can induce one or Inore of the stages involving DNA damagc [Ul, U2]. Guidance as to likely
dose and dosc-rate effects may therefore be soughtfrom radiobiological data on the cellular cffccts that
result from DNA damage. Gcncral mcchanistic concepts derived from these data have had a considerable
influence on attcmpts to understand and extrapolate
available data on carcinogcnesis. It should be rccognized, however, that the cellular data are mostly
for singlc-stage radiation effects, principally related toinitiation, and that they therefore represent only a partof the complex process of carcinogcnesis.
30. It is usually assun~cdthat the primary mutagenic
and carcinogcnic cffccts of radiation arise as rclativcly
rare stochastic consequcnccs of damagc to individuals
cells. Insult from ionizing radiation is always deliveredin the form of separate charged particlcs traversing thc
cells, each leaving behind a "track" of ionized molecules. Each discrete track consists of the stochastic
spatial array of initial ionizations and cxcitations ofmolecules in the cell along the path of a primarycharged particle and all its sccondaries as they passthrough the cell in ~ 1 0s .[P9,~ PIO].
~The pattern of
ionizations in each track is govcrncd by cross-sections(probabilities) for individual molecular interactions.

625

Each track is thcrcforc diffcrcnl but has statisticalfeatures ch;~ractcristicof thc radiation. On thc nanomctrc scale of DNA and rildical diffusion distances in
iclnizations ;ire likely tocells, rilally of l l ~ ci~~dividual
occur alor~carid far fronl any olhcrs in thc salnc track,cspccially for low-LET radiations. I-lowcvcr, manyothcr ionizations occur in clustcrs of dimcnsio~~scomparable to Lhosc of DNA. This clustering is particularly marked for high-LET radiations, but i t is also
common in tracks of low-LET radiations, largcly
bccausc of the likclihood of low-cncrgy secondary
electrons being produced within the cell [ B Z , G6,
G16, M27, NlO]. Bccausc the radiation insult isalways in the form of discrctc tracks, the radiobiological process may be described in terms of damage
to particular target material, using concepts of target
theory. In its gcncral form, target theory assumes thatthe observed all-or-nothing effcct is caused by one ormore radiation tracks passing through the cell anddirectly or indirectly causing specific damage tocritical components within it. Almost all biophysicalmodels of radiation action incorporate at least someessential concepts of targct thcory. Model descriptionsof the possible radiobiological mcchariisms are usuallyconstructed on sclcctcd assumptions and deductions[E2, G3, G5]. An approach based on the gcncral concepts of target theory can dcscribe essential elementsof the mechanism of radiation insult in an approximately modcl-independent way. It can indicate how biological processes may rnodify the simplest responses
and how there may bc a dependence on physical parameters such as dose rate. This dcscription could apply
to any single radiation-induced stage of the multi-stage
process of carcinogcnesis and to some combinations ofstages. Within this gcncral description many specificmodels can and have bccn constructed, based on theirown specific mcchanistic or phenorncnologicalassumptions (see [B33, C5, G17, G22, H23,K5,K6,
M34, M39, R12, T21I).

1. Single-hit tnrget theory
31. In the simplcst form of targct theory, a direct"hit" of any type (i.c. orlc or more ionizations) in a
critical component by a radiation track is assumed tolead, with certainty, to thc obscrvablc cffcct in thatcell. In this casc, thc frcqucncy of affcctcd cells in an
irradiated population of cclls should increase with dose
according to thc probability of a ccll rccciving one ormore critical hits. Assuming that thc hits occur
randonlly according to a Poisson distribution in a
homoge~~cous
population, then lhe frequency, f, ofcells with onc or more hits iswhere n is the mean number of critical hits per ccll at
dose D and A is the mean riumbcr of critical hits per

UNSCEAR 1993 REPORT

626

cell per unit dose. For small n (that is, low frequer~cy
effects and/or low doses), the dose response is approximately linear, with
f

-

AD

(2)

At higher frcque~lcicsthe dose response takes the formof equation 1, which saturates at high frequency
because, after the first critical hit in a cell, subsequent
hits in it cannot lead to additional effect. If a negative
effect is being measured, such as frequency of surviving cells (that is, cells without a critical hit), then thedose response is
f1 = 1 - f

=c-AD

(3)

where f1 is the frequency of cells without a critical hit.
This very simple form of target theory, where every
elementary hit is biologically effective, may be applicable to the inactivation of many ~noleculesin the dry
state and to some viruses, but it is not, in general,
appropriate for micro-organisms and mammalian cells,
because of their well-established capacity to repair
radiation damage and the consequent modification ofdose response.
32 More refined forms of single-hit target theory
could include variable probability of effect dependingon the type ("severity") of a hit and on the cellular
reparability of the damage and could also include
extension of t l ~ esize of the target for indirect effects.
Provided that the tracks act totally independently of
one another in regard to each of these processes, thedose response should still conform to equations 1-3
because the final effective damage should still be randomly distributed among the cells [W].
The numericalvalue of h should now be modified to reflect the combined probability, per cell and per unit dose, of allthese single-track processes leading to final effeclive
damage. Indirect effects should increase the value of)C, while biochemical repair should reduce it. Therefore, experimental observation of linear or exponential
dose response does not, of itself, indicate that damage
cannot be modified and/or repaired by the cell.

33. Furthcr extension of concepts of target theory
can consider additional contributions born two or
more tracks, which may modify the probability ofeffect due to thc damage from single tracks alone.
Since this modification may be positive or negative, it
may introduce corresponding visible curvature to thedose response. Ways in which multiple tracks could
increase the probability of effect include the following:(a)@)

reduction in efficiency of cellular repair ofindividual points of damage by increasing theoverall burden of damage (for exan~ple, bypartial saturation of the repair process [G17,(c)S40, WlO] or induction of danii~ge-fixation
proccsses);interaction or i~~terference
between points ofdamage to make them less repairable [CS, C28,
K6] (for example, formation of exchange events
wilhis or between chronlosomes 11-1231):
production of a series of other independentchanges that togctl~er increase the overall
probability of the final effect (for example, tocause a single-stage effect [KS]or to cause
multiple stages in full neoplastic transformation
IM391).

By contrast, decreases in the probability of effect bymultiple tracks could occur by the following means:(d)(e)

enhancement of cellular repair (for example,
induction of additional repair capabilities [B37,G5, 03, P81);
elimination of some of the cells from the
population by transferring them to a state inwhich the effect cannot be expressed (forexample, by loss of cell viability).

Other processes, such as multi-track pcrturbation of
the cell cycle, have the potential either to increase or
to decrease the probability of effect The reduction ofdose rate increases the time intervals between tracks
and acrefore is likely to alter the contributions fromthese multiple-track processes.
34. Simple mathematical extension of equations 1-3,
now to include multi-track effects, may be made bymeans of a general polynomial. Those equations are
therefore replaced in general by

For low-frequency effects, the equation isand for negative effects it isdesignating the coefficients as B1 and P2 to denote lhat
these are negative effects.

35. Attempts to interpret and apply the coefficientsal,9,... and B1, p2, ... nlust usually rely on particular assumptions of radiobiological nlechanisms.
Many investigations, including experiments, theory
and lr~odelforniulations, are aimed at identifying theassumptions that may be most reasonable under given
circumstances. Without such mechanistic considerations, the coefficients provide no more than finedvalues, which may be valid only in the limi~edrangeof the experimental data themselves. Quite different
mecha~~istic
assumptions can lead to equations such as

A N N M F: INFLUENCE 01: DOSE AND DOSE R A n ON STOCIiASIlC EI'FE(7IS OF RADIAION

627

equations 4-6, either directly or as the first terms ofpolynomial expansion approximations. For exanlple, adose-squared tern1 can arise directly fro111two tracks
damaging separate chromosoolcs, which then undergo
an exchange interaction, or from two tracks creating
deletions in con~plen~entarychromosomes, causing theloss of both alleles of a gene. By contrast an apparent
dose-squared term can arise from nlultiple tracks
increasing the overall burden of damage in a cell andtbereby partially saturating a repair system andreducing the probability of repair of particular damage
from any one track [G17, S40, WlO]. The reliabilityof extrapolations to low doses, below the range of thefitted data, may depend substantially on the appropriateness of the mechanistic assumptions for thesesingle cellular effects as well as their relevance tocarcinogenesis. For example, for exchange aberrations
there would be a clear expectation of a substantial
linear term to the lowest doses owing to the ability ofa single track to damage two separate chromosomes;
such a one-track occurrence would be much lessprobable for a deletion of two identical alleles, butmuch more probable for a single deletion, which alone
may be adequate to enhance carcinogenesis. In thecase of saturable repair, extrapolation to low doses
would depend largely on the competition between
repair and fixatiodmisrepair processes and whether
any types of damage are essentially unrepairable.

tenn polyno~nialis unlikely, howcvcr, to be adequate
to describe and i~~terpolate
over the full dose response,
if it irlcludcs processes (c) and (d). Fronl reviews ofpublished data it can be deduced that co~~siderable
differences are observed between cells of different
origins with respect to the values of aland 9 [B6,
B7, T61. For a dose response that can be fitted with
only the first two ternls in the polynomials inequations 4-7 the quotient a,/% equals the dose atwhich the linear and quadratic components contributeequally to the observed cellular damage.

36. When the equation is applied to describe a lowfrequency effect, such as carcinogenesis or mutagenesis, arising from a given initial population ofcells, it may be convenient to separate out the
influence of radiation-induced loss of cell viability byreplacing equation 5 withThe latter function was rejected because no cell
survival response depending solely on D~ is known.
The observed data could therefore be well fitted by thefunctionwhere S@) is the fraction of cells wllich survive
dose D. S O ) itself may be described by the form ofequation 6. With high-LET radiation, it may benecessary to consider also correlations between
induction of the initial carcinogenic damage and lossof cell viability by the same radiation track [GlS].
Additional non-linearity may arise if adjacent cells canbe involved in control of the growth of an altered cell.

37. It is frequently found that only the first two
terms of the polynomials in equations 4 7 are needed
to describe the experimental data. Most effects oncells (e.g. chronlosome aberrations) resulting from low
to intermediate doses are fitted, therefore, to a linearquadratic equation without including powers of dose
greater than D ~This. simplification may be reasonable
for radiobiological mechanisms underlying some of thepossible multi-track processes described in paragraph 33, particularly under processes (a) and (b) andespecially if only two-track interactions occur. A two-

38. An example of the type of response of equation
7 is provided by observations of myeloid leukaemia
frequency in male CBA/H mice after 1 0 different
doses of x rays in the range 0.25-6 Gy inclusive,
delivered at 0.5 Gy min-I [MI41 (Figure 11). Mediansurvival in all groups was similar, and there was
essentially no association between induction period
and dose. The results were fitted by a four-term
polynomial of the fornl

and four simplifications of it. The only functions withall parameters significantly greater than zero were:andalthough none of the alternative functions could be
rejected on statistical grounds. A similar dose response
for myeloid leukaemia induction in CBA mice wasreported by Di Majo [D2].
3.

Low doses and low dose rates:
microdosinietric considerations

39. For a homogeneous cell population, the dose
response for an effect arising solely from a single
track interacting independently with cellular targeqs)
should conform with equation 1and should be simply
linear with dose (equation 2) if the frequency of effectis small. It should extend linearly down to zero dose,with no threshold, because reducing the dose simply
reduces the number of tracks proportionately and, consequently, the Gequency of effect. The dose response
should be independent of dose rate, because the timeinterval between tracks is irrelevar~tif the tracks are
acting totally independently. There may, of course, bemany other interactions that are adequately repaired
and do not manifest themselves as damage.

62 8

UNSCMR 1993 REPORT

40. If t l ~ ccell p o p ~ l l a t i ois~ ~inhoniogcncous, with
subpopulations of differing sensitivity, the dose res p o ~ ~ sforc single-track effects in cach subpopulatior~should follow the for111 of equation 1, and the overall
response should therefore show a dccrcasi~~gsensitivity with i~~crcasir~gdose. Any clther deviations fro111
the lorn1 of cquatioo 1 must be doe to the effect ofmultiple tracks in SOIIIC way or allother. These deviations, however, nced not be obviously apparent ovcr
all portions of the dosc rcsponsc. Hence, apparent
linearity ovcr an cxpcrimca~~lly
accessible portion of
the dosc rcsponsc docs not guarantee that o111ysingletrack processes arc involved in that region or thatextrapolation to lower dosc is linear. In general, it isexpected that multi-track processes nlay depend on
dose rate as the mean tinic interval bctween cracks isvaried. Referring to the exar~iplcabove, simple expectations are that a reduction of dosc rate would reduce
the effectiveness of radiation acting via processes (a)and @) (paragraph 33). Predictions for the otherproccsscs are less clear, bccausc they are likely todepend on the timings of the particular proccsses inrelation to the intervals between tracks and the overall
irradiation time. For most single-stage proccsscs, it
may be expected that at very low dose rates multitrack effects will beconle negligible, because the tracks
become effectively ir~dependcntin time: in this limit
the dose rcsponsc should conform to equations 1-3.
41. Available experimental and cpideniiological dataon radiation carcinogcr~csiscan be cotsidered in termsof three regions of the dosc response on the basis offundamental microdosimctric considerations assumingthat the cell nucleus is the relevant sensitive volunie todefine the limit of possible multi-track effects. These
are illustrated in Figure 111 by schematic dose-response
curves, consistent with the Corm of cquation 7, forfrequency of an cffcct such as a type of tumour induced by gamma rays, neutrons or alpha particles. The
upper part of the Figure shows the responsc plottedagainst dose on a linear scale. The lower part shows
the identical curvcs plotted on a logarithmic scale tomagnify the lower dosc region; on this part a separate
dose axis is provided for each radiation type. The
logarithmic plot also marks on a common axis themean number of tracks per cell nuclcus (assuming
spherical nuclei of 8 pn1 diarnctcr for these illustrations). In this way, the corrcspondcnce between doseand number of tracks can be read off for cach radiation. This corrcspondcnce has been calculated IC2.5,
G5] by established niicrodosimctric melliods based on
experimental and theoretical data [B42, C24, G2, G4,
221. In this Figure the dose scale is divided into three
approximate dosc regions, as described below.
42. Dose region I (low-dose region). In this dose
region there arc so few radiation tracks that a single
cell (or nucleus) is very u~~likcly
to be traversed bymore than o r ~ ctmck. In this region of "definite"~tl~an 4 . 2 mGy for 6 0 ~ osingle-track a c t i o ~ (lessgamma rays; see Section IV.A), the dosc rcsponsc for
single-ccll effects is almost hound to be lincar andindependent of dose rate. This is because varying thedose proportio~~i~tclyvaries the nu~nhcrof cells singly
traversed, and varying l l ~ edosc rate varies only thetinic bctwecn tliesc i ~ l d c p c r ~ d c v~c~~t ~ tTl~cse
s.
si~iiple
expectations would bc violated only if the rare multitraversals greatly cnl~anccdt l ~ cprobability of effect,
such as may be t l ~ ccase if radiation carcinogenesis
requires two radiation-induced stages well separated intime. There arc no epidemiological or experimental
data in or near this region for low-LET radiation, atthough a few may approach it for high-LET alpha particles and neutrons (C2.5,D51. There is, therefore, little
direct information about how a cell or a tissue may
respond to the damage from a single radiation track.
43. This is, however, the region of main concern inradiation protection. For exaruple, a worker who hasreceived uniform whole-body gamma-ray exposure
spread over a year equal to an annual equivalent dose
limit of 50 niSv [Ill, corresponding to an absorbed
dose of 50 mGy (Q = I), will have received ovcr thefull year an average of about 50 electron tracks
through each cell r~ucleus in his body. Multi-trackproccsscs should tl~cnbe relcvar~tonly if they operateover long periods of time con~parableat least to thetimes between tracks (days). If, instead, the irradiationis unifonii with only 1 MeV neutro~ls(and ignoring
attenuation, energy degradation or gamma-ray production in the body), then the 50 nlSv limit corresponds
to 5 niGy of neutrons (Q = 10) and an average ofabout 0.05 directly ionizing tracks (mostly high-LET
recoil protons from the indirectly ionizing neutrons)
through each ccll nucleus during the year. These tracks
must clearly act independently unless multi-crack
processes persist over very long periods of time,extending to many years. Exposure is seldonl uniform
in the body or in time, and cell nuclei have a variety
of sizes and shapes. Nevertheless, the dose anddose-rate region of main practical relevance inradiation protection (0-50 mSv per year) is characterized by small average numbers of tracks pcr cell withlong intervals of time beween them. Effects are,therefore, likely to be dominated by individual track
events, acting alone. This dominance will be evengreater with llie introduction of the ICRP rccommendations of 1990 [12] which propose an average
dosc of 20 mSv andannual limit of equivalc~~tincreased radiation weighting factors for neutrons(>I00 keV to 2 MeV, w R = 20).
44. For tlic purposes of this rnicrodosinlctric criterion
for a low dose, the ccll nucleus (approximated here asan 8 pm diarnctcr sphere) has been considered to be
the sensitive volunlc in which multiple tracks niay be

A N N I S I:: INFI-IJENCE OF DOSE AND DOSE RATE ON STOCI4ASTIC E F E C I S Of: RADIATION

able lo ir~flucnccthe effects of one another. This
choice is based on the assumption that radiatiol~caris due to radiatio~~damagc to t l ~ cnuclear
cinogc~~csis
DNA of a single ccll end that biochcniical proccsscs,
including repair and misrcpair, may operate ovcr the
If influence can extend
full dirnensions of tlic ~~uclcus.
ovcr larger distances, say Sronl kicks in the ccll
cytoplas~nor in i ~ d j a c c ~cells,~ t then the microdosimetric criterion for a low dosc would nccd to be
decreased. Conversely, if smaller regions can act
totally autononlously in respect of initial radiation
damage and its repair or misrepair, the11 the criterion
would be increased. In the extreme, if cach short (say,6 base pair) segment of DNA were totally autononious
for damagc and repair, then the microdosimetriccriterion for a low dose of low-LET radiation would
be as large as lo9 mGy [G6]. This is clearly much toolarge compared to the doses at which multi-track processes have becn observed experimentally by curvatureof dose-response or dose-rate dependence in cellularand animal systems (Chapter 11). Criteria for designating IOW doses and low dosc rates are discussed further
in Chapter IV.
45. Dose region 11(inferrnediate-dose region). In
this dose rcgion it is comnlonly assumed that tracks
act independently if a linear tcml (a,) is obtainable bycurve-fitting to equations such as 4-7. However, formost of the epider~liologic;~land experiniental animal
data used for dose-response curve fitting, the lowest
dose at which a sig~~ificant
effect is obtained is usually
towards the higher doscs of this dose region, when
individual cells may, in fact, have becn traversed byconsiderable nun~bcrsof tracks.
46. The assumption of one-track action for thisregion considers that the relevant metabolic processesof the cell are not influenced by the additional tracks
in any way that could alter the efficiency of these processes and, therefore, the expression of the ultimate
biological damage of each individual track. Thisregion of the dose response, then, should be independent of dose rate. On these assumptions, it is conventional to interpolate linearly from this rcgion to zerodose in order to deduce the effectiveness of low doses
and low dosc rates of radiation, dosc region I. Suchinterpolation is based on the coefficient al in equations 4 7 and on tile assumption that it remains unchanged even to vcry low doscs and very low dose
rates in dosc rcgion 1. There are a number of radiobiological studics, 111osUy with cclls in vilro, but also
from i~nimalsexposed at different dosc rates, whichsuggest Ihat this common assumption is not universally valid (see Sections I.A.4, I.A.5, 1I.A. and 1I.B).
47. Dose region 111 (high-dose region). In this dose
region, there are often clearly observable multi-track
processes causing upward or dowl~wardcurvature of629

the dosc rcsponsc, including coopcrativc effects andalso con~pctingprocesses suc11 as ccll killing. Dcpendcncc on dose rate is, thercforc, usually to be expected
because of time dcl)cl~dcnccin t l ~ cmulti-track process.
Mechanisms in Illis dosc rcgio11 need lo be adequately
understood and dcscribcd if such d;~titarc to be used
for curve-fitting and e ~ t r i ~ l ) ~ l togctl~er
a t i ~ ~ ~with,data
from dose region 11, to tllc low doscs and low dosc
i n radiation protection.
rates of prin~crclcva~~cc

4. Radiation quality nnd
relative biological effectiveness48. A vcry wide range of radiobiological data on thedoses required to produce a given level of effect haveshown that high-LET radiation, including neutrons andalpha particles, is more effective than low-LET radiation [S12]. This greater effectiveness is usually particularly marked in the regions of intermediate and low
dose, which implies that the individual high-LET
tracks have a greater probability of effect than a verymuch larger number of low-LET tracks. Thus the concentration of energy deposition within the high-LET
tracks more than compensates for the reduced numberof tracks per unit dose.
49. The relative biological effectiveness (RBE)values of particular relevance in radiation protection
are those that apply in the true low-dose rcgion I, in
which tracks are most likely to act individually. At
these minimally low doses the RBE of a givcn radiation should be constant and independent of dosc anddose rate, because varying the dosc for both high- andlow-LET radiation varies only the number of cells thatare traversed by single tracks. This RBE, at minimal
doses, could in principle be calculated by direct comparison of measured effectiveness per unit dose ofneutrons and low-LET radiation in the low-dose region
I, or from cxperin~entalmeasurenients of the effectiveness of single tracks of the radiation. Current experimental methods have not been able to achieve this.

50. Instead, it is cor~ventional to assume that the
RBE at minimal doscs is also the maximum RBE andthat it can be estimated as the ratio of the al values of
the two radiations, determined by fitting equations
such as 4-7 to t l ~ eavailable data at intermediate andhigh doses. This n~cthodassumes that the multiple
rcgion do not influence
tracks in the i~~tcnncdiate-dosethe effectiveness of cach other at all and, conscquently, that the a,values arc const;lnt down to zerodose and independent of dosc rate. This assumption isbcst supported for high-LET radiation, for which invirro radiobiological data usually show strongly linear
dosc responses that vary little with dose rate, withsome data approaching the true single-track region.
Notable exceptions have been reported, however, in630

UNSCEAR 1993 REPORT

cellular, animal and hun~ansystems (see, e.g. [C22,C25,D5, F9, F10, J2, K8, H9, M28, R13, S13, T7,
T8, U161). The assumption of comtant al,independent of dose rate, for low-LET rcfcre~~ceradiation is
also called into question by data from numerous
studies oa cellulrr, and s o ~ i ~ani~nal,esystems (e.g.
[B34, C12, C20, F1, F10,F13, F4, 18, K8, M16, M33,
0 4 , S3, S14, S32, T2, WG]). The general approach of
estimating risks of high-LET radiations by means of
RBE values would not be applicable to effects thatwere qualitatively different for, or unique to, high-LET
radiations. There are indications that such uniqueeffects may arise in some cellular systems, including
the induction of sister chromatid exchanges by irradiation of human lymphocytes before stimulation[ A l l , A4, S42] and the radiation induction of chromosomal instabilities in haemopoietic stem cells (K91.
There are also indications of qualitative differences inearly cellular changes during the development of
mammary tunlours in n ~ i c e[U25] and in other in vivo
effects [H33].

5.

Deviations from eonventionnl expectations

51. The conventional approach to estimating bothabsolute biological effectiveness arid relative biologicaleffectiveness at minimal doses is based on the assump
tion of constant alvalues fro111 dose region LI down
to zero dose and independence of dose rate. There are,in principle, many ways in which this may not be theMSC.

52. For single-cell effects, the assumption may nothold if there are significant multi-track processes in
the intermediate-dose region. Such processes could
include, for example, the induction of multiple independent steps in radiation carcinogenesis, cellular
damage-fixation processes and the induction of enhanced repair by small numbers of tracks. There isstrong evidence of induction of repair or amplificationof gene products in microbes IS411 and some such indications in mammalian cells [L15, W6]. Possibilities
that have been suggested to explain observed dose-rate
dependence of neutron-induced cell transformation
include promotion by multiple tracks or enhancementof misrepair [HlO], variatior~sof cell sensitivity withtime [B30, R5] and induction or enhancement of
repair [GS].
53. The general approach described in this Annex
would also need appreciable modification if the biological effect of interest required damage to more than
one cell or if it is influenced by damage to additional
cells. For example, van Bekkun~et al. [ V l ] and Mole
[MI41 have hypothesized that radiation tumorigenesis
involves the transfer of DNA from one radiationinactivated cell to an adjacent radiation-damaged cell.

In this case the true low-dose region 1 of action byindividual tracks alone would corrcspor~d to evenlower doses than in Figure 111, because the volumecontaining the target woulil nccd to be enlarged toinclude adj;icent cells. This two-cell hypothesis could
testable witti cpithcrnmi~l~icutrons,
be expcrirne~~tallywhose individual proton-recoil [racks are too short tohit the ~ ~ u c l ofe i two adjacent cells [G51.
54. Sor~leof the above processes allow, in principle,
for the possibility of a true tl~resholdin the dose-effectcurve, especially for low-LET radiation. The mostbasic, although not sufficient, condition for a true dosethreshold is that any single track of the radiation
should be totally unable to produce the effect Thus,
no biological effect would be observed in the true
low-dose region (region I), where cells are hit only bysingle tracks. There is little experimental evidence todemonstrate such a situation, although collaborative
studies in six laboratories on the induction of unstable
chromosomal aberrations in blood lymphocytes given
acute doses of x rays of 0, 3, 5, 6, 10, 20, 30, 50 and
300 mGy were able to demonstrate significant
increases in aberration yield at doses greater than
20 mGy. Below 20 mGy the observed dicentric yield
was generally lower than in controls, but notsignificantly so. Excess acentric aberrations and centricrings, on the otl~erhand, were higher than in controls,
although the increase was gcuerally not significant. It
was concluded that even though these studies involved
scoring chro~t~osome
aberrations in a total of about
300,000 metaphases sorile variation was observed
between the different laboratories involved, and thelack of statistical precision did not allow linear or
threshold models at doses below 20 mGy to be
distinguished [L14]. Data on the induction of stable
chromosome aberrations in blood lymphocytes fromindividuals of various ages have also been reported[Ll] for doses in the range 5 0 to 500 mGy. In lymphocytes from newborns chromosome aberrations increased roughly in proportion to the dose. In young
adults, however, aberrations were not detected at dosesof 5 0 and 100 mGy and for adults not even at
200 mGy. The difference in detection of aberrations
was attributed to a high background of aberrations inolder ages, compared with the newborn. Of the aberrations examined, one-break terminal deletions were thebest indicators of exposure at low doses.

II.

MULTI-STAGE MODELSOF CARCINOCENESIS
1. Multi-shge models

55. In order to become fully malignant, a cell needs
to undergo a number of phenotypic changes (seeAnnex E, "Mechanisms of radiation oncogenesis").

ANNEX F: INFLUENCE OF DOSE AND DOSE AATE ON STOCI IASTIC EFIZCTS OF WDIATlON

Evidence from diverse sources suggests that changes
can be considered as occurring in many stages. Thismodels that have been
Section dcscribcs quanti~~tivc
prcvio~rslydcvclo1)cd for multi-stage carcinogcncsis.
The true nature of ttic individual biological changes is
co~isidcredin more detail in Annex E.
56. The first stochastic multi-stage model for the
devclopnient of fill1 malignancy from a nornial ccll
was proposed in 1954 by Armitagc and Doll toaccount for observations that the age-specificincidence rates for many adult carcinomas were
proportional to a power of age [A8]. According to thismodcl, which has been widely used in risk assessment,a normal cell can undergo progressive deterioration ina finite number of stages to reach full malignancy.
The authors later proposed a two-stage nlodel in whichcells multiply exponentially after undergoing the firstchange and become malignant after the second change[Ag]. A similar two-stage model was proposed for
carcinogenesis in animals [N8].
57. None of the above models take into account thegrowth and development of the normal tissue. A
model that does include growth and differentiation was
proposed by Knudsen et al. for embryonal tumours[H24, K7]. This model has subsequently beendeveloped to a form that is claimed to give a goodqualitative description of the age-specific incidence
curves of all human tumours [M17, M38] and an
excellent quantitative fit to incidence data for several
human tumours that were tested [M42]. The working
hypothesis underlying this model is based on a genetic
regulatory schema postulated by Comings in 1973
[C27]. However, the formalism and parameters of themodel are not dependent on the particular biological
identitics of the critical targets and changes. According
to the schema all cells contain genes, termed"oncogenes", capable of coding for transforming
factors that can release the cell from normal growthconstraints. The oncogenes are expressed duringhistogenesis and tissue renewal and are normallycontrolled by diploid pairs of regulatory genes, termed"anti-oncogenes". A ccll acquires the malignant
phenotype when an oncogene is expressed at an
appropriately high level, owing either to inactivationof both of the appropriate pair of anti-oncogenes or bydirect activation of the oncogene itself. This latter may
occur, for example, if the oncogene becomes
positioned adjacent to a promoter as a result ofchromosomal rearrangement or viral insertion. This
two-stage model presupposes that human tumours
most commonly arise by mutations of the antioncogenes. Evidence for this process of carcinogenesis
comes from, among other things, analyses of familial
tumours, such as childhood retinoblastonla and Wilms'
tumour and adult familial polyposis carcinoma of thecolon. Studies of these tumours indicate that an

631

inactiva~ed anti-oncogcnc can be inherited, whichmeans that it is present in tliis stage in all cells of theindividual, greatly increasing the potential for
malignancy to develop. Ncverthclcss, in such anindividual at least one otl~crevent is necessary formalignancy. In a norr~ialindividual, whose cells carryoldy normal pairs of anti-oncogenes, at least twochanges should be necessary. It is recognized that thistwo-stage model may not apply to some tumours thatare due to direct oncogene activation and that rnay becharacterized by specific chromosome rearrangements,
possibly including lymphonla and lcukaemia [M42].

58. In this two-stage model, agents that act as
mutagens, to increase the probability of inactivating
either one or both of the anti-oncogenes, may be
regarded as tumour "initiators". Tumour "promoters"
may be assumed to modify cell kinetics and inparticular to encourage clonal expansion by greater
mitotic activity of cells that have undergone the firststage change, thereby increasing the chances that atleast one of them subsequently undergoes the second
change and hence becomes malignant [M41, M421.
59. To apply these multi-stage models to environmental mutagens, one or more of the rates of muiation, or of other changes, may be made a function ofdose [M38]. Dose rate or duration of exposure would
also need to be considered in relation to the kinetics ofthe nonnal and changed cells [M39]. When the twostage model was fitted to data on lung cancer in mice
exposed to a single acute dose of gamma rays, theresults were consistent with the hypothesis that brief
exposure to radiation acts by enhancing the rate of thefirst mutation in a proportion of the cells [C21]. It
might be expected that subsequent exposure, either by
protraction or as a later brief second exposure, would
also be capable of inducing by chance the second
mutation in those few cells that had undergone thefirst mutation.
60. A two-stage model of induction of osteosarcoma
by alpha particles was formulated by Marshall andGroer [M34] to f i t the entire dose-time-response datafrom radiation in nlan and dog. The model assumed
two alpha-particle-induced initiation events and asubsequent promotion event not related to radiation.
Competition by alpha-particle killing of cells was
included. The model predicted that the tumour rateshould become independent of dose rate at less than
10 mGy d-' and (hat over the lower dose range of theavailable data the rate would be proportional to dosesquared and at high doses becornc independent of dose(plateau). On the assumption that the two initiation
events arise from damage to two difierent structures in
the cell (rather than to one structure thar nlust bedamaged at two separate times), it was concluded thatat doses of less than 400-1,000 niGy the lumour ratewould be predominantly due to a linear component ofdose, because both structures are damaged by a single
alpha-particle track IM34, M351. In an earlier twostage model for radiation carcinogenesis, Burch [B35]
assumed that the two changes (regarded as chrornosome breaks) needed to be caused by radiation at
diffcrcnt times and, as a consequence, the turnour rate
at low doses depended purely on the dose squarcd.
61. The net effect of protracting of radiation
exposure would generally be dillicult to predict frommulti-stage models, because it would depend on acomplex conlbination of the effcct of dose rate oneach individual mutagenic or other change; the cell
kinetics, and therefore cell numbers, between thechanges; and whether or not there is a preferred or
required temporal relationship between the changes
themselves. Even wilhin the relative simplicity of a
two-stage model, clear expectations for dose and doserate dependence would require determining numerous
parameters of the model, including their radiation
dependence (dose, dose rate, quality), for the particularcancer [L24]. There is clearly scope, in principle, for
expectations of reduced effectiveness at reduced dose
rates, owing for example to reduced mutation rates at
each stage or to selective disadvantage in growth
kinetics for cells that have undergone the first change
relative to normal cells. Conversely, there is also
scope for expectations of increased effectiveness at
reduced dose rates, due for example to inaeased rates
of mutation at each stage (by analogy, perhaps, with
the increased transformation and mutation rates
reported with high-LET radiation in some in vifro
systems [H9.J2, M28, R131) or to selective advantage
and clonal expansion of cells that have undergone thefirst change. The range of possible expectations
becomes even wider in the likely event that carcinogenesis depends on more than two stages, particularly
if radiation as well as other environmental or spontaneous factors can play a role in a number of thesechanges.

2.

Thrtsholds in the dose-effect relationships

6 2 A necessary, but not sufficient, condition for an
absolute threshold in the radiation dose-effectrelationship is that any single track produced by theradiation is totally incapable of producing thebiological effect. This absolute criterion can beconsidered at three levels of changes in the carcinogenic process: the initial elementary physicochemical changes to biological molecules, therepairability and combinations (if any) of moleculardamage required to produce single-stage cellularchanges, and the combinations (if any) of separate
cellular changes required for a cell to reach fullmalignancy. Even when the criterion does apply,

multi-track cffccts rnay be sufficient to preclude a true~hrcshold,although the dose response should then tend
to zero slope as the dose tends to zero.
63. Biophysical analyses based on Monte Carlosiniulations of radiation track structure show clearly
that all typcs of io~~izing
radiation should be capableof producing, by single-track action, a variety ofdamage to DNA,includi~lgdouble-strand breaks alone
or in combination with associated damage to the D N A
and adjacent proteins [C26, G6, G201. In essence, thisis because all ionizing radiation produces low-energy
secondary electrons, and tl~esecan cause localized
clusters of atomic ionizations and excitations over thedimensions of the DNA helix. Hence, for these typesof early ~uolcculardamage there can be no real prospect of a threshold in the dose-response relationshipfor any ioi~izingradiation. This statement is even morecategorical for bigh-LET radiation, which is capable ofproducing even greater clusters of ionizations andexcitations over the dimensions of DNA and its
higher-order stnlcturcs (see Table 2 [G6, G201).
64. Expectations of a dose threshold for cellulareffects depend on the assumptions that are maderegarding cellular repair and the combinations ofmolecular damage that are required to cause the effect.
Very many different mechanistic biophysical models
have been proposed to explain radiation-induced cellular effects such as cell inactivation, mutation andchromosome aberrations. Solne of these models havebeen summarized by Goodhead [G3, G191. There hasdeveloped from these models a near-consensus that thebiologically critical damage by which single tracks canlead to cellular effect is dominated by local propertiesof the track structure over dimensions of 0.1-50 nm.
The mechanistic models variously assume that thecellular effect is the result of the following: DNA
double-strand breaks either singly [C5, C23, R12],
both singly and in pairs p7] or in larger numbers[G22]; pairs of DNA single-strand breaks [R15] orsimple damage to pairs of unspecified atoms such thatthe damage to each is due to single ionizations or
excitations only, independent of radiation quality [K6,Zl]; pairs of unspecified chromatin damage [H23,V4]; localized clusters of radiation damage in unspecified molecular targets, either singly or in targets ofdimensions similar to DNA [G16, G20] or nucleosomes [GI& G20] depending on radiation quality, or
singly and in pairs in targets of unspecified dimensions [C28]; unspecified single or double lesions,probably in DNA,but qualitatively similar independentof radiation quality IT211; multiple (two or more) ionizations in small structured targets 18361; or damage to
DNA and associated nuclear membrane [A7].In allthese mechanistic nlodcls a single radiation track fromany radiation is capable of producing the full damage
and hence the cellular effect.

ANNEX F: INFLUENCE OF DOSE AND DOSE RA,TE ON STOCI IASTIC EFECTS OF RADIAVON

65. In agreement with thesc mechariistic models.
track structure analyses, as well as sirnple linear extrapolations to low dose of nieasured biocheniicaldamage, indicate that a single track, even from tlle
lowest-LET radiation, has a finite probability of
producing one, or more than one. double-strand breakin a ccll (Table 3). Hence, cellular consequences of adouble-strand break or of interactions between then1should be possible even at the lowest doscs or dose
rates. This expectation would be contradicted for lowLET radiation only if cellular repair ol'small nunibersof double-strand breaks, even with associated daniage,
were totally efficient in all the cells. There is noevidence to demonstrate this, but existing experimcnta!
assays arc not able to test it extensively due to limited
resolution of types and quantities of damage.

66. In addition to mechanistic models of cellulareffect, as above, there are current phenomenologicalmodels based on correlation of effect with patterns ofradiation energy deposition over much larger distancesof -1p[B33, F12, H Z , KS]. Even these approaches,with one exception [ H Z , K5], agree that a single
radiation track can produce the cellular effect. The one
exception agrees for high-LET radiation, but it
assumes that for low-LET radiation the damage froma number of tracks has to accumulate before any cellular effect is possible. This assuniption leads to an
initial slope of zero, although not a true threshold.
Experimental support for this assumption is lacking.
67. Despite their very different assumptions andalmost without exception, these biophysical models
lead to the common view that a single track of any
ionizing radiation is capable of producing cellularchanges, including mutations and chromoson~eaberrations. On this basis no absolute dose threshold would
be expected for the individual cellular changes
responsible for individual stages of the carcinogenic
process. The difficulty of experimentally proving, or
disproving, this expected total lack of a dose thresholdfor single cellular changes is complicated by thepossibilities of adaptation or induced repair after small
numbers of tracks [C20, 18, M33, 0 3 , 0 4 , P8, S3,
S32, W6]. However, unless such "adaptation" is so
fast that it can act with total efficiency on the very
first track itself, it would not be able to introduce atrue dose threshold, although it might complicate theshape of the dose response at slightly higher doses andalso its dose-rate dependence.
68. The final level at which an absolute dosethreshold might exist is at the two (or more) stages of
two-stage (or multi-stage) carcinogenesis. The simplest
such situation would arise if the malignancy requiredthat radiation should bring about both changes and thatthey should be well separated in time. Then, one track
would be totally unable to achieve this, and so even633

would any single, brief exposure. If tlle exposure were
protracted or repeated, or if the time separation were
not required, but if a single track were still incapable,
then the slojle of tlie dose response would tend to zcro
as the dose tcndcd to zcro (as, for example, in a pure
dose-squared dependence), Although this would not
imply a true thresliold, tile risk would beconle vanishingly snisll at the lowest doses. There arc, however.
many ways in which thesc requirements could, in principle, be violated and thereby introduce a finite slope
without a threshold or vanishing risk. These include:
(a)

(b)

(c)

(d)

if malig~iancycould result from the two essentialchanges occurring at the same time from a single
track, especially if it were a high-LET track;
if one or other of the two changes could occur
spontaneously, or as a consequence of otherenvironmental factors, so that only one radiationinduced change was necessary, as suggested, forexaniple, when the two-stage model was fitted tolung tumours in mice after brief exposure toradiation [C21]; the occurrence of spontaneous
tumours does also indicate that all the changes
can occur without radiation;
if the cells of an individual already had one
change due to inheritance s o that only one
radiation change was sufficient for malignancy;
if the malignancy could result from a single
radiation-activated oncogene instead of solely
from a pair of inactivated anti-oncogenes;

69. In view of these many possibilities, it would be
difficult to conclude on theoretical grounds that a true
threshold should be expected even Gom multi-stage
mcchanis~nsof carcinogenesis, unless there were clear
evidence that it was necessary for more than one
time-separated change to be caused by radiation alone.
The multitude of animal and human data showing an
increase in tumours after a single brief exposure toradiation and also the occurrence of spontaneous
tumours in the absence of radiation, implies that theserestrictions do not apply in general. These theoreticalconsiderations cannot preclude the possibility ofparticular situations where the probability of an effectat low doses may be very small, and even practicallynegligible, compared with that at higher doscs. This
topic is considered further in Annex E, "Mechanismsof radiation oncogenesisn.
C. MECHANISMS OF DOSE-RATE EFFECTS
W MAhlMAIAAN CELLS

70. For low-LET radiation, dose rate has been shown
to be a major factor in the response of mammaliancells. Since the early days of cellular radiobiology, thesparing effeck of dose protraction have been intcrpreted as reflecting increased repair of induced cellulardaniage. Thc magnitude of dose-rate effect for ccll

UNSCFAR 1993 REPORT

634

inactivation varies between different cell strains; thisis reflected usually, but rlot always, by the cxtcnt of
the shoulder on acute dose-responsc curves [H2].

1. Repair of DNA dunloge

71. There is strong evidence fro111a rangc of in vilro
cellular studies that the most significant detrinicntal
effccts of radiation derive from its ability to damage
DNA in mammalian cclls (see Annex E, "Mechanismsof radiation oncogcncsis"), and if this is the case thenit can be assumed that the fidelity of repair of induccd
DNA damage is a major detemiinant of the dose-rate
effect, although there arc nlarry other factors involvedin the subsequent dcvelopnicnt of a tumour following
Ilrc initial DNA lesion. Direct evidence on this issue
has becn obtained through studies with radioscnsitive
mutants of nianimalian cells that carry defects in DNA
processing.
7 2 Ataxia-telangicctasia (AT) is an autosomal
recessive genetic disease with complex clinicalnianifestations [MlO]. Radiotherapeutic obscrvations
provide clear evidence of the in vivo sensitivity of
ataxia-telangiectasia patients to low-LET radiation.
Studies in vitro show ataxia-telangiectasia radiosensitivity to have a cellular basis, and for acute doses AT
cclls show a two- to tl~recfold iricrease in their
sensitivity to the leffral and clastogenic effects of
low-LET radiation [L5,TS]. However, most importantly, the ataxia-telangiectasia mutation(s) alniost
completely abolishes both the capacity of cells to
repair x-ray-induced potentially lethal damage and any
sparing effect of gamma-ray dose protraction. The
effect of the ataxia-telangiectasia mutation(s) on
hurnan cellular radiosensitivity was most dramatic
aftcr chronic gamma-ray exposure at a dose rate of
2 niGy min".; where aftcr an accumulated dose of
2 Gy, the number of unrcpaircd lethal lesions in anormal ccll strain was -0.3 per cell, while thecorresponding value for ataxia-tclangiectasia strains
was -5.0 [C12]. Thcsc data, together with those on
potentially lethal damagc repair after acute doses, havebecn used to argue that the rate at which cells sustain
radiation darnage is a major factor in the efficiency of
repair and that ataxia-telangiectasia cells are blocked
in a major radiation repair pathway [C12]. Biochemical studies so far appear to have failed to identify aconsistent DNA-repair defect in auxia-telangiectasia
cases, including DNA double-strand break rejoining[L5, T41. However, usirrg a niolecular assay based on
the cell-mediated rejoining of restriction endorrucleaseinduced DNA double-strand breaks in plasmid DNA
substrates, some evidence for reduced fidelity of
double-strand break rejoini~rghas been obtained in
Ihe Sv40-transfornied ataxia-telangiectasia ccll line
IC13, T4]. However, further studies failed to observea similar cffcct with a related plastirid [ G l l ] , suggesting Urat an apparent cffcct on overall lransfection
frequency is related not only to repair deficiency but
also to sensitivity of potential transfcctants to thc
selective agent. A reduction irr repair fidelity has also
been rcportcd i n a radioscl~sitive n i u t a ~ ~oft V79
Chincsc I~;~rnstcr
cells [Dl], but ll~crcare still no dataon dosc-riit~ effects in this niubnt. It might be
expected ll~atinaccurate repair of double-strand breaks
in viva might lead to inneased ionizing radiation
mutability. Ataxia-telangiectasia cells, however, shownonnal spontaneous or ultraviolet mutability, andalthougli they show increased chronrosome reanangen~entsfollowing exposure to ionizing radiation, theyshow eilhcr a reduced mutability or an increased
incidence of mutation similar to nornial cells [ G l l ,7221. In Annex E, "Mechanisms of radiation oncogenesis", it is rioted that cell rilutageriesis and DNA
repair data rnay be used to argue that oricogenic initiation following ionizing radiation may occur more
frequently through DNA deletions and/or rearrangements than through point n~utations.There is, however, insufficient evidence at present on this important
aspect of orrcogenic initiation.
73. A correlation between reduced dose-rate effects
for cell inactivation and deficiency in DNA doublestrand break rcpair has also becn established inradiosensitive mutants of CMO Chinese hamster cclls[ K l , T3] and L5178Y mouse lyniphonia cells [BlO,
E4, ES, WS], further strengthening the link between
dose-rate effects and the repair of a specific radiationinduced DNA lesion. In addition, some of the above
data also indicate &at the fitted initial slopes, a,,of
dose-effect curves are riot constant and may be
modified by cellular repair processes.
74. The extent to which radiation-induced DNA
damagc may be correctly repaired at very low doses
and very low dose rates is beyond the resolution ofcurrent experimental techniques. If DNA double-strand
breaks are critical lesions determining a range ofcellular responses, includi~rg perhaps neoplastictransformatioli, then it niay be that wholly accurate
cellular repair is unlikely even at Ihc very low lesion
abundance expectcd after low dose and low-dose-rateirradiation [TS].

75. Radiation-induced molecular damage to both
DNA strands at the same point has a finite probabilityof generatilrg a scission in the initial DNA substrate,with nuclcotide base modil'ications on both strands.
activity may remove these but, in
Repair c~rzyr~redoing so, it will create a secondary substrate thatcannot be retunled to its original undamaged form
without the prescnce ofthe necessary template [F3]. In
the absence of such aids to repair, the lesions will tend
to be nrisrepaired, producing ir~trachromosomaldele-ANNEX I.': INFI-UENCE OF DOSE AND DOSE R A E ON STOCIIASTlC EI:ECIS OF RADIAllON

lions or intcrchromosonial translocatiol~sthat arc thehallmarks of radiation danlagc in mammalian cclls(see Annex E, "Mechanisms of radiation oncogcnesis",and [El 1). The existence of such radiation-induced
double-strand DNA lesions, which may be cxtrcmcly
difficult to repair correctly, would in~plythe absenceof threshold for initial d;~mi~gc
to DNA, CVCII when
there arc very few double-strand breaks, and hence
absence of thrcsl~oldsfor stable changes to individual
cclls.
76. This postulate may be contrasted with that for
ultraviolet, whcre there is experimental evidence that
biologically critical cellular damagc arises as a consequence of the induction of ultraviolet photoproductsthat principally affect the nucleotidc bases on one
strand of the DNA duplex. Ultraviolet-modified bases
may be excised from lhc damaged strand by DNA rcpair complexes, leaving a gapped strand that may thenbe accurately filled with the appropriate nucleotides
using the coding sequence of the undamaged strand as
a template [F3,M2].
77. From a mechanistic standpoint such single-strand
damage excision proccsses, which also act on many
chemically induccd DNA base adducts, nlay be regarded as potentially error-free [M2], although even here
mistakes in copying may occur. Thus, although inprinciple the efficient (subsaturation) operation of
single-strand excision processes in cells could result inwholly accurate rcpair and ;I dose-effcct relationshipwith a threshold at low doscs, in practice such
thresholds are unlikely to exist for the initial damage
to DNA from ionizing radiation. Apparent low-dose
thresholds for the ultraviolet-inactivation and mutationof cultured human cclls have, howcvcr, been demonstrated [M2].

2.

Effect of dose rate

78. A number of studies have been reported on theinfluence of dose rate from low-LET radiation on cellmutagcnesis. In cultured rodcnt cells, radiation mutagenesis may be considerably reduced by dose protraction [T2, T5]. In contrast, in a human lymphoblast
system, continuous exposure to radiation from tritiatedwater [L6]or from daily exposure to x-ray doses~ 0 . 1Gy [ G l l ] failed to produce any rcduction in
induccd mutation frequency. This response may not,however, be characteristic of the response that would
be obtained for nonnal cclls in vivo. In human TK6cells, the llprr and tk mutation frequencies after acutex-irradiation and continuous gamma-irradiation (0.45
and 4.5 mGy rninm1)showed linear responses and nodose-rate dependency [K4]. The dose rate of 0.45
mGy min-' is one of the lowest used for mutation
studies of cclls in culture. While it is possible thatthese observations highlight a real difference between

635

human and rodcnt cclls in it low-dose radiation
response and in the potc~~tialfor rcpair, there arecomplex issues rcg;~rding dose-rate cffccts on ccll
n~utagcncsisUlat nccd to bc considcrcd [T5].
blcaber79. For tllc induction of u ~ ~ s t ; ~ cl~rornoson~crations (diccntrics and a c c ~ ~ t rrings)
ic
in human lymphocytcs by low-dose atld low-dose-rate radiation,
there has been co~~sidcrablc
interlaboratory variation in
aberration yield, so the nlagnitudc of any dose-rate
effect at low doscs is not clear [L14]. It has becn concluded, howcvcr, that at low doses, bking all data together, aberration yicld is probably linear with doseand independent of dose rate [El]. Recently, however,of a radiation-induced
observations on the cxiste~~ce
adaptive response in hurlla11 lymphocytes have raisedquestions about the response at low doses. In theseexperiments it has been shown, for example, that lymphocytes exposed to an x-ray dose of 0.01 Gy (corresponding to an average of 10 tracks per cell) become
adapted s o that only about half as many chromatid
deletions are induccd by a subsequent challenge withhigh doscs (e.g. [W7]). The mechanisms and gencrality of this potentially important post-irradiation
response have yet to be established, but it has beenshown that cellular protein synthesis is necessary forthe development of the adaptive response and that adose of 0.01 Gy from x rays reproducibly induces thesynthesis of a nurnber of cellular proteins (putative
repair enzymes) not found i n unirradiated lymphocytes[W7]. The effect of radiation on cellular processes has
recently been reviewed by Wolff [W4].
80. A number of models have becn published thatascribe the rcpair of radiation damage in the quadratic
region of the dose response to a rcduction in sublethalor submutagcnic damage. Thus, Leenhouts et al. [L20]modelled cellular damagc and its repair in terms of
induced DNA double-strand breaks; these may be
reduced in number in a cell either by the rcpair of
single-strand breaks or by the rcpair of double-strand
breaks, which might not always be perfect On thisbasis, three regions of the dose response can be
distinguished: an acute dose-rate region (>60 Gy h-I),
where exposures are very short compared with therepair rate of sublethal or submutagcnic damage andwhere a linear quadratic dose-effect relationship ismeasured; a region of protracted dosc rate, whcre theradiation effect decreases with decreasing dose rate;
and a region of lower dosc rates, where the rcpair ofsublethal damage is essentially complete and tllc doserate effect is cssenti;illy negligible. These different
be the sanlc for all ccll
regions will not ~~cccssarily
types. Sinlilar pattcn~sof response could be obtained,
however, if the feature of cellular response giving riseto the quadratic component included a component that
could be attributed to the saturation of repair
processes.

636

UNSCEAR 1993 REPORTp, are lillcar and quadratic tcrnm for cell killing. It
81. Guida~lceon expected effects at low doscs andlow dose rates can be sought froin the quantitativemodels that have been devclopcd to describe theavailable radiobiological alld epidemiological data.
Radiobiological data for effects on single cells undera variety of conditions have led to the developmentof many quantitative models, mechanistic or
phcno~nenological, for single radiation-inducedchanges in the cells. Multi-stage models of radiation
carcinogenesis, based on epidemiological or animal
data, assume that a series of two or more changes isrequired before a cell bcconles nlalignar~tand thatradiation can induce at least some of these changes.
The biophysical concepts underlying the different~iiodelscan be described in ternis of general featuresof target theory, because the insult of ionizing
radiation is always in the form of finite numbers of
discrete tracks. In this way fundamental expectation
can be sought on the nature of overall dose
responses, their dependence on dose rate and theirfeatures at the low doscs that are of greatest practicalrelevance. Radiation carcinogenesis involves complex
changes after the initial cellular damage. The cellulareffects and concepts of appropriate models have beenenlphasized in this Chapter. Other aspects, includingorgan effects, arc considered later in this Annex.

82. Dose responses can be subdivided into regions.
In region I, a negligible proportion of cells (or cell
nuclei) are intersected by more than one track andhence dose responses for single-stage effects can be
confidently expected to be linear and independent ofdose rate. In region 11, many tracks intersect eachcell (or nucleus), but multi-track effects may not be
observed in the experimental data, s o independent
single-track action is commonly assumed, although
true linearity and dosc-rate independence hinge on
the validity of this assumption. In region 111, multitrack effects are clearly visible as non-linearity ofdose response, and hence dose-rate dependence, islikely. The simpler forms of the dose-response
relationship can be expanded as a general polynomial, with only the dose and dose-squared terms
being required to fit most experimental data,
although sometimes a separate factor is added toaccount for competing effects of cell killing at higher
doses. The induction of an effect can then be
represented by an expression of the following form:

in which aland a, are coefficients for the linear andquadratic terms for the radiation response andandis generally assumed that at sufficiently low doses,
alwill bc constant irnd indcpende~~tof dose rate. In
this approach i t is conimon to regard the fitted linear
cocfficici~tas being constant and fully representativeof the response extrapolated down to minimally low
dose and dosc rate. However, there are in the literature d;~ta froni numerous studies that violate thissimple expectation, for both low-LET and high-LET
radiation. Many of these imply that multi-trackeffects can occur in the inter~ncdiate-doseregion (II)and that even when the dosc response appears linear
it may be dose-rate dependent and non-linear atlower doses.

83. Low-dose and low-dose-rate expectations basedon multi-stage processes of carcinogenesis depend
crucially on the detail of the radiation dependence of
the individual stages and on the tissue kinetics.
Expectations could, in principle, readily range
between two opposite extremes. On the one hand alinear term could be absent entirely, implying
vanishing risk as the dosc tends to zero, as should be
the case if two (or more) time-separated radiation
steps were required. On the other hand, there couldbe, right down to the lowest doses, a clear linear
term that even increases with decreasing dose rate, as
may occur if either of the stages can occur spontaneously and if there is clonal expansion between
them.

84. Consideration has also been given to thepossible existence of a true dose threshold in the
response to radiation. It is highly unlikely that a dosethreshold exists for the initial molecular damage toDNA, because a single track from any ionizing
radiation has a finite probability of producing asizable cluster of atomic damage directly in, or near,
the DNA. Only if the resulting molecular damage,plus any additional associated damage from the same
track, were always repaired with total efficiency
could there be the possibility of a dose threshold forconsequent cellular effects. Almost all of the many
biopliysical models of radiation action assume that
there is no such threshold for single-stage changes iri
cells. Multi-stage models of carcinogenesis could
lead to expectations of a dose threshold, or a
response with no linear term, under particular, highly
restricted sets of assumptions. Available data imply
that these restrictions d o not apply in general to all
turnours, although they may in some particular cases.
These fundamental considerations cannot preclude
practical situations where the possibility of effects at
low doses may be very small or where significant
tissue damage is necessary for particular types oftunlour to develop.

ANNW F: INFI-UENCE OF DOSE AND DOSE RATE ON STOCIlASnC EFIFCIS 01: RADIATION

11.

637

DOSE-RESPONSE RELATIONSHIPSIN EXPERIMENTAL SYSTEhlS

85. To provide an expcri~ucntalbasis for assessing
the effccts of dose rate on cnllccr induction in man.
information is aveilablc fro111 a 11u111bcrof sources.
Tumour induction in ani~nnls provides the main
source, but both the transformation of cells in culture
and the induction of somatic and gem1 cell mutations
arc also valuable for assessing thc influence of doseand dose rate on Uic initiating cvent(s) resulting fromdamage to DNA. The following Sections review
information from these areas of rescarch that are
relevant to considerations of dose-rate effects forcancer induction by both low- and high-LET radiation.
86. In the UNSCEAR 1986 Rcport [U2] information
on dose-response relationships for mutations, chromosomal aberrations in mammalian cells, cell transformation and radiation-induced cancer were reviewed.
Three basic non-threshold models were considered forbolh cellular effects of radiation and for cancer induction: linear, linear-quadratic and pure quadratic models(Figure IV). It was concluded that for most experiments and end-points the prevailing form of the doseresponse relationship at intermediate to high doses of
low-LET radiation is concave upward and can be
represented by an equation of the fonnin which a. is t l ~ espontaneous incidence, al and %are coefficienls for the linear and quadratic terms forthe specific cellular response and S@) is the probability of survival of transformed cells having received
the absorbed dose D.The probability of survival may
be expressed aswhere and & are coefficients of the linear and quadratic terms of ccll killing. For mammalian cells exposed to low-LET radiation, values of the parameteral/q for mutations and chromosome aberrations(equivalent to the dose at which the linear and quadratic terms contribute equally to the response) clusteraround 1 Gy (geometric mean, 1.27 Gy) while valuesof the parametcr p1/p2 for cell sterilization are
generally much higher, in the range 2-10 Gy (geometric mean 7.76 Gy) [B27]. The difference appears to be
due mainly to higher values of the linear term for cellkilling, in accordance with conclusions that, at least at
low doses, Ulc loss of proliferative capacity of cells is
caused by damagc that is not all observable as chromosomal changes at mitosis IB31, B381. Some may be
associated wilh less scverc damagc [B13].
87. An exaniple was given in the UNSCEAR 1986
Report [U2] of how the range of survival parameters

for ccll lilies of varying sensitivity for ccll killing
would affect the sl~apcof the dosc-response curve forturriour induction, and hcncc tllc reliability ofiate
extrapolation fro111risks obtained at i ~ ~ ~ c r ~ i i c ddoscs
to the low doses that arc generally of practicalconcern. In this analysis [U2], the C o ~ ~ i ~ i i i tselectedtce
two values of the al/a2quoticnt for tuniour yield (ormutation/aberration yield) applying to x rays andgamma rays: 0.5 Gy and 2.OGy. For survival
characteristics, the bone marrow stem cell was
selected as the most sensitive. Its survival curve is- &~ = 0.08 G ~ [El.
- ~described by fll = 0.4 G ~ andFor h e least sensitive cell, a hypothetical cell line wasassumed with survival parametcrs fll = 0.1
andp2 = 0.08 G ~ [B5].
- ~To normalize the d a b , a lifetime
cumulative incidence at 3 Gy of 150 cases per 10,000
population (150 lo4 G ~ - ' )was assumed. The resultsin terms of the cumulative tumour incidence fromdoses of 1 mGy to 4 Gy for all combinations of a,/%andare plotted in the upper part of Figure V. In
the lower plot of Figure V, the data have been
redrawn giving relative risks normalized to the samevalue of the al cocficient.
88. From this analysis, three conclusions can be
drawn. First, the sensitivity to ccll killing has a more
pronounced effect on the shapc of the dose-response
relationships than the a,/% quotient. Secondly, for thecells most sensitive to killing (S,,;,, minimal survival),
the relationship is concave downward, with maxima at
2-2.5 Gy. Since such curves are not observed forhuman cancers after exposure to low-LET radiation(i.e. reaching maximum values at doses of about
2 Gy), it seems likely that the assumed sensitivity is
too high for in vivo irradiation. This would beconsistent with the lower sensitivity of single cells
irradiated in situ. Thirdly, for the cells leastsusceptible to killing (S,,,maximum survival), theoverestimate of the tumour yield per unit dose at low
doses by linear extrapolation from 1-2 Gy down to
0.001-0.01 Gy ranges from 3.0-2.5 at a l / a 2 = 0.5 Gy,
to 1.2-1.3 at a 1 / a 2 = 2 Gy, respcclively.
89. The maximum overestimation of the risk resultsfrom totally neglecting cell killing. In such a case theoverestimate of the risk at low doscs from risks
observed at high doscs, D, can be calculated fromequation 12:

The extent of overestimation of the risk corresponds tothe dose and dose-rate effectiveness factor @DREF)
of ICRP 1121.

638

U N S C M R 1993 REPORT

90. Lincar cxtrapolatio~lfro1113, 2 and 1 Gy down toa low dosc of, say, 0.01 Gy for ccllular systems w i ~ ha riingc of a , / q quoticr~lsh c t w c c ~0.5
~ Gy aud 2 Gy
wol~ld U~us i~lvolvc the ovcrcsti~~latcsof radiationcffcct shown ill UIC Tablc below. Thus, for a ccll
rcspollsc wit11 all u l / u 2 quotient of 1.0 Gy, if tllc risk
is i~sscsscdat 2 Gy tl~cnlincirr cxlrapolation lo asscss
Ulc risk at low doscs will ovcrcstinlatc the risk
cocfficicnt by ;I factor of about 3. If thc risk isassessed a t 3 Gy, however, tile DDREF would be 4. In
practice, h e availablc cpidcmiological and cxpcrimcn-

gcncrally do not allow
tal data on luluour i~~cidcncc
rciiablc csli~natcs to hc I I I : I ~ C of u , and %, andtunlour i~~cidcncc
d:tti~111) to i~hout2 Gy arc frcqucntly
compatible wit11 lilrcar or lincar-quadri~tic modcls,
althougl~:I variety of tlosc-rcsj)onsc curvcs have beenobtained (Figurrs VII-XV). This typc of nlodcllingtl~attu~uourinducapproach docs, I~owcvcr,i~ldici~tc
tion ralcs at low doscs, whcn bascd on i n f o r n ~ a t i o ~ ~obtained at i ~ ~ t e r ~ n c d doscs,
i i ~ t c will, in t l ~ cabsence ofsignificant ccll killing, trlld to be overcstilnated bylincar cxtrapolalion.

DDKEF

20

25

91. Of concern for radiation protection is how
cellular damagc by ionizing radiation ~rlallifcstsitself
as long-tern1 effccts, with cancer induction andhcrcditary discasc bcing the main cffccis of conccrn at
low doses and low dose rates. The induction of
hcrcditary discasc by ionizing radiation may be readily
explained in tcnns of damage to the genetic material
that is manifcstcd in futurc generations. For cancer
induction in both animals and humans the situation ismore complex, because tumours in somatic tissue canarise many years aftcr cxposurc to radiation, followi~lg
dcvclopment through a succcssion of events. Expcrimentally, cancer caused by exposure to radiation or
olhcr agcnts appcars to bc thc result of a multi-stage
proccss. In the liver, skin, oesophagus, colon and othcr
complex epithelia the cancer induction process can beconsidered to consist of three stages: initiation,
promotion and progression, which are described in
Anncx E,"Mechanisn~sof radiation oncogcnesis". An
initiating event can rcsult from a single exposure to a
genotoxic carcinogen that altcrs a ccll or a group ofcells, giving a potential for cancer to devclop. Thisdamagc may be repaired but it may also be irrcvcrsible, although the cell and its progeny may neverdcvelop to form a tumour. This initial damage may
conform to single- or multi-hit models. Subsequent
exposure to tulnour prolnotcrs pennits the neoplasticchanges to bc cxprcsscd in initiated cells, with thercsi~ltLhat tumours dcvclol). Further sti~nulationnlay
thcrcforc aid tbc progression of the tumour. Sonle
chcn~icalagcrlls act as iniliators, s o ~ n cas promotersand olhcrs as both [A3]. Ri~dia~ion
can act in a dual
capacity, as cancers nlay sppcilr lliany years aftcr
exposure to radiation witl~outany furthcr radiation
stimulus, howevcr, a1 rclativcly high doses, radiation
damage to s u r r o ~ ~ n d tissue
i ~ ~ g nlay also play a pronlotional role in canccr dcvclopmcnt. Many other envi-

1.5

ronmental factors, i~lcludinghorn~ones,immunologicalfactors or cigarette smoke, nlay also play a promotingrole aftcr an initiating cvcnt.

92. The problcms in a s s c s s i ~ ~risks
gof cancer for
exposures to low-LET radiation at low doscs and low
dose rates, whcn human data arc available mainly athigh doscs aud liigl~dosc riitcs, were sunirnarizcd by
the NCRP [Nl]. The dosc-rcsponsc rclatio~~ships
areillustrated in Figurc I, which givcs scl~crnaticallydata
points and possible dose-response curvcs for cancer
incidence. Frequently, as in this example, data points
arc only availablc at rclativcly high doscs. The
approach cornlnonly used in risk asscssrncnt is to fit
a linear dose-response rclationship to the data
(curve B), a proccdurc that is usually considered togive an uppcr linlit to Ulc risk at low doses [C4,11,
U4]. If this lincar relationship is due to single tracks
acting independently, then the effect per unit dose (theslope of the line, a l l ,or risk cocfficicnt at high doses
and high dosc rates) would be expected to bc indepcndcrlt of dose magnitude and dose ratc. In practice,
howcvcr, this is not gcncrnlly the casc, and experin~cntal data suggcst dlat a lincar-quadratic rclationship(curve A) will frcqucntly provide a better fit to thedata, ilnplyir~gIllat d i ~ ~ n a gisc the result not only of
singlc inlcractio~~sbut also of othcr, more complex
interactions. Otl~cr explanations for the quadratic
function ill thc rcsporlse arc also possible, such as
saturation of rcpair proccsscs [T16].
With a progrcssivc l o w c r i ~ ~ofg tile dosc and/or thc dosc ratc, allowi ~ l gnlorc opportul~ity for rcpair of da~nagcand less
opporlu~ityfor interacting cvcnls, a point may ultimately bc rcachcd at which dami~geis produccd as ats
alo~lc,giving a linear
rcsult of si~lglcc v c ~ ~ ;~cting
rcspossc (curve D, slope aL)with tile c h c t proportiorla1 10 dose. A sinlil;~rrcsponse would be obtainedANN1:X F: INFLUENCE OF DOSE AND DOS13 KATE ON STOCIlASTlC EI:ITCTS OF RADIATION639

by lowering the dose rate alone, as eve11 at high total
doses, lesions accun~ulatemore slowly. Thus, experimentally, the effect per unit absorbed dose at low dose
rates (even at high total doses) would be expected to
become progressively less as tlle dose rate is lowered.
Hence, the limiting slope ( a L of Figure 1) would bereached either by reducing the dose to very low values
where tile effect is independent of dose rate or by
reducing the dose rate to very low values where theeffect is dependent only on the total dose. On thisbasis, even fractionated exposures will not necessarily
give slopes approaching aL, as the overall dose
response will depend on both the total dose and thedose rate per fraction.

epidemiological studies. In general, a significant
increase in tunlour incide~lcein expcrimcntal anin~als
is found at doses of about 0.2 Gy and above (seeSection 1I.A). Some radiation-induced cancers havebeen detected in human populations at relatively low
doses. Hunian data on cancer induction relevant toconsiderations of dose and dose-rate effects from lowLET radiation arc reviewed briefly in Chapter 111.

93. In practice, because of statistical limitations it isextremely difficult to detect radiation-induced effects
in the low dose range (c0.l Gy) at any dose rate; thus,
there are uncertainties in the determination of thelimiting slope, a L , in both animal and human studies.
The initial slope of the dose-response curve can be
more readily examined by changing the dose rate, as
can be done in studies with experimental anitnals. In
many experiments, however, even at low orintermediate dose rates, the limiting slope may not bereached, and a dose response in between the twoslopes a~and aLis obtailled with slope ahp.Despite
this limitation, animal experiments provide the bestindication of the extent to which lowering the dose
rate of low-LET radiation, even at intermediate orhigh total doses, can reduce the effectiveness ofradiation in inducing cancer. They therefore providc
the most useful guidancc on the extrapolation of risks
observed at high doses and high dose rates to the low
doses and low dose rates generally of concern inradiological protection.

96. Extensive studies in experimental animals havereported radiation-induced life shortening as a result ofwhole-body external irradiation and as the result of
intakes of radionuclides. This is a precise biologicalend-point that reflects the earlier onset of lethal
diseases: an increased incidence of early occurring
diseases or a combination of the two. To understandthe effects of radiation on life-span it is important toknow the underlying cause of death, although this isoften difficult and in some cases impossible, as deathmay be the result of a variety of causes acting
together. This is particularly the case in older animals,
in which multiple lesions are often present. In contrast,
in younger animals a specific pathological lesion canfrequently be identified.

94. The ratio of Ule slope of the no-threshold,"apparently" linear fit to the high-dose and high-doserate data (aH)to the slope of the linear fit to the lowdose-rate data (aL or aExp) has been used as ameasure of the dose and dose-rate effectiveness factor.
The terms dose-rate effectiveness factor (DREF) [Nl],linear extrapolation overestimation factor (LEOF) andlow dose extrapolation factor (LDEF) [P2, P3] havealso been used for this reduction factor. In this Annex,
the term dose and dose-rate effectiveness factor(DDREF) (or, more simply, relative effectiveness) will
be used for comparing the response at different dose
rates.
95. The data on tumour induction in experimental
animals that are most directly useful for the derivationof DDREFs for man are, surprisingly, very restrictedin their extent Significant effects have been obtained
mainly with intermediate or relatively high doses,
although at very different dose rates. Thus, only
limited evaluation of the shape of the overall doseresponse curve has been achieved, as is also true forA. TURIONGENESIS IN
EXTERIhlENTAL ANIMALS

1. Radiation-induced life shortening

97. Life shortening is an effect that must be
estimated by comparing irradiated and non-irradiatedpopulations. The different ways of describing andexpressing the effect quantitatively have beenreviewed in the UNSCEAR 1982 Report [U3].The
mean or median life-span, the per cent cumulative
mortality or the age-specific mortality rate may all be
regarded as compounded expressions of specific andnon-specific causes, acting within each individual todecrease fitness and ultimately to cause death.
98. There has been considerable discussion in the
published literature about the specificity or nonspecificity of life shortening in experimental animals
exposed to ionizing radiation. Life shortening must
ultinlately be due to an underlying cause, and the lackof specific information Gcquendy results Crom the lackof detailed pathology. A "specific" cause of death has
therefore been taken to mean that irradiated animals
die earlier than controls and show a different spectrumof diseases or causes of death. Since not all diseases
are readily induced by radiation, interest has centred
on whether or not radiation may produce life shortening by inducing tumours and how much of the observed shortening can be accounted for by neoplastic
diseases. The words "specific" and "non-specific" havegenerally been taken to indicate neoplastic and nonneoplastic contributions to life shortening.

640

UNSCEAR

99. Life shortening by r:~tliatioti was comprehensively revicwcd in the U N S C W 1982 Report [U3].
Although lire shortening can only be assessed on thebasis of death, an end-point that can be defined
precisely in time, it is usually more infornlative toknow the cause of death, as most irradiated animals
die of diseases that are unrelated to radiation exposure,complicating the identification of the terminal pathological syndromes. Some of the difficulties in interpreting niuch of the work were summarized in that
Report [U3]. Thcse included the lack of careful pathological observations on the animals at death or of arefined niultifactorial analysis, particularly in earlier
studies. So~tiestudies at low doses have even reported
life lengthening, although any increase has generally
not been statistically significant Another problem isthat even when good pathology is available, infonnation is usually collected at death, when it is impossible
to assess the contribution of each specific cause to life
shortening, since there is no reason to presunic that allcauses are equally accelerated by irradiation. While
serial sacrifice experiments might provide this information, they are time-consuming and expensive. The
additional erfort required to implement this technique
is considerable and, as a consequence, such information is uncommon in the literature.
100. Radiation-induced life shortening appears to havebeen f i s t described in the rat by Russ et al. [R9] andin the mouse by Henshaw [H18]. They reported that
irradiated animals had a shorter life-span and appeared
to age more rapidly than non-irradiated controls. Theseand olher studies led to the view that Ihe life-shortening action of radiation was due to its enhancement of
natural ageing processes. Early reviews of mammalianradiation injury and lethality by Brues et al. [ B B ]and
Sacher [S18] recognized that single acute exposures toradiation tended to displace the Gompertz age mortality function upward and chronic exposure throughout
life increased the slope of this function.
101. The concept that radiation-induced life shortening
might be equivalent to aging was criticized by Mole
[M44],
who considered that this view had arisen largely as a result of observations on surviving animals
given single large doses in the lethal range. The
similarities and differences between natural ageing andradiation-induced life shortening were considered by
Comfort [C16]. His review was a significant attempt
to differentiate bctween the various biological effects
observed. Neary [N3, N4] regarded theories of ageing
as belonging to one of two main groups: those interpreting ageing as due to random events in a populationof supposedly uniform individuals and those examining the individual and its component cells. He proposed a theory that ageing proceeds in two successive
stages, induction and development, each characterized
by appropriate parameters. Experiments reported later

froni the Soviet Union [V2, V3, V5, V6] tended toshow that induction consists of the spontaneous
occurrcnre of lesions in cellular DNA and that develop~neilt (promotion) results from tlic activation ofendogenous viral gcnonies by chen~icalcarcinogens orradiation.
102. The first experimental series that allowed
analysis of specific causes of death were those ofUpton et al. in 1960 [U27] in RF mice. The authors
could not, however, establish any clear-cut relationshipbetween life shortening and the incidence of turnours,as the dose-response relationships for different tumour
types varied: sonic incrcascd with dose and some
decrcascd. 'These data gave some support to the viewthat radiation could cause non-specific life shortcning.
A statistical evaluation of these data by Walburg in1975 [W8], using a method that allowed for competingprobabilities of death, indicated that life shortening,which was clcarly apparent when all deaths were considered together, disappeared when tumours were excluded froni the analysis. Table 4 shows the mean age
at death adjusted for competing probabilities of death,for deaths from all causes and from all non-neoplastic
diseases, of female RF mice exposed to 1 and 3 Gy of*CO gamma-radiation (0.067 Gy min") at 10 weeks
of age compared with data from controls. For thesemice, niyelogeneous leukaeniia, thymic lymphosarcoma and endocrine tunlours were induced or accelerated by irradiation. When only non-neoplastic causesof death were considered, there was no significant
effect on life shortening, and the mean age at death
increased in irradiated animals relative to controls.
103. In a scries of studies in mice Storer [S33] notedin the dose range 1-5 Gy from x rays a tendency forneoplastic diseases to occur earlier in irradiated thanin control mice. In extensive studies by Upton et al.
[U21, U28] in male and female RF mice exposed toeither fast neutrons or to gamlna rays, detailed pathology was not performed, but the authors consideredthat the death of irradiated animals was characteristically associated with tumours and degenerative diseases of old age, although the induction of neoplasms
could not entirely account for life-span shortening.
These data were subsequently analysed in more detailby Walburg [W8], who demonstrated that, in theabsence of tunlour induction, life shortening was
negligible, at least for exposure to ganlnia rays in thedose range of 1-3 Gy.
104. A nulnbcr of more recent publications have also
addressed the question of life-span shortening in mice.
have been that for doses ofIn general, thc co~~clusions
up to a few gray, life-span shortening is due to anincrease in turnour incidence. Thus, Grahn et al. [G23]showed that at doses up to 4 Gy life shortening wasdue to excess turnour mortality, although at higher

ANNE3 I:: INFLUENCE OF DOSE AND DOSE RA.TEON SMCIIASTIC liFlT,CIS OF RADIATION

doses dccrcascd lifc cxxpcclancy was not accompanied
by a parallel incrc;~sein tu~irour incidcnce. Maisin(M451 attributed lifc shortrsing in BALBIc and
C57BL mice at intcrnicdiatc doscs csscntially tothymic lymphonia and at higher doscs to glomcrulosclerosis. Sirililar conclusions lravc bcen reached byother authors [L21, L221 in studies with rats; and thesame is true for dogs in the series of Andersen et al.
[AS], according to an analysis by Walburg [W8].
105. For exposures to high-LET radiation similar
conclusions can be drawn. In an analysis of causes ofdeath in B6CF1 mice exposed to single and fraclionated doses of fission neutrons Thompson and Grahn
IT121 concluded that practically all (>90%) of thecxccss mortality could be attributed to tumour deaths.
106. From his comprehensive review of publisheddata, Walburg p 8 ] concluded that at the low to intermediate doses of practical interest in radiation
protection, life shortcning after irradiation may
principally be explained by the induction or accelcration of neoplastic diseases. This conclusion was
supported by Storcr [S19], although it was recognizedthat at highcr doscs other mechanisms were involvedin early radiation damage.
107. The majority of cornprcl~erisivestudies that givequantitative infor~nationon the effects of dose, dose
fractionation and dosc ratc on life-span shortening
have used the mouse as the experimental animal. Substantial diffcrcnccs in sensitivity have, however, been
noted betwecn strains and between the sexes. A reviewof 1 0 studies involving about 20 strains of mice given
single exposures to x or gamma radiation showed that
estimates of life shortening ranged from 15 to 81 days
G ~ - ' ,although the majority of values (9 of 1 4 quoted
in the review) were betwecn 25 and 45 days Gy" withan overall unweightcd avcragc of 3 5 days Gym' [G8].
In general, in the range Gom about 0.5 Gy to acutely
lethal doses, the dose response was either linear or
curvilinear upwards. In nialc BALBlc mice exposed toacute doses of I3'cs gamma rays (4 Gy min-I), life
shortening was a linear furrctiorr of dose between 0.25
and 6 Gy with a loss of lifc expectancy of 46.2 2
4.3 days G ~ [MS].
- ~ The eKccts of acute single doses
on life-span shortcnirig in other species are
summarized in thc UNSCEAR 1982 Report [U3].
108. The sensitivity to tumour induction has also beenshown to depend on age at exposure as well as thegender of the animals. Thus, the lifetime excess ofneoplasia in Sprague-Dawley rats following exposureoby a factor of
to gamma rays from 6 0 ~ decreased
about 10 in 9-month-old rats as compared to animals
irradiated in ufero, and the spectrum of tumours wasdifferent The higher incidence of tumours observed in641

the fetal-exposed group appeared to be rirai~rlydue tothe high sensi~iviticsof h e ccntr:~lnervous system a ~ r dgonads during organogcncsis. Diffcrcncm in tunlour
incidences were observed bctwccrr male and female
rats and bctwccn the incidences of primary cancers
and benign tumours irr the differcnt groups of animals[M29].
109. Partial-body irradiation is niuch less effective
than whole-body irradiation in causing lifc shortening.
Thus for female ddY/SLC niicc following hcad or
lower body exposure to doses of 1.9 G from x rays,
life shortening was 23 and 26 days Gy-! respectively,
with almost no further life shortcning up to 7.6 Gy.
After irradiation of the trunk with 1.9 Gy, life
shortening was 38 days G ~ - ' ,with a further increaseof 6 days G ~ at- doses~ up to 7.6 Gy. In contrast, forwhole-body exposures between 0.95 and 5.7 Gy, themean survival time decreased linearly with increasing
dose, with a loss of life expectancy of 37 days G ~ - ~[S37]. Extensive studies on the effects of incorporated
radionuclides have also shown a reduction in life-span
as a result of tumour induction resulting from intakesof radionuclides. Some of these studies are describedlater in this Chapter in sections which relate to effects
on specific organs and tissues. It is noteworthy that ina number of studies, where non-fatal tumours are
induced in particular organs and tissucs, this does notnecessarily lead to a loss of life-span (e.g. [M24]).

110. Summary. It may be concluded on the basis of
a number of studics that, although irradiated animals
do experience, on the average, a shorter life-span than
non-irradiated controls, the hypothesis that life shortening at low to intermediate doses up to a fcw gray of
low-LET radiation is due to the samc causes of death
as is normal in the animals (although appearing earlier
in time) is not substantiated by experimental evidence.
In general, life shortening as a result of exposure toionizing radiation arises largely as a reSult of anacceleration or higher incidence of fatal tumours inirradiated populations. At higher doscs that are wellinto the lethal range, a non-specific component of life
shortening becomes apparent from ccllular damage tothe blood vasculaturc and other tissues. This does not
imply that dose-response relationships for tumour
induction and life shortcning are directly comparable,
because even for h e samc radiation dose, the niean
latcnt period of some tuniours in a given species canbe influenced by a number of factors including thedosc, dosc rate, gender and age at exposure. Furthcrmore, some tumours that may be induced arc non-fataland do not influence life-span. If the induction of fatal
tumours is the main influence on lifc shortening,
however, then a comparison of survival following
various patterns of exposure should provide someindication of the effects of dose, dose rate arid dose
fractionation on lumour induction.

642

(n)

UNSCEAR

Dose fmclianetion

111. In the UNSCEAR 1982 Report [U3], theConimiltee reviewed data on fractionated exposures inwhich a give11dose ofwl~olc-bodyirradiation was split
into a series of doses given ia two or more fractions.
Tlie dosc per fraction, fractiorratiol~interval and tohl
tin~eof irradii~tionarc all i~rtcractingvariables thatcannot normally be scpara~ed.Frequently, therefore,
the coniparison is between a single exposure given
acutely and the same dose given in fractions over a
period of time. Fractionation of a given dose into two
equal or unequal fractions at an interval of about a day
or less has, in general, not altered life shortening
significantly, although such a dose-fractionation
schedule can decrease acute effects significantly [G8,M21]. Longer dose-fractionation intervals have been
more comprehensively studied. In some cases survival
has been unaltered or only slightly prolonged byfractionation [G8, K2, L16, U181; in others it wasslightly shortened [AS, C15, M221. Many of the differences are perhaps due to differences from one
animal strain to another in sensitivity to the inductionof various tunlour types, although a number of studies
have also demonstrated how the spectrum of diseases
that can result in life shortening may be influenced by
the pattern of radiation exposure. Thus, Cole et al.
[C15] examined the influence of dose fractionation on
the life-span of W 1 female mice. Animals were
exposed either to an acute dose of 6 Gy (250 kVp
x rays) or to about 7 Gy given in two, four or eightequal fractions separated by 8 weeks, 19 days or 8days, respectively. Irradiation shortened survival in all
the groups compared with controls, but the greatest
effect was seen in the group given eight fractions, forwhich the mean age at death was about 15 months
compared to about 21 months in the group given asingle exposure. This was attributed to an increased
incidence of lcukaemia in the eight-fraction group(39%) compared with the sin& fraction group (13%)
and the controls (29%). It was noteworthy that nephrosclerosis, which was the main cause of death in thegroup given a single dose (53% incidence) was verymuch reduced in the group given eight fractions (5%).
112. Dose fractionation at progressively longer
periods of tinle seenis to decrease the effects of radiation, but again lhc variability in results obtained has
been considerable [ A l , A5, G8. M5, M20. S17j. Ainsworth et al. [All rcportcd that exposing both male andfemale B6CF1 mice to fractionated doses of *CO
gamma rays (8.4 Gy total in 24 equal fractions over
23 weeks) produced an al~proxinrately threefold"sparingn effect compared to a sirrrilar (7.9 Gy) acutedose (corresponding to life shortenin of 45 days G ~ - 'for acute exposure and 18 days Gy' for fractionatedexposure) in both sexes. In contrast, Grahn el al. G8compared the cflects of 4.5 and 7 Gy froln C'!

fgamnia rays given as acute cxposurcs or as two fractions separated by tinie intervals between 3 l~oursand
28 days. No significant effect of dosc fractionation onlife shortelling was found, and the incidencc of leukacmia was not altered in any consistent way. In apreli~uineryexpcrilncnt, Silini et al. [S16] co~npared
Uie effecls of ;I single dosc of 5 Gy frorn 250 kVp
x rays on adult ~naleC3f-I lnicc will1 the same dose
given as two fractions (1.5 i~nd3.5 Gy) at different
intervals of time (4-48 hours). The results suggested
an increase in survival t i ~ n cwith increasing fractionation interval, but there was considerable variability inthe results obtained. The 50% cuniulative mortality forthe acutely exposed aninials was 450 days; for the
animals given fractionated exposures at an interval of
36 hours, it was 520 days.
113. A series of papers have been published byThomson et al. [T7,T10, TI21 that cornpare survivalof male BGCFl niice following single and fractionatedexposures. Mice were exposed to 6 0 ~ gammaorayseither as single exposures or as 24 or 60 weekly
fractions. With single exposures the average loss oflife-span was 38.5 2 2.9 days G~.', whereas with 24
weekly fractions it was 22.6 2 2.2 days G ~ - and' with60 weekly fractions 17.5 2 3.3 days G ~ - ' .This study
therefore showed that prolonged dose fractionation had
a significant effect on life-spiln, reducing the effectiveness of the radiation by a factor of about 2. Table 5summarizes s o n ~ eearly results on the effect of dose
fractionation on survival in rodents and beagle dogs.
114. Maisin and his colleagues have reported a seriesof studies on the effect of dose fractionation on survival in C57BI and BALB/c ~nicc.A preliminary study
compared the sun~ivalof C57BI mice given either asil~gleexposure to x rays (3.5 or 6.5 Gy) or four equal
fractions delivered at weekly intervals, with total doses
from 2 to 15 Gy [M19]. Although the r&ults for thetwo patterns of exposure were not striclly comparable,
as the cumulative doses were not the same, the datasuggested that life shortening after a fractionatedexposure was slightly greater (-20%) than after anacute exposure. The disease spectrum was also different for single exposure and fractionated exposure.
Thus the incidence of thymic ly~nphoma nearly
doubled with dose fractionation and that of reticulum
cell sarconia B increased even more, while otherdiseases decreased ill incidence.
115. Maisin et al. IM5, M47j reported a more comrehensive study in rnale BALBic rnice exposed to
P37Cs ganrnra rays (3 Gy III~II-I)
given eitlier as single
or fractionated exposures (10 fractions at 24 hourintervals) in the range 0.25-6 Gy. A significant
shortening i l l lice-span (1) < 0.05) was obhilred froma dose of 1 Gy for s i ~ ~ gexposuresleand from 2 Gy for
fractionated exposures. Both p;~tternsof exposure gave

ANNEX F: INFLUENCE OF DOSE AND DOSE RATE ON STOCIIASTIC EFFECE OF RADIAION

nearly the same lincar dependence of survival on dosewith a life shortening of 46.2 2 4.3 days Gy-' forsingle exposures and 38.1 2 3.1 days Gy-' for fractionated exposures (Figure Vl). After a single exposure n~alignantturnours were the principal cause ofdcath in the dose range up to about 2-4 Gy; detcnninistic cffects in the lung and kidr~eywere preponderant
at higher doses. In general, the total incidence ofmalignant tumours increased with dosc after fractionated exposures, compared with controls, but decreased
after single exposure. The difference between the twogroups was significant (p < 0.05), although neither
differed significantly from the controls. This waspartly accounted for by an increase in the proportionof animals with two or more tunlours after fractionatedexposures in the higher dose groups [M25, M471. The
main exception to this trend was thymic lymphoma,
where the incidence remained constant after fractionated exposure. This finding is contrary to observationsin other studies, as thyn~iclymphoma incidence can besubstantially increased by dose fractionation [K3,
M19] and may be explained by the lower doses per
fraction used in this study. Deternlinistic effects (e.g.
lung pneumonitis and kidney damage) appeared, however, to diminish significantly with fractionation, andthis may have allowed more tunlours to develop. In
this strain of mice there is, however, a high spontaneous tumour incidence (>60%) which could haveinfluenced the results obtained and which also limits
detailed analysis of the rcsults.
116. In a more rcccnt study [M20, M471, 12-week-old
CS7BICnb mice, for which there is a lower spontaneous cancer incidence, particularly with respect tothymic lymphoma and lung cancer, were given either
single or fractionated exposures (10 fractions separated
b 24 hours or 8 fractions separated by 3 hours) to'CS gamma rays (3 Gy mil<'), with total doses Gorn
0.25 to 6 Gy. The data on tunlour incidence and noncancerous late degenerative changes in the lungs andkidneys were evaluated by the Kaplan-Meicr procedure, using cause of death and probable cause of deathas criteria. In general, survival appeared to be a linear
function of the dose received in all the experimentalgroups, although survival was longer with fractionatedthan with single exposures (Table 6). Survival of thecontrol animals was shorter than in the previous
studies with C57BI mice and may have resulted fromthe use of specific-pathogen-frce animals that are moresensitive to non-cancerous late degenerative changes
in the lung. Life shortening, calculatcd by linear
weighted regression on dose of the values obtained by
the Kaplan-Meier calculiitio~~for survival time,amounted to 31.1 t 2.6 days Gy-' for a single
exposure, 19.6 2 2.9 days Gy-' for a 10-fraction
exposure, and 16.5 2 3.4 days G ~ - for' an &fraction
gamma exposure. Malignant rumours, particularly
leukaemia and including thymoma, as well as

'r

643

non-cancerous late degenerative changes were theprincipal causes of life shortening after a single highdose exposure to gamma rays. Fractionated cxposurcs,
in particular eight fractions delivered 3 hours apart,appeared to result in an earlier and more frequentappearance of Ieukacmia and solid turnours in therange 1-2 Gy, a finding sirnilar to Illat obtained with
BALB/c mice [MS]. Since the average life-span islonger after fractionation, earlier death after single
exposure may be attributed to the development of
non-cancerous late degenerative lesions. It was noteworthy, however, that following single exposures theincidence of all turnours except thymoma was significanlly less in the low dose groups (0.25-2 Gy) than in
the controls (Table 6). This was a significant factor in
the observation of an enhanced tumour incidence foranimals given fractionated exposures compared with
controls.
117. Summary. Studies on cxperin~ental animals,
mainly mice, have shown no clear trend in effects ofdose fractionation on life-span. The results from anumber of studies suggest that, when compared withthe effects of acute exposures, the effects of dose
fractionation are small and, at least for exposure times
of up to about a month, siniple'additivity of the injury
from each increment of dose can be assumed. In general, fractionated doscs were given at thc same dose
rate as acute exposures. For fractionation over a longer
time period there is a tendency to a longer life-spanwith a longer interval between the doses. A reduction
in life-span shortening by a factor of -2, comparedwith acute exposure, was obtaincd in one study inwhich the dose was given as 60 weekly fractions.

(b)Protracted exposures

118. There are far fewer studies of the effect of dose
rate on life-span in experimental animals. The majorityof studies have been undertaken in mice, allhoughsome work has also been reported with rats [R9], rabbits [B26], and beagle dogs [F13]. A number of earlystudies were described in the UNSCEAR 1982 Report[U3], but they relate mainly to early effects of radiation and do not provide any insight into the effects ofdose rate on tumour induction.
119. In a series of studics by Bustad el al. [B29]hybrid male mice (C57BLx101) were exposed for 8hours daily, between the ages of 6 and 58 weeks, tooeither 1 n ~ G yh-' or 2 mGy h-' from M ) ~gammaradiation giving total doses of 2.9 and 4.8 Gy. The
animals were then rnaintai~red for their normal lifespan. The average life-span for two subgroups ofanimals exposed to 1 mGy h-' was about 863 days
and for two further subgroups exposed to 2 mGy h-'it was about 875 days. The life-span of the control

6.44

UNSCEAR 1993 KEPORT

animals was about 920 days. Although there weresonic differences in Ule survival times between the
different subgro~ips of irradiated animals and thecontrols, no significant increase in turnour incidence
was observed in the irradiated animals.
120. Mole ct al. [M23] exposed female CBA niice togamma rays to give daily doses ranging froni 0.03 to
0.5 Gy for progressively longer tinies (froni four
wceks to the duration of life). The shape of the cumulative mortality curve depended systematically on theparticular level of daily exposure and on the cumulative dose, except possibly at the lowest daily dose.
However, the total doses received by the animals werehigh: 0.6-72 Gy, causing substantial tissue damage,and many of the aninials died of acute effects. It was
concluded that lower total doses were needed for examining the relationship between dose rate and the lateeffects of exposure. The experimental results are described in detail in the UNSCEAR 1982 Report [U3].
121. More comprehensive studies that are more
directly relevant to the effect of dose rate on life-span
and tumour induction were undertaken over many
years by Grahn et al. [G8, G9]. This work with micehas been summarized in a scries of publications. A
number of niouse strains and hybrids were exposed for8 hours daily to gamma rays in doses ranging from0.003 to 0.56 Gy per day. Exposures began when themice were 100 days old and continued throughout life
[G8, G9, Sl]. The results were analysed in terms ofthe nlcan survival timc after the initiation of the
exposures, designated mean after survival ; (MAS).
Thus, the MAS equalled the mean age at death minus
100 days. There was good consistency in the degree oflife shortening for cuniulative doses above a few graywhen expressed as the MAS, between and among thestrains as a function of daily dose. The MAS declined
exponentially with increasing daily dose. D (in gray),and could be represented adequately by
MAS (treated) = MAS (controls) e 4D (I5)
At the lowest daily doses, no consistent life shortening
was found, and in some groups there appeared to belife lengthening. This was possibly due to any effectof radiation being lost due to variation between theaninials (e.g. see Table 4).
122. This information on life shortening in mice
exposed at low dose rates has been compared with thatat high dose rates [Nl]. Since animals exposed at low
dose rates were exposed u~ltil death, the total dose
accuniulated by each anirl~iildepended on its survival
time. Thus. a wide range of total doses is represented
in the population exposed at any given dose regimen.
However, by calculating mcan loss of life-span (indays), in ternls of the mean accuniulated dose to
low dose range, life
death, it was shown that inshortening amountcd to 4 diiys G ~ - ' .This niay becompared with the reslllts of 10 studies sumniarized
by Grahn ct al. [G8], w l ~ i c giivel ~ all average of about
35 days Gy-' (range: 15-81 days Gy-') for acuteexposures, and tllosc rcportcd for BALB/c nlice [M5],which gave 46.2 t 4.3 days G ~ . 'at acute doses down
to 0.25 Gy.

123. Thcse data suggest that for radiation-induced life
shortening cithcr sil~glebrief exposures to low-LET
radiation or fractionated exposures at high dose rates
are about 8-10 times as effective as the same total
dose given in a long protractcd exposure at low dose
rate. In a review of sonic of Ulese data and allowing
for uncertainties, including the effect of age-dependent
decreases in sensitivity wiUi increasing age, it was
concluded by NCRP [ N l ] that protracted exposures
may be co~~sidered
to be one fifth to one tenth aseffective in the niouse as single, high-dose-rate
exposures (at total doses >0.5 Gy), assuming linearity
for life shortening in both cases.
124. The above analyses assumed a linear dose
response, with 110 Itiresliold, for doses above 0.5 Gy at
high dose rate. Storcr el al. IS131 have, however,reported non-linear dose responses for life shortening
in female RFM mice. Groups of niice were exposed toeither 0.45 Gy niinmlor 0.06 rnGy min-' from a 1 3 7 ~ sgamma-ray source to give a range of doses from 0.1
to 4 Gy and 0.5 to 4 Gy, respectively. Life shortening
was calculated by subtracting the mean survival timein each cxpcrimer~talgroup from the mean survival
time of the appropriate control. The dose-response~ ~curve for female RFM mice exposed to 1 3 7 ganimarays between 0.1 and 4 Gy at high dose rate
(0.45 Gy min-') showed that significant life shortening
occurred at doses of 0.25 Gy and above. There was a
rapid rise in life shortening with doses up to 0.5 Gy,
followed by what appeared to be a generally linear
upward trend with a much shallower slope in therange 0.5-4 Gy (Figure V11). In the region up to
0.5 Gy, the relationship between life-shortening anddose could be described by a dose-squared model (p >0.80) or a linear-quadratic niodel, with the quadraticcomponent predominating above about 0.04 Gy. These
mice appear to bc more sensitive than other mousestrains. Storcr et al. IS131 have speculated that acontributory factor may have been the barrier environment in which the mice were maintained, as Upton etal. [U20] found lcss life shortening in collventionallyhoused RFM female mice. For femalc mice exposedat the interrnediatc dose rate (0.06 niGy win-'), there
was a significant reduction iu life-span co~nparedwith
controls at all doses exaniined (0.5-4 Gy), and a linear
relationship adequately described the dose response(p > 0.5), with tlie intercept being not significantly
different from that for controls (Figure V11). The
weighted regression line to the intermediate dose-rate

ANNEX F: INFLUENCIJ 01:DOSIi AND DOSE WIT ON STOCI LhSTIC I i F K C E OF FbWIAllON

data at total doses above 0.5 Gy could be described by
the equation Y = 37.5D, where Y reprcsc~ltst l ~ edaysof life shortening and D is the dose, in gray. For thehigh-dose-rate data a weighted linear regression could
be lilted, giving an intercept of 57.5 days. The
equation of the line was Y = 57.5 + 46.3D. It was
concluded that the main difference in response at highand intermediate dose rates was an upward dispiacemen1 of the regression line at high dose rate, reflecting
an increased sensitivity at doses up to about 0.5 Gy.
At total doses of 1-2 Gy, protraction of the dose
reduced life shortening by about one half and at lower
doses by a factor of 2 to 3.
125. Thomson et al. [T8] have published inforn~ationon the sunrival of male B6CF1 mice exposed for 22hours per day, 5 days per week, to 6 0 ~ galnnlaoradiation at dose rates of 14-126 pGy min'l for 23 weeks,giving total doses behveen 2.1 and 19 Gy, or at 1463 pGy mid1 for 59 weeks, giving total doses
between 5.3 and 25 Gy. For deaths fro111 all causes,
linear dose-response curves were obtained with slopes,
corresponding to days of life lost per gray, of 15.8 5
1.6 and 7.7 t 0.2 for exposures of 23 and 59 weeks,
respectively. These values were not significantly
altered if the analysis was restricted to those nlice
dying with tumours, as about 90% of the radiationspecific mortality was tumour-related.
126. Thomson et al. [T8] conlparcd the data they'obtained in their study with data previously published[T7,
T10, T12j on mice exposed either to single acute(20-minute) exposures or to 24 or 60 fractions given
once weekly (20- or 45-minute exposures). The life
shortening coefficients for single, fractionated andcontinuous amrna exposures, expressed as days oflife lost Gy-', are shown in Table 7. Dividing the total
dose into 24 once-weekly fractions (total exposure
time: 18 hours) reduced the effectiveness of theradiation by about 40% 22.6 days lost G ~ - compared'with 38.5 days lost Gy- for acute exposure). Giving
the same total dose allnost continuously (total
exposure time: 2,530 hours) over 23 weeks reduced
the effectiveness by a further 30%. The effect of dose
protraction was more pronounced if fractionated andcontinuous exposures were carried out over about 60
weeks. Forty-five hours of fractionated exposure had
about 45% of the effect of acute exposure, and 6,490
hours of almost continuous exposure had o~lly20% of
the effect of the single exposure. Also shown in
Table 7 are the days of life lost per weekly fraction
for the different exposures. Thus the maximum
reduction in effect is obtained by compari~~g
acute
exposure with the effect of continuous exposure over
5 9 weeks, when the effectiveness is reduced by awill tend
factor of about 5. However, this compariso~~to overestimate the effects of protraction, as a fractionof the radiation exposure will not have contributed to

I

6.15

although it could have influenced
tumour i~~itiation,
tumour devclopmcnt. However, the extent of thiseffect, if any, is difficult to quantify. For comparing
the effectiveiless of differe~~t
pattenrs of exposure it
may, therefore, be more al)propriate to conlpare theeffect of co~~tinuous
and fractionated exposures given
over tlle same period of time. On this basis, areduction in effect in the range of 1.4-2.3 is obtained.
127. 111 an exte~~dedanalysis of the data on life
shorlcning obtained in mice exposed to acute or protracted exposure to low doses (less than a few gray) of
low-LET radiation, Scott el al. [S34] have developed
a model based on the assumption that life shortening
from late effects is caused mainly by radiation-induced
tumours. The state-vector model adopted for the analysis was kinetic in nature, with a two-step process
leading to partition of the irradiated population into
two groups: a group with radiation-induced tumours,
in which it was assumed that mean survival is relatively independent of the radiation dose, although thei~icidencein the population is dose-related and a group
without induced tumours, in which the mean survival
time is nearly identical to an unirradiated control
population. The results based on the model were in
reasonable agreement with the available experimental
data and were consistent with curvilinear doseresponse relationships for acute exposures as well aswith a reduced effect after fractionated exposure to
6 0 ~ gammaorays.
125. The effect of dose and dose rate on life-span has
also been. examined in rats [M43]. Male Spra ue
Dawley rats (3 i n o ~ ~ t hold)s were exposed to 'Ci
gamma rays to give 2.83 Gy 304 rats, 1.34 mGy h-I),
1 Gy (505 rats, 78 mGy h- ) and 3 Gy (120 rats,
78 lnGy h-I). The mean survival time of the controls
147 days) was greater than that of the two(837
groups of animals given about 3 Gy, but there was nodifference between the animals given high dose-rate
exposures (life-span: 738 5 160 days) and those
exposed at the lower dose rate (726 t 160 days).

+129. There are few studies that have exanlined theeffect of dose rate on life-span and tunlour induction
in large animals. Carnes and Fritz [C30] have reported
the results of a comprehensive study in young adultbeagle dogs exposed to "CO gamma rays to give total
accumulated doses of 4.5, 10.5, 15 and 30 Gy at dose
rates of 38, 75, 128 and 263 mGy d-'. Hazard models
were used to identify trends in mortality associatedwith radiation exposure. The probability of an acutedeath (related to haematopoietic aplasia) was positively associated with the total dose received and thedose rate. For late effects, although there was goodevidence. of an increase in tumour mortality relative tothe controls in all the irradiated groups, no relationshipwas found between tunlour mortality and dose rate.
There was, however, a clear relationship between

UNSCEARa 6tumour niortality and cumulative dose. This lack of adose-rate effect may be a consequence of the relatively
s111all range of dose rates used (38-263 mGy d"); in
the n~ajorityof rodent studies in which such an effectwas observed, the high and low dose-rate exposures
II.A.2).
varied by a factor of 100 or more (Sectio~~130. Surnmary. Experimental studies in niice havedcn~onstratedthat with protracted exposures over a
period of a few n~onthsto a year there is less life
shortening by factors of 2 to 5 compared with exposures at high dose rates. In two studies in rats andbeagle dogs no evidence was found for an effect ofdose rate on tunlour mortality. This lack of an effectmay be a consequence of the fact that the dose rates
used in these studies varied by factors of about 60(rats) and 7 (dogs), while in the rnouse studies theyvaried by a factor of 100 or more. It is noteworthy
that not all tumours are a cause of life shortening.
(c)High-LET radiation

131. Since the 1970s, the Argonne National Laboratory has carried out a series of experiments to examine
the effect on life shortening of brief, fractionated andprotracted neutron exposures. Early results by Ainsworth et al. [All indicated that fractionated fission
neutron exposures induced Inore life shortening inmale B6CF1 mice than did single exposures. Thus,
with a single dose of 2.4 Gy the mean survival timewas 636 + 13 days, whereas with fiactio~~ated
exposures (various schedules) survival was 553 ? 6 days
(controls: 838 2 13 days). At a lower dose of 0.8 Gy,life shortening was also reduced, but there was lessdifference between the two treatment schedules, although the data still suggested that life shortening was
greatest with fractionated exposures.
132. Data published before 1981 suggested thatregardless of the mode of exposure (single, fractionated or chronic) the RBE could be expressed by the
relationship RBE = AD^, where the value of B wasapproximately -0.5 and that of A (the RBE value at
10 mGy) ranged from 10 to 80, depending on a number of factors, including the inslantancous dose rate of
the reference low-LET radiation [T7, TlO]. This observation was compatible with suggestions that the RBE
increased over a wide range of doses as the inverse of
the square root of the neutron dose, to values inexcess of 100 [RlO].
133. h t e r studies at the Argonne National Laboratory
showed, however, that when total doses are low andlhe doses per fraction sniall, there is no significant
difference in life shortening between fractionated andsingle exposures IC18, T181. When the effects ofsingle brief exposures of male and female B6CFl
niice to 0.83 MeV fission neutrons giving total doses

from 10 to 400 inGy [TI51 were compared with theeffccts of 60 equal, once weekly exposures giving
doscs of fro111 20 to 400 mGy [T12], the doseresponse curves were linear and of siniilar slope
betwee110 and 300 mGy. Based on a linear-quadratic
fit to the data for fcnl:~le n~ice,the days of life lost
were 46 Gy" for single exposures arid 44 Gy-' for the
60-week fractio~ri~ted
exposure. Data for male micegave sin~ilarresulls but were less extensive [T12]. At
a dose level of about 400 mGy the dose-response
curve for single exposures starts to become less steep
and to separate from that for fractionated exposures.
Overall, a significa~~teffect of exposure pattern wasobserved at neutron doses ill the range 400-600 mGy.
Significant augnle~ltation of radiation damage withdose protraction was observed in both sexes fromdoses above -600 mGy. No difference in the doserespolrse curves for mice given 24 equal once-weekly
or 60 equal once-weekly exposures was obtained.
Although for exposure to neutrons the dose response
at intern~ediateto low doses was linear and independent of dose pattern, this was not the case for exposures to gamma rays. As a consequence, RBE values
from 6 to 43 were obtained, depending on the protraction period (1 day, 24 weeks or 60 weeks) [C18]. At
low doses there is likely to be a limiting value for the
RBE when the dose-response curves for both theneutron and the reference (gamma) radiation arelinear. For single low doses, this has been calculated
to be 15.0 t 5.1 for B6CF1 mice [T15]. In a supplementary analysis it was shown that practically all of
the cxccss niortality resulting from radiation exposure(93% r 8%) could be attributed to tunlour deaths[T12].
134. Results obtained by Storer et al. [S13, S27] at
Oak Ridge National Laboratory, using RFM andBALB/c n~ice were similar to those obtained at
Argonne Natio~~alLaboratory. Thus, female BALB/cmice were given total neutron doses between 25 mGy
and 2 Gy in a single brief exposure or in equal
fractions at either 1- or 30-day intervals. The neutrons
were those of a slightly degraded 23s~-fission
spectrum. After single or fractionated exposures, theextent of life shortening ilkcreased rapidly over the
0-0.5 Gy range a ~ then
~ d began to plateau. While nosignificant increase in effectiveness of dose fractionation on life shortening was observed at total doses
below 0.5 Gy, between 0.5 and 2 Gy there was anincrease. With protracted neutron exposures using amoderated *'*~f source giving dose rates ranging from
1 to 100 rnGy d", with total doses between 25 and
400 n~Gy,again no increase in effectiveness on life
shortening was observed at doses below 0.5 Gy. 11 wasalso co~~cluded
that life shortening resulted pri~narily
fro111ae increased incide~~ce
and/or an early onset ofnialigna~~t~reoplasms, particularly in the low tomoderate dose range [S27].

A N N M F: INFLUENCE OF DOSE AND DOSE RA

135. Maisin et al. [M20] havc reported tl~atfractions
ated exposures to high-crcrgy n c u t r o ~ ~(d(S0McV)Be:
8 fractions, 8 hours apart) appeared to have a slightly
but not signific;~nlly greater cffcct than sirlgle cxposures on life s h o r l e ~ ~ ini ~ nialc~ g C57BI niice at doses
up to 1.65 Gy. There appeared to be no significanl
difference ill turnour incidc~icc in the two groups,
although in animals exposed to 1.65 Gy ~nalignant
tumours appeared earlier with fractionated than withsingle exposures. Life shortening could be describedby a linear function of dose up to 3 Gy.
136. The results of lt~cscstudies on a number ofstrains of mice are all reasonably consistent andsuggest that the dose rcsponsc for life shortening
following exposure to high-LET radiation is a linear
function of dose, at least for total doses up to about
0.5 Gy, and that neither dose fractionation nor dose
protraction has much effect.
137. Summary. A number of studies in ~iiicehave
examined the effects of dose fractionation and protraction of neutron doses on life-span shortening. Most
recent studies have shown that when total doses arelow (<0.5 Gy) and the dose per fraction is small there
is no significant difference between acute and fractionated exposures. Data on protraction effects are rather
limited but again suggest that protraction of exposure
from high-LET radiation does not alter life-span
shortening.
(d)Sunlmary138. At radiation doses up to a few gray (low-LET),
life shortening in experimental animals appears to bemainly the result of an increase in tumour incidence,
although this could also be influenced by the early
appearance of some tumours. There is little suggestionthat there is a general increase in other non-specificcauses of death. At higher doses, into the lethal range,a non-specific component of life shortening becolncs
apparent due to cellular damage to the blood vasculature and other tissues. Accordingly, life shortening at
low to intermediate doses can be used as a basis for
examining the effcct of dose fractionation and dose
protraction on tunlour induction.
139. The majority of coniprel~ensivestudies on theeffect of dosc fractionation of low-LET radiation onlife-span have used the mouse as the experimental
appears to beanimal. The effect of dose fractionatio~~very dependent OII the strain of mouse and the spectrum of diseases contributing to the overall death rate.
For example, in some strains thymic lymphoma incidence is increased by fractionation [M19]. Where thisis a major contributor to the fatality rate, dose fractionation can result in a greater loss of life expectancy
than acute exposures. Overall thcrc is no clear trend in

the cffcct of dose fractionation on life-span shortening,
and the results fro111a nurnber of studies suggest that,when compared witti acute exposures, tile effects ofdose fractionation are sniall a ~ in
~ dsome studies havc
given either sniail increases or decreases in life-span.
However, at least for exposure times of about amonth, simple additivity of the injury fro111 each dose
increment can be assurucd. One study in mice hasin survival timc with eightreported that the rcductio~~
fractions given 3 hours apart is half that obtained withan acute exposure, although this was accompariied byan enhanced tumour incidence. For fractionation intervals over a longer timc thcrc is a tendency to a longer
life-span with an increasing interval between thedoses, but the variations observed are generally lessthan those observed with protracted exposures.
140. When the effects in niice of acute exposures to
low-LET radiation are compared with those of protracted irradiation given more or less continuously, it
is seen that the effectiveness of the radiation decreases
with decreasing dosc rate and increasing timc of exposure. With lifetime exposures h e r e is some difficulty
assessing the total dose contributing to the loss oflife-span. Thc results available suggest, however, thatwith protracted exposures over a period of a few
months to a year the effect on life-span shortening is
reduced by factors of bctwcen about 2 and 5, compared with exposures at high dose rates. The effects ofdose rate on tumour induction and life-span shortening
have also been exanlined in rats and beagle dogs, although no significant differences have been seen. In
these studies, however, dosc rates varied by a factor of
60 or less, whereas in the studies in mice they varied
by a factor of more than 100.
141. A number of early studies suggested that fractionated exposures to high-LET radiation induced
more life shortening than single exposures. Morerecent studies have shown, howcvcr, that when total
doses are low (c0.5 Gy) and the dose per fraction
small, there is no significant difference in life
shortening between fractionated and acute exposures.
Although the data are less extensive than for low-LET
radiation, the availablc information suggests that
protraction of exposure does not affect life-span
shortening.

2.

Tunlour induction

142. Infor~liation on radiation-induced tumours inexperinlerital animals was extensively reviewed in the
UNSCEAR 1977 Report [U4], in the UNSCEAR 1986
by Upton [U22] andReport [U2], by the NCRP [Nl],in a comprehensive nionograph on radiation carcine
genesis IU231. Despite a substantial body of researchpotentially available for analysis, there are in practiceordy a lirilited 11u1nberof studies on tumour induction
in experimental anin~alsfollowing exposure to lowLET radiation that can help to define the doseresponse relationship for cancer induction over areasor~abledose range and to assess the influence ofdose rate on tunlour response. Important inforniation
conies from a series of studies with mice reported by
Ullrich and Storer [Ull-U16]. Although these investigi11i01is covered turnour induction in a number oftissues, it is coevcnient to discuss the results fordifferent tumour typcs separately, in Ule context ofother studies. It should be stressed, however, that theexperinieiltal animals used in many studies are illbred
strains, with patterns of disease that are very different
from those found in man. One of the main differences
anlong mouse strains is their varying susceptibilities toboth spontaneous and radiation-induced tumours; furthermore, wi~hina given strain, there are frequenlly
sex differences in the incidence and time of onset of
specific tunlour types. For example, the commonlyused BALB/c strain has a very high incidence of spontaneous tumours, and the C57B1 strain has a much
lower incidence [M25]. A number of tumour types forwhich information is available are either not found inman (Harderian gland) or appear to require substantial
cell killing for heir development (ovarian tunlour,
thymic lymphoma). For a number of other tumours
there may be a human counterpart (myeloid leukaemia
and tunlours of the lung, the breast, the pituitary andIhe thyroid), but even here there can be differences in
the cell types involved and in the development of thetumour. Furthennore, the development of tumours inboth man and animals is subject to the modifying
influence of various internal and external environmental factors, all of which can potentially influence
dose-response relationships. There are also substantial
differences in the rates of turnover of cells and in thelife-span of the majority of experimental animals andman. Interpreting the results of animal studies andextrapolating hem to man is tl~ereforedifficult. Nevertheless, such studies can make an important contribution to understanding the influence on turnour induction of factors such as dose rate and dose fractionation, radiation quality, dose distribution, age, disease
and other internal and external agents. The use ofanimals to provide a basis for understanding factors
influencing tunlour i r ~ d u c t i o applies~~
1101 only toradiation but also to other agents such as chemicals
and is considered further in Annex E "Mechanisms ofradiation oncogenesis".
143. In assessing the influence of dose rate on tumour
induction, a particular problem is that the doseresponse relationship can vary substantially for different tunlour types (Figures VIII-XV) [U22]. As aresult, published reports describe the dose response interms of a wide range of functions. Where data fits are
given in the published papers that allow tultiour inci-

dences at differer~tdose races to be compared, theo ~ ~ 111other cases, however,relevant i ~ ~ f o r r ~ i aist igiven.
it has b c e ~necessary~
to fit the data reported. In
general, the nl)proach used has been to fit a linearfi~nctionto
data obtai~ledup to the highest dose atwhich there is no apparent influence of cell killing on
die tumour yield. Generally this is Lhe case for doses
up to 2-3 Gy Tor acute exposures, but for low dose
rates higher doses may bc used. In some cases themost appropriate dose ranges for assessing dose anddose-rate effectiveness factors (DDREFs) are not clear
from the data. In lhesc cases, data fits have been
calculated for a nu~nberof dose ranges.

144. The data from experimental animals on the effectof dose rate fro111low-LET radiation on tu~nourinduction that are described in the following Sections are
sum~narizedpri~lcipallyin Tables 8-10. Table 8 gives
best estimates of the DDREF for a range of tumour
types in different aiiimal species, together with inform a t i o ~on~ the dose rates at which the studies wereconducted and t l ~ edose ranges used for the calculationof the DDREF. Table 9 gives the results of fining thedata fro111 a nu~iiberof studies in mice over various
dose ranges, and Table 10 examines uncertainties in
the calculation of DDREF from studies in male andfen~alemice. Results from a number of individual
studies are given in Tables 11-15.

(a)Myeloid leukuemia

145. The effect of dose and dose rate on the inductionof myeloid leukae~niahas been examined in a numberof strains of mice. Upton et al. [U21]compared theeffect of a wide range of x- or gamma-ray doses in
RF mice in the dose range from 0.25 to -10 Gy. Malerilice were substa~~tiallymore sensidve than females,with ae increased incidence of the disease detectable
at 0.25 Gy given at a high dose rate (0.8 Gy min-l,
250 kVp x rays). The incidence passed through amaxiniurn at 3 Gy and declined at higher doses(Figure VIII). At doses up to about 1.5 Gy thei ~ ~ c i d e of~ ~thec e disease appeared to vary roughly withthe square of the dose, although a linear dose response
would fil the expcrimental rcsults up to about 2 Gy.
Low-dose-rate irradiation was much less effective thanacute exposure. At dose rates of 0.04-0.6 mGy min-',no significant l c u k a e ~ n o g c ~effects~ic
were evident at
a total dose of 1.5 Gy, although a significant increase
was found at a dose of about 3 Gy. The induction
period, as judged by rncan age at death of mice withthe disease, varied il~verselywith the dose and doserate, suggesting that the disease contributed to thein the life-span of the population.
overall reductio~~
The exposures at different dose rates entailed time
periods of between a few minutes up to about amonth, so age effects are unlikely to have affectedM N M F: IN17LUENCEOF DOSE AND DOSE fb?,TEON STOCIIASTIC EFI.ECTTS OF RADIATION

tumour response, and differences between acute a~rd
chronic exposures appear 10 be predominantly due todifferences in dose rate.
146. A linear fit to the incidence data up to 1 Gy inmale mice [U21] exposed to high dose rates (slope:
14.4% 5 3.2% G ~ - ' ) and to 3.1 Gy following low
dose rates (slope: 2.8% -t 0.8% Gy.l) suggests that
effectiveness at low dose rates decreased by a factorof 5.1 (Tables 8 and 9). A linear fit to the i~lcidencc
data up to 3.0 Gy at high dose rate (slope 14.3% -t
1.7% G ~ - ' )gave a similar result. In an earlier analysisof the high-dose and low-dose incidence data obtained
up to 3.0 and 3.3 Gy, respectively, a dose-rate effectiveness factor of 6.7 was reported [N I].
147. In female RF mice the incidence of ~nyeloidleukaemia following acute high dose-rate exposure was
highly variable, and no clear dose-response relationship was obtained, although an overall increase inincidence was found at doses of 1 Gy or more at
0.067 Gy min" (Figure VIII) [U12]. At low dose
rates, 0.004-0.7 niGy min-l, the incidence of myeloid
leukaemia (45%) in mice exposed to doses between
1 and 6 Gy was approximately double Lhat in controls(3%), but it showed no trend with increasing dose.
The variability in results obtained for mice at highdose rates makes any estimates of dose-rate effect very
uncertain. Based on a weighted least-squares fit to thedata obtained up to 3 Gy at high dose rates (slope
6.8% 2 2.0% G ~ - ' )and up to 5.8 Gy at low dose rate
(slope 1.04% t 0.38% G~.'), a dose-rate effectivenessfactor of 6.5 is suggested (Table 9). A somewhat
higher dose-rate factor (9.6) is obtair~ed if thehigh-dose data on myeloid leukaemia incidence arecompared with low-dose data over the range 0-6.1 Gy.

148. In contrast to these studies involving variatio~ls
in dose rate, Upton et al. [U19] also examined the incidence of myeloid leukaemia in male RF niice given
fractionated doses (2-3 exposures) of 0.75-1.5 Gy fromx rays at high dose rates and found it to be similar to
the incidence after single acute exposures. Robinson etal. [R3] re-analysed part of Upton's data on male RF
mice p 1 8 , U20, U211, considering those irradiatedwith 250 kVp x rays up to 4.5 Gy (-2,000 male mice)and correcting for competing risks. They obtained agood fit to the experimental data with a linearquadratic model having an al/a2value of 0.5 Gy anda P1/F2 value of 2.4 Gy. It appears from these datathat the decreased incidence of myeloid leukaemia at
low dose rate can be interpreted in terms of anincreasing linear component of the response and adiminishing quadratic component. The generalizationof these results to other tissues is complicated,
however, by the fact that the females are less sensitive
than the males; also, it has been shown that theincidence of myeloid leukaemia is influenced by a64 9nutuber of host factors, including genetic background,lronuonal status n~ldthe environmerlt in which theanimals arc nlaintai~~cdIU19, U201. Thus, animals
niaintained in a germ-free environment are lesssensitive to the disease than animals housed inconventional facilities. It is not clear, Urerefore,
whether tlre data suggesting dose-rate effects can be
i~rlluenccd by cnviroi~nie~italfactors irlvolved intumour illiliation or expression.
149. Ullrich and Storer [U15] have reported dose-rate
effects for myeloid leukaenlia induction in 10-weekold specific-pathogen-free RFM/Un female mice
exposed at 0.45 Gy min-' or 0.083 Gy d-I to 1 3 7 ~ sgamma rays. Comparative data on dose response wereobtained up to 2 Gy. Low-dose-rate exposure wasmuch less effective than high-dose-rate exposure; infact, no significant increase above control levels wasobserved at the low dose rate at doses up to 2 Gy. At
high dose rate, a significal~t increase in myeloid
leukaemia incidence above control levels was apparent
at doses of 0.5 Gy and above, although the difference
was only significant at 1.5 Gy or more. Even at 3 Gy
the incidence was only 5.2%. Although the data could
be fined with either a linear or linear-quadratic model(p > 0.5 and p > 0.8, respectively), the dose-squared
component was not significant, and linearity
predominated over the dose range used in the study[U13]. A linear model fitted to the high-dose-rate data
gives an incidence of 1.38% ?r 0.12% G ~ - ' ,while that
fitted to the low-dose rate data gives -0.050% ?
0.096% G ~ - ' , reflecting the lack of any significant
increase in incidence. The data therefore suggest adose-rate effectiveness factor of infinity with a lower
95% confidence limit of 9.7.
150. Ullrich and Storer [U13] have also given doseresponse data on male RFM mice exposed at
0.45 Gy n~in-' to total doses between 0.1 and 3 Gy.
Myeloid leukae~nia incidence was higher than infemale mice, and it was notable that the dose response
could again be fitted with either a linear or a linearquadratic model, with the linear component predominating over the dose range used in the study. The ratioof the linear slopes indicates that the sensitivity of
male RFM mice to myeloid leukaemia (I = 0.67 +
6.5D, where I is the incidence in per cent and D is thedose in gray) is greater than that of female niice (I =0.63 + 1.4D) by a factor of nearly 5.
151. The effect of variation in dose rate on the
induction of myeloid leukaclliia in male CBA/H micehas been exalnined by Mole et al. [M13]. This strainof mouse is exceptional in that no case of myeloid
leukaemia has been observed in more than 1,400
unirradiated male mice, so that every case occuning in
irradiated ani~llalscan be regarded as radiation-induced[HI71(see Annex E, "Mechanisms of radiation onco-

UNSCEAR 1993 REPORT

650

genesisn). Gro~lpsof rl~iccrrccived exposure to *CO
gamma rays col~tinuously ovcr a four-wcek period(0.04-0.1 1 n ~ G ywin-') or sillglc hricf exposures fivedays a wcek for four sucrcssivc weeks (0.25 Gy
niin-I) or a single hricf exposure (0.25 Gy minwl).
Total doscs wcrc 1.5, 3 or 4.5 Gy. The results of thestudy, sulnrnarizcd i n Table 11, demonstrate a dosedependent irlneasc in incidcl~ccof mycloid leukaemialswith conin the acutely exposcd a l ~ i ~ n a compared
trols, with a higher incidence than tllosc groups givcn
protracted exposure. Howcvcr, in the groups in whichradiation exposurc was sprcad ovcr a pcriod of fourweeks, cithcr continuously or in 20 equal fractions(giving differences in dose rate of several thousandfold), the incidence was the same, and within the dose
range used appeared indepcndcnt of the total cumulative dose. There is no obvious cxplanation for thisresult. Mole el al. [MI31 speculated that the rridcal
factor determining leukaernogenic frequency in thisexperiment was not the instantaneous physical dose
rate but some biologically important factor correlatedwith protraction. Nevertheless, the frequency ofleukaemia induction was already reduced by protraction of the dosc. As a corlscqucllcc of the lack of adose-response relationship for niyeloid leukaemia
i~lcidencewith protractcd exposure, in contrast to theresults for acute cxposure, the factor for reduction in
myeloid leukaemia induction at low dose rates varies
from 2.2 at 1.5 Gy to 5 at 4.5 Gy (Table 11).
152. Summary. Thcsc studies have shown that radiation-induced myeloid lcukacniia can be induced in
RFM and CBA mice, although tt~crearc differences insensitivity between the strains and between both sexes.
For dose rates varying by factors ranging fiom 100 to
more than 1,000, DDREFs bctwecn about 2 and morethan 10 have been obtair~cdfor doses in the 1-3 Gyrange given at high dose rates, but thcre is no
consistent trcnd (Table 8).

(b)Lung cancer

153. Information on the effect of dose and dose rateon carcinogcncsis in the respiratory tract Gom lowLET radiation has come rlioslly froni whole-body
exposurc of animals to x rays and gamnia rays. However, comparative data are also available on the effects
of inhaled radionuclidcs with different effective halftimes in the lung: these data provide funher
infonnation on dose-rate effects.
154. Tbe induction of lung ;~denocarcinomasat highdose rates (0.4 Gy mill-') and low dosc rates (0.06
mGy win-') has beell cornpiired in female BALBIc
mice (U12, U15] in the dose range 0.5-2 Gy. Tumour
induction was less at low dose rates than at high dose
rates. After high dose-rate exposurc, the age-correlated

incidc~~cc(%) could be rcprcsentcd by a linear
function [I(D) = 13.4 + 12D; p > 0.5); at low dosearalso gilvc a good fit to the data
rates a l i ~ ~ c fu11ctio11[1(D) = 12.5 + 4.3D; p > 0.81. Since lllc authors indicated here wcrc 110 cl~al~gcs
in sensitivity wiU1 age
ovcr tllc period of irradi;ltior arid t l ~ cd a b wcrc adjusted for diffcrcllccs in t l ~ cdistribution of ages at
deaUi amolrg t l ~ cvarious trcatmcnt groups, the diffcrcnccs ill slopc can be co~~sidcrcd
to reflect differcnccs in cffcctivc~lcssat tlic two dosc rates and suggcst a dose-rate cffcc~ivencssfactor of 2.8 (Table 8).
The data on lung tuniour illduction in lnice were
cxtcndcd in a further study [U24] which provided
information on the dose response at high dose rates(0.4 Gy min-l) in the dose range froni 0.1 to 2 Gy.
Although the tulnour incidence data could again be
fitted by a linear model [I@) = 10.9 + 11D; p >0.70)], they could also be fitted b a linear-quadraticmodel [I(D) = 11.9 + 4D + 4.3D , p > 0.701. In thisequation the linear tenn was very similar to thatobtained for low-dose-rate exposures, and it was
concluded that the result was in general consistent
with a linear-quadratic modcl in which the linear term
is indepel~dc~~tof dosc rate at high and low dose rates.

r155. Recently, Ullrich et al. [U26] tested thepredictions of the linear-quadratic modcl in a series ofstudies with BALB/c mice using fractionated exposurcs. Thc model prcdicts that fractionating an exposure using high-dose-rate fr;~ctionsbut with a small
total dose per fraction, w11icl1would lie on the predominantly linear panion of the dose-response curve,
would have all eCfcct similar to that obtained with lowdose rates. Mice wcrc exposed to total doses of 2 Gy
from 13'cs ga1n111arays given in different daily Gactions (0.1, 0.5, and 1 Gy) at high dose rate (0.35 Gy
min-l). The linear-quadratic dose-response curve forlung tumour induction gave an all% quotient of 0.93,
indicating that at doses of about 0.9 Gy, the al and a;!
terms contribute equally to the tumour response. At
doses substantially bclow this, the linear term should
predorninate, giving a tumour induction rate similar tothat at low dose ratcs (0.06 rnGy min-l) (Figure IX).
156. The resulb of the study are shown in Table 12,
which gives bolh the obscrvcd incidences of lungadenocarcinomas and those calculated fiom the predictions of a linear-quadratic model, on the assumptionthat Ulc effects of each dose fraction are additive andindepcndel~tof ear11 other. The lung tumour incidence
followil~gdaily fractioas of 0.1 Gy (group 3), which
would be on tllc linear cotn1)onent of the response
curve, was rornp;rrable to Ulat obtained following lowdose-rate cxposurc (group 2). If the dosc per fraction
was ir~creascdthc quadratic term would be expected toto the response, withrnake all irlcreasillg col~tributio~~an increase ill thc tunlour illcide~rceper unit dose, as
was indeed observed (groups 4 and 5), although not toANNEX P: INI:I-UItNCE OF DOSE AND DOSE RATE ON STOCllASTlC Iil'EClX OF RADIATION

the level obtained with a single cxposurc to 2 Gy at
high dosc rate (group 1). The results arc seen to bc
consislel~twith thc prcdictio~~sof tlic lincar-quadraticmodel, whicli call thcrcfore bc used to assess theeffect of dosc rate on tumour rcsponse at various
doscs and dosc ratcs. Tablc 13 gives botli total turnour
incidcncc and radiation-induccd cxccss tumours for arangc of doscs (0.1-3 Gy) ;~cln~inistcrcd
at both highand low dosc ratcs. The incidcncc of tumours has notbcen calculated at doscs abovc 3 Gy, bccause at highcr
doses cell killing is cxpcctcd to bccome significant. At
the lowest dose (0.1 Gy), the linear term dominates
and the tumour incidence is largely indcpcndent of thedose rdte (DDREF = 1.1). At highcr doscs, however,the quadratic ten11 becomes of increasing importanceat high dose rates, giving a DDREF of about 3.2 at
2 Gy and 4.2 at 3 Gy (mean: 3.7). These experimental
data illustrate vcry clearly the extent to whichlowcring the dosc rate can reduce the tuniour incidence. They also suggcst that for lung adenocarcinoma
in mice, a low dose, at which there is no significant
effect of dose ratc, is in the rangc 0.1-0.2 Gy.
157. Extcnsivc long-term studics on the cffccts ofinhaled beta- and gamma-cmitting radionuclides indogs have bccn rcportcd by McClellan ct al. [MI].
Groups of about 100 beagle dogs about 13 months old
were exposcd to aerosols of ii rangc of radionuclides
bound in fused aluminosilicatc particles and having
different half-livcs
64 hours; 9 1 ~ 58.5:
days;
1 4 4 ~ e285
: days; %r: 28 years) to give a range ofinitial lung contents. In this insoluble form, theradionuclides are poorly transportable in the lungtissue and do not readily translocate to the blood. The
different radioactive half-lives of the nuclides gave
effective half-timcs in thc lung ranging from 2.5 daysfor 9 to 600 days for %r. As a consequence, very
different dose rates were obtained for the same
cumulative dose (Figure X). For w ~ more,than 90%of the total dose to the lung was received within two
weeks of exposure, for 9 1 ~ about,
90% of the dosee 90~r,
was received by six months; while for 1 4 4 ~andonly 77% and 34% of the total doses were received by
one year. The dogs arc being observed for their active
lifetime, and the study is not yet complete. Some dogs
exposed to high radiation doses died early withradiation pneumonitis and fibrosis; others died latcr
with lung tumours. Tumours occurred with absorbed
doses to lung ranging from 11 to 680 Gy. Preliminary
data on the incidcncc rates of radiation-induced lungtumours have bcen rcportcd [GlO, H121. The
estimated risk cocfficicnts for lung tulnour induction
in dogs exposcd to 9 0 ~ 9, 1 ~1, 4 4 ~ande %r at times
up to more than 10 years after cxposurc were 0.036,
0.032, 0.011 and 0.013 Gym'.Thus, the relative risk oflung cancer in dogs exposed at the higher dose ratefrom 9 0 is
~ about thrce times the risk observed indogs exposed at low dose rates.

65 1

158. Silmrttary. Two studics in mice have four~dan
cffcct of dose and dosc rate OII lung tunlour induction,with DDREFs in the range of 3-4 for doses in therangc 2-3 Gy givcn at high dosc ratc. Studies inradiobeagle dogs cxposcd to inhalcd, i~~%olublc
nuclides wi& diffcrcnt cffectivc half-limes have givcn
a range of risk cacficicnts for induced lung cancer,
that varicd by a factor of about 3 bctwecn w ~ whichgave the highest dose rite, and ? S r , which gave thelowest (Tables 8 and 13).

(c)hinnininry tuniours

159. Maniniary carcinogcncsis in inbred strains ofmice is highly dependent on hormonal, viral, genetic,
immunological, dictary and environmental factors [S7,S8]. As a consequence, irradiation may affect manimary carcinogcnesis either directly, by affecting thecells of the breast, or indirectly by causing functionalchanges in the endocrine glands or by activating mammary tumour virus or other viral agents. In somemouse strains thcre is evidence that ionizing radiation
can induce marnmary tumours by "abscopal" effects,
i.e. tumours can be induced in the mammary tissueirrespective of the area irradiated [B19, S8]. Similar
considerations also apply in the rat. Rat mammary
tumours can be classified as fibroadenomas and adcnocarcinomas [Y3]. The incidcncc and proportion ofthese tunlour typcs is vcry dcpcndcnt on the strain of
rat irradiated.
160. The most extensive expcrimental data on the
induction of marnmary tumours by ionizing radiation
come from studies in Sprague-Dawley rats. However,in this strain of rat, which is sensitive to thc inductionof adenocarcinomas by radiation, there is a high spontaneous tumour incidence beyond about 15 months ofage, so that in many experimental studies a cut-off
period of approximately 12 months is imposed. Near
the end of life of these animals the total tumour incidence in controls approaches that seen in irradiatedanimals, with the result that the absolute excess incidence is increased minimally, if at all. Thus, it may bethat the effect of irradiation is to accelerate the appearance of tumours rather than to increase the overall incidence [C14, S8]. For rats of other strains and forother spccics the incidence of radiation-induced
mammary tuniours is lcss than in Spraguc-Dawlcy rats
[Ull].
161. In Spraguc-Dawlcy rats given whole-body
x-irradiation or %o gamma-irradiation at 1-2 monthsof age (0.25-4 Gy), the incidcncc of turnours at one
year increased as a linear function of the dosc IB17j.
Similar results were obtained by Shellabarger et al.
[S6] in the dose range 0.16-2 Gy with %o ganimarays. The incidc~ice of mammary tunlours in rats

1993 REPORT
dose rates has bcen
cxposcd to "CO at two dil'fcrc~r~reported by Shcllabargcr ct 111. ISIS]. Groups of rats
werc cxposcd at eid~cr0.0003 Gy tnin-' or 0.1 Gymin" to give total doses of 0.9 Gy and 2.7 Gy. In
alrinrals exposcd lo 2.7 Gy, tile irrcidcncc ofnlarnmary
was Iriglrcr in the high-dose-rate
adcrrocarcir~o~~ras
group (8/20, or 40%) llia~rin tlic low-dose-rate group(4135, or 11%). With an incidence in controls of
1%-2%, this suggests a dose-rate effectiveness factor
of about 4. Howcvcr, no effect of dosc protraction was
found in the low-dose group, and for both dosc Icvcls,
no protraction cffcct was observed for mammary fibroadenomas or total mammary tumours. The overall
incidence of tumours in the animals exposed at low
dose rate was also lower than in the aninials cxposed
at high dose ratc, largely because of the effect on
adenocarcinomas. Shcllabargcr ct al. [S4, SS] havealso compared mammary tumour induction in rats
given 4 5 Gy from x rays, either in a single exposure
or in up to 32 fractions delivered over a 16-weekperiod. No apparent change in the total tumour incidence was observcd with dose fractionation, but thismay have been because the total dosc exceeded thelevel at which the response reached a maximuni withsingle-exposure irradiation.
162. The incidence of mammary tulnours in SpragueDawley rats exposed at different dose rates has bcen
reported by Gragtmans et al. [G7]. Groups of approxicxposed
mately 120 SPF rats werc eitllcr cliro~~icallyto 200 kVp x rays ovcr a 10-day period, to give doses
between 0.3 and 2 Gy, or given acute exposures of 0.6
or 1.8 Gy over one hour. In all dose groups, total
tumour incidence was significantly greater than incontrols, and by 450 days the average number oftumours per animal excecdcd unity for the highest
dose groups followirrg both acute exposure (1.52
tumours per animal) and chronic exposure (1.14 peranimal) (controls: 0.17 per animal). The best fit to thedata up to 450 days was obtained with a linear function with cumulative tumour incidences of 78.3% 2
10.4% G ~ for- acute~exposure and 45.5% ? 5.4%
G ~ - for' chronic exposure. A linear dose response wasalso obtained for the proportion of animals wilh
tumours at 450 days with parameter values of 40.5% 2
0.4% G ~ - 'and 24.8% ? 2.4% Gy" for acute andchronic exposures, respectively. These results indicate
dose-rate effcctivcness factors in the range 1.6-1.7.
which is the same range in which other data on
manimary tumour induction fi~ll.
163. The effect of fr;~ctionatcd or single doses of
x rays has bcen reportcd for WAG/RIJ rats [B23]. The
rats were eight wceks old wlicn irradiated and were
kept until death. The frcquc~rcyof fibroadenomas andcarcinomas was based on histological examination.
Wcibull functions were fitted to the dose-response
data, and the probability of survival without evidenceof a tuniclur was calculated according to the L p l a n Mcicr life-tablc analysis. The analysis showed tllat
irradiatiorr accclcr:~tcd the appcarancc of fibroadc~ro~nas
and carcinoniiis. Fractionatio~rof the dose
(10 cxposurcs of 0.2 Gy ill one ~nolrllri~itcrvals)was
only ~ni~rginallylcss cl'fcctivc in respect of the effecton appearance t i ~ n cof ~ ~ i i l ~ i i ~carcirrornas
t ~ i ~ r y than asi~igiedose of 2 Gy; this stody, U~ercforc,provides noevidence for a reduction fi~ctor(kc. DDREF 1.1).
164. The effect of dosc ratc on niammary tunlour
induction in niice has been rcportcd by Ullrich andStorer [U12, U1.51. In fernale BALBIc mice exposed
to 1 3 7 ~gammasrays, groups of niice werc cxposed ateither a low dosc ratc (0.06 niGy n~in-l)or a highdose ratc (0.45 Gy min-l) to give total cumulative
doses of 0.5 Gy or 2 Gy. At both dose levels theirrcidelrce of Inamniary adc~rocarci~ronlas
could be adequately dcscribed by linear relationships and washigher at high dose rates [I(D) = 7.9 + 6.7D; p > 0.51
than at low dose rates [I(D) = 7.8 + 3.5D; p > 0.251(Figure XI). The ratio of the slope constants formarnmary tumours suggests a dose-rate effectivenessfactor of 1.9.
165. These data on niamniary tuniour induction wereextc~rded in a further study [U24] which provided
information on the dose rcspoasc at high dose rates(0.4 Gy min-') ill tlic dosc range fro1110.1 to 2 Gy.
The i~rcidenceof Inanrmary tulnours i~icreascdrapidly
ovcr the dosc range up to 0.25 Gy. At higher doses,
although there was some response, it was roughly flat.
The high initial sensitivity to tunlour induction was
surprising in the light of thc previous results [U12],
which, however, wcrc based on fewer data points anddoses no lower than 0.5 Gy. Taken together with theprevious data, the data obtained up to a dose of about
0.25 Gy were consistent with a linear-quadratic niodelof the form I@) = 7.7 + 3.5D + 1 5 0 ~ The~ . linear
term was similar to that obtained after low-dose-rate
exposures.
166. Ullrich ct al. [U26] have tested the predictions of
this linear-quadratic model in a series of studies wirh
fractionated exposures. The fit to the data gives an
al/a2quotient of 0.023, ir~dicatingthat doses as low
as 0.1 Gy will give a signilicant coritribution from thequadratic component. BALBIc niice wcrc exposcd tototal doses of 0.25 Gy given as daily fractions ofeither 0.01 Gy or 0.05 Gy. The incidence of mammary
tunlours for these two groups aed for o h e r grou s ofmice cxposcd at high dose rate (0.35 Gy mill- ) to
give total doses of 0.1-0.25 Gy and at low dose ratc
(0.07 nlGy niilr-') to give 0.25 Gy arc compared inTable 14 with tumour il~cidc~icespredicted by thelinear-quadratic arodcl. Acute daily fractions of
0.01 Gy gave a tulnour irrcidence sir~rilar to thatobserved following low-dose-rate exposure and inPANNM F: 1NFI.IJI~NCEOF DOSE AND DOSE RATE ON STOCI IASTIC E F E C J 5 OF RADlKIlON

good agreement with n~odclpredictions. 111 general the
results dc~iloristratcthat for nialiiniary tulnour induction, the effects of dosc fractionatioo call be predictedby dlc linear-quadratic dose-response niodel. The rcsponsc of this stri~iaof nlousc appears, Iiowcver, to hemarkedly diffcrc~~t
fro111 tll;lt of the rat strains described above, as a substa~~tialdosc-rate effect isapparent, with an iniplied DDREF at 0.25 Gy, thehigtiest dosc at wllich tumour incidence was measured,of about 12 (Table 15). In rats evaluation of the
DDREF was made at doscs up to about 3 Gy
(Table 8).
167. Summary. A number of studies have been published on the effect of dose rate on manunary tumour
induction in rats. These studies give DDREFs fromless than 2 to about 4 for dose rates varying by afactor of 150 or niore and for doses at high dose ratein the range from about 2 to 3 Gy (Table 8). One
study in mice gives an implied DDREF based on anassumed linear-quadratic response of about 1 2 at
0.25 Gy for dose rates varying by a factor of about
5,000, although interpretation of the data is limited by
the lack of information at higher doses.
(d)Pituitary tunlours

168. The effect of dose rate on the induction of
pituitary turnours in RFM rnicc has been reported by
Ullrich and Storer [U14, U15] for fernale mice exposed at hifh dose rates to 13'cs gamma-radiation (0.45
Gy m i d ) giving total doses of 0.1-3 Gy. The incidence of these tumours with radiation dose was foundto increase at doses of 0.5 Gy or higher, although the
response was sonlcwhat irregular and did not differ
significantly Gom controls, even at 2 Gy. The incidence rcmaincd at approximately control levels(6%-7%)
over the range 0-0.25 Gy, increased to9%10% at 0.5 Gy, rcmaincd at that level over therange to 2 Gy, and increased to 20.9% at 3 Gy. Botha linear model [I@) = 5.7 + 4.4D; p > 0.2) and alinear-quadratic model [I@) = 6.3 + 0.8D + 0 . 0 1 3 ~ ~ 1
adequately described the data. Lowering the dose rate
to 0.06 rnGy m i d 1 resulted in a reduced tumour incidence up to a total dose of 2 Gy; this incidence wasbest described by a linear n~odel[I@) = 6.3 + 0.73:
p > 0.951. When the linear dosc responses fitted at low
arid high dose rates were compared, low-dose-rate
exposures were found to be less effective in inducing
pituitary tumours, by a factor of about 6 (Table 8).
However, if a linear-quadratic response is assumed
after h i h dose-rate exposure [I@) = 6.3 + 0.8D +0.013D 1,-then the linear term is simili~rat botb dosc
rates, suggesting that the primary effect of dose rate is
to alter the dose-squared component. Male RFM mice
were exposed only at the higher dose rate, and theincidence of pituitary tumours was too low to warrant
analysis.

8653

169. Sunrnrary. Oilly one study has been publishedthat allows an cstiniatc to be made of a DDREF forthe induction o l pituitary tunlours. In fc~nalemice, avalue of about G c;~nhe obtained for doscs up to about
3 Gy give11 at high dose rate and for dose rates thatdiffer by a factor of about 8,000.

(e)Tllyroid tunlours

170. Thyroid cancer in animals can be i~lducedby
iodine deficiency, chemical carcinogens, and goitrogens, and exposure to ionizing radiation. Information
is available from hulnan populations on the effects ofboth external radiation and internal radiation fromintakes of iodine isotopes; it suggests that 1 3 1 ~is lesscarcinogenic than external radiation (see Chapter III),although whether this is due solely to dose-rate effects
or to other factors as well is not clear. In principle,
animal studies should be able to provide informationon the relative effects of external radiation and l3'1,
but in practice the reported results present somedifficultics in interpretation, and there are species
differences in the way thyroid canccr is expressed.
171. Doniac [D4] reviewed a series of studies in ratsthat could be used to compare the tumorigenic effectsof x r a y s and 13'1. Results from three studies
suggested that the carcinogenic effect of 11 Gy fromacute x-ray ex osure was comparable to that of
1.1 MBq of 134, which would give a dose to thethyroid of about 100 Gy. The dose rates are substantial, and significant cell killing might be expected,
although higher doscs of 1 3 1 ~are needed to cause
atrophy. With this proviso, the data suggest that
protracted irradiation from 1311 is less damaging, by afactor of about 10, than an acute dose of x rays.
172. Walinder [W2] con~paredthe carcinogenicity of
x rays arid 1311 in adult CBA mice. His results indicated thatwas one fourth to one tcnth as effective
as x rays for the production of thyroid adenomas andcarcinomas; doses from x rays were 15 Gy and from1311, 64-160 Gy. He also found that at somewhat
lower doses (10 Gy from x rays and 22-110 Gy from131~),1311 was one half to one tcnth as effective as
x rays.

173. Whether this diflcrcnce in effect is due solely todiffcrcnccs in dosc rate is difficult to dctcnnine, as anumber of factors influerice the dosimetry of 1311 [C8,D4, Jl], As a consequence of the small mass of the
thyroid in the rat or nou use, considerable beta-radiation
is lost from the peripheral portions and h e isthmus.
Thyroid cells near the surface may receive as little asl
an effect that
50% of the dosc to the c c ~ ~ t r acells,
becomes niorc important as the gland size decreases.
Unlike the dosc from external radiation, the dose from654

UNSCMR 1993 REPORT

intakes of 13'1 nlay be hctcrogcneously distributed
owing to variation in uptake bctwecn follicles, although Walindcr cl al. [ W l I have re ortcd mcasurcnients of the dose distribatio~~for "1 andinmouse thyroid and found i t to bc gcncrally unifomi,
but wilh dccrcascs at the tl~yroidcdgcs, as would be
cxpcctcd for a uniform c o ~ ~ c c ~ ~ t r a tWalindcr
ion.
ct al.
[ W l ] also observed a si~nilarcffcctivcness of 1 3 2 ~(TIA
2 2 h) and x rays on l t ~ cthyroid in the inhibition of
goitro en-stinlulatcd growtl~in the CBA mouse andwas one half to one tenth as effective asthat 1'x rays. Book et al. [B14] observed in die SpragueDawley rat a difference in cffcctiveness of 13'1 to 1 3 2 ~o l about 1:9, in terms of average thyroid dosc, for the
suppression of thyroid gland weight i~lcreasestimulated by goitrogen. The dosc distribution in the thyroid
gland is similar for the two radionuclides, and theobserved difference in radiation is likely to be due todifferences in dose rate. Liu ct al. [L2]found that thetumour incidence was lower following exposure to
l3'1 than 1311. Although this difference ma have been
panly due to higher radiation doscs from 1' ,the doserate may have also been a factor in the response.
Since 13'1 uptake by the thyroid in laboratory animals
varies with environmental temperature and the dietary
content of stable iodide, the administration of similar
amounts in separate expcrinlents in different laboratories may give rise to varying doses. The usualassumption, for dosirnetric purposes, of a single
exponer~tialfunction for loss of activity from the gland
may also result in some uncertainty in the calculated
doses, although by a factor of less than 2 [C8].
Despite these uncertainties, it seems likely that thedifferences in the incidence of cancer resulting fromintakes o t 13'1 and froni exposure to external radiation
cannot be readily explained by differences in dose
distribution.

-

174. In a subsequent study, Lee et al. [L4]comparedtumour induction in six-week-old female Long Evansrats given 13'1 or localized x-irradiation of the thyroid.
Three groups of 300 rats were injected inka eritonally with 18, 70 and 200 kBq of sodium P311iodide, giving thyroid doses of 0.8, 3.3 and 8.5 Gy(maximum dose rates: 0.17, 0.69 and 1.6 mGy min-l).
Three furthcr groups received localized (colliniated)
x-ray exposures of the thyroid gland giving doses of
0.94, 4.5 and 10.6 Gy (dose rate: 2.8 Gy min-I). Six
hundred animals wcrc kept as controls. All the animals
surviving to two years (-62%) were killed, and a sixmonth minimum latent pcriod for radiogenic thyroid
cancer was assunled. The doscs from 13'1 in this study
were considerably lower than those in thc earlier ones.
Exposure to 13'1 was found to be about 40% as effective as x-irradiation at the highest dose for the
production of adenonias, but there was no significant
difference from x rays at the lower doses. For the
production of thyroid carcinomas the two radiations

appear to be of cqual cffcctivcncss at all three doses,
alll~oughlhc statistics wcrc sucll that the results do not
exclude a two- lo tl~rccfolddil'fcrcncc i11 tllc effcctivc~lcssof x rays and 13'1,
175. l'f~cscdiffcrceccs ill cffcctivcncss obscrved in
the studics by Lcc ct al. [Ujand the carlier rat
studics arc not easy to cxpli~in. They niay reflect
differc~lccsin the doses used, in the ages of a ~ ~ i n i aor
lsgrats are also
in the strains of rats. Fe~ualcI ~ n Evansmorc se~~sitivc
1l1;ln males, which has been attributed
to hormonal fluctuations. Thc rcsulls of Lee et al. [LA]provide probably thc largest single body of information on thyroid cancer induction by I3l1 or x rays inan animal model. Furhermore, the dose range was low
and more relevant to the assessment of risks from lowlevel exposures. That study, however, terminated at
two years, rather than a l l o w i ~ ~theg animals to live out
their natural lifc-span. This may have prevented theappearance of sonic late tumours, an important feature,
as about two thirds of the anirnals remained alive at
the end of the two-year study.
176. Surnrnary. Arrinial data do not support large
differences between 13'1 and x rays for thyroid cancer
induction for doses below about 10 Gy. Early cxperiments that indicated differences of up to a factor 10
were at doses that would 11i1vc caused appreciabletissue damage. However, differences in tumour
response of a factor of about 3 between 13'1 andx rays cannot be rulcd out.

(0 Liver tunlours
177. Di Majo et al. [D3] have reported dose-response
relationships for liver tumour induction in BC3F1 malemice. Three-month-old niice were exposed to x rays
(0.133 Gy min-l) in graded acute doses from 0 5 Gy
to 7 Gy. A significant increase in liver tuniours wasobserved from 2 Gy, and the dosc response was best
fitted by a pure quadratic response [I@) = 11.3 +1 . 2 ~ (Figure~1XI]). Although the animals were notexposed at diffcrcnt dose rates, this pattern of dose
rcsponsc would imply that tumour induction would be
rcduccd at lower dose rates.

178. The induction of Hardcrian gland tumours at
different dose rates has bee11 cxarnined i n RFM niice[U12, U14, UIS]. This iefonnatio~~is included here
although it is noted thatfor the sake of cornpletc~~css,there is no human counterpart to this tu~nour.The data
are, however, co~rsidercdto be relevant to understanding the overall response of tissues to radiation.
Low-dose-rate exposures (0.06 ~ n G ymin-l) were lesseffective than high-dose-rate exposures (0.45 Gy

ANNEX F: INFLUENCE OF DOSE AND DOSE RATE ON S'TOCIIASnC EFFECTS OF RADIATION

niin-l), wiUi i~lcidencesat 2 Gy being significantly
different for the two treatments (Figure XI11). Doseresponse relationships at high dose rates suggested alinear-quadratic model for both niales [I@) = 1.5 +0.3D + 0.012D2; p > 0.991 and females [I@) = 1.2 +1.5D t 0.022D2; p > 0.251, illtilough lincarity could
only be excluded with confidence for females (p <0.05). At low dose rates, a linear dosc response gave
the best fit to the data for female mice [I@) = 1.2 +1.5D; p > 0.91, suggesting, as in the case of p i t u i ~ ~ r ytumours, a similar linear response for low and highdose rates, and that the primary effect of lowering thedose rate was to diminish the dose-squared component.
On the basis of a simple linear fit to the high- doserate dose-response data [I@) = 0.93 + 4.7D; p< 0.051, the results for female nlice indicate thatturnour incidence at low dose rates is reduced by afactor of about 3 for doses of about 2 Gy (Table 8).
179. Summary. The dose-response for Harderian
gland tumours in female mice resulting from high-dose
rate exposures can be fitted by a linear-quadratic relationship. The data suggest a DDREF for high-doserate exposures of about 3 for doses of about 2 Gy andfor dose rates varying by a factor of about 8,000.

(h)Ovariun tumours

180. The induction of ovarian tumours in gammairradiated mice has been shown to depend on the dose
rate [U12, U21, Y4]. Interpretation of some of thedata is complicated, however, by a decrease with age
in the susceptibility of the niouse ovary to tumorigenesis. Furthermore, since the sti~nulusfor tumorigenesis is believed to involve killing of oocytes andassociated changes in honnonal status [U21], this is
likely to contribute to observed dose-rate effects.
181. The induction of ovarian tumours by x rays wasstudied by Ullrich and Storer [U15] using SPF/RFM
female mice exposed at 0.45 Gy min-' and 0.06 mGy
min-l. After high-dose-rate exposures, a significant
increase in tumour incidence relative to controls wasobserved for doses of 0.25-3 Gy. In the group exposedat the lower dose rate, no significant increase inincidence was seen until 1 Gy, when the incidence
was similar to that observed in the groups receiving
0.25 Gy a t higher dose rate (Figure XIV). The highdose-rate data could be adequately described by alinear-quadratic model with a negative linear
component [I@) = 2.3 + (-23) D + 1 . 8 ~ p~ >: 0.251
or by a threshold plus quadratic model [I@) = 2.2 +2.3 @-D*)~;p > 0.75, where the threshold dose. D*.
was estimated to be 0.12 Gy] [U14]. Linear and quadratic models were rejected. For the low-dose-rate
response linear, quadratic and threshold plus quadratic
niodels could be rejected (p < 0.01). Tlie two models

65 5

to describe the relationship adequatelythat al~l~carcd
were a linear-quadratic niodcl [I@) = 2.3 + (-3.7)D+ 0.068D2; p > 0.251 and a threshold plus linear
niodcl [I@) = 2.07 + 14.9@-D*); p > 0.75, where thethrestiold dosc, D*, was estimated to be 0.1 15 Gy].
182. I n fernale BALB/c mice similar results have beenobtained [U15]. Ovarian turnours were readily inducedwith high-dose-rate exposures (0.40 Gy min'l) to1 3 7 ~gammasrays, giving a 66% incidence at 0.5 Gy,
the lowest dose used, conlpared wiU~a 9.9% incidence
at low dose rate (0.06 ~nGymin-l) for h e same total
dose (dose-rate effectiveness factor: 6.7, Table 8). As
in the case of RFM mice, linearity could be rejected(p < 0.05) at low dosc rate, and the dose response up
to 2 Gy could be described by a linear-quadraticmodel [I@) = 6.0 + 8.3D + 0 . 0 5 ~ ~ 1There.
wereinsufficient data at high dose rate to define a doseresponse function: doses below 0.5 Gy would havebeen required.
183. This pattern of response for ovarian tumour
induction seen in both RFM and BALBIc mice is
explained by the mechanism of induction for ovariancancers, which is considered to involve substantial cellkilling. This mechanism will be less effective at low
dose rates and may account for the apparent thresholdin the response. Linear functions fitted in this Annex
to the dose-response data in RRvl niice obtained up to
2 Gy for both high- and low-dose-rate exposures[U15] give a crude overall DDREF of 5.5 (range: 4.16.8, Table 9), compared with a value of 6.7 for
BALB/c mice (Table 8), but because of themechanisms involved, the extrapolation of these results
to marl is uncertain.
184. Summary. The induction of ovarian tumours has
bccn shown in mice to depend on dose rate. DDREFs
of 5.5 and 6.7 have been obtained in RFM andBALBjc mice at doses up to 2 Gy for dose rates
varying by a factor of about 8,000. Since the stimulus
for tumorigenesis is believed to involve killing ofoocytes and associated changes in honnonal status,
extrapolation of these results to man is uncertain.

(i) l'hymic lymphomn

185. A number of investigators have studied theincidence of thymic lymphoma after radiation
exposure. However, many of these studies have bccn
concer~~edwith modifying factors that influence thecourse of the disease or the sequence of events leading
to its dcvelopment rather than with dose-response
relationships. An added complication is that doseresponse curves of a threshold type have been reported[M5], indicating that cell killing is important in the
induction mecl~anisnl.

1993 REPORT186. Ullrich and Storcr IU12, U15] studied the doseresponse relationship and dose-rate effects for exposure to 1 3 7 ~ gamniasrays in 10-week-old feniale
RFMNn mice. The incidence of thyniic lynr honia
after high-dose-rate exposure (0.45 Gy niin- ) was
subsla~rtially greater than after low dose rates(0.06 niGy min-l) at all doses for which coniparable
data wcrc givcn (0.5, 1 and 2 Gy) (Figure XV). In
fact, no significant increase in incidence relative tocontrols was observed after low-dose-rate irradiation
up to a total dose of 1 Gy, whereas at high dose rates
a significant increase in irrcidence was observed atdoses of 0.25 Gy. Examination of the relationshipbetween the incidence of thymic ly~npho~iia
and theradiation dose at high and low dose rates indicatedboth quantitative and qualitative differences. The dose
response after high-dose-rate exposure appeared tohave two components. Up to 0.25 Gy, the incidence ofthymic lymphonla increased with the square of thedose, with a second, linear component describing the
response over the range 0.5-3 Gy. At the lower dose
rate the response was best described by a linearquadratic model with a shallow (perhaps zero) initial
linear slope, and linearity could be rejected.
Considering that Ihe mechanis~nof thymic lymphoma
induction is thought to involve cell killing or the
possible release of viruses and subsequent target cell
viral interactions, it is not surprising that somewhat
complex dose and dose-rate response relationships
have been obtained.

P

187. An early analysis by the NCRP [ N l ] gave adose-rate effectiveness factor of 6.4 for these data.
Alternatively, the high- and low-dose-rate dataobtained up to 3 and 2 Gy may be fitted with linear
models, giving t i e of 16.7% t 1.8% Gy-l and 2.9% 2
1.9% Gy-', respectively, corresponding to a dose-rate
effectiveness factor of 5.8 (Tables 8 and 9). In males[U13]no dose-response data were obtained at low
dose rates, but at high dose rates (0.45 Gy min") a
significant increase in incidence occurred at doses of0.25 Gy and above, and the data over the entire dose
range up to 3 Gy could be adequately fitted by alinear function (6.7% 2 6.9% Gy-l). Overall, males
were less sensitive than fenlales by a factor of about
2.4, reflecting the difference of a factor of about 2 in
the incidence in controls.
188. An increased incidence of thymic lymphoma has
also been reported by Upton et al. [U21] for male andfemale RFM mice exposed to x rays. Lymphoid neoplasms occurred in about 4%- 10% of controls, and theincrease in incidence depended on both the total dose
and the dose rate, with a significant increase, relative
to controls, at doses of about 2 Gy or more. Withdecreasing dose rate, the effectiveness of gammaradiation in inducing turnours declined. A linear dose
functio~rfitted to both high-dose-rate (0.8 Gy mill-')

and low-dose-ratc (0.04-0.6 nrGy niin-l) irrcidence data
for ninlcs suggests a dose-rate effectiveness factor of
about 2.6 (Table 8) at doscs up to about 4 Gy. Forfc~nalcsh e data arc too variable to infer a dose-rate
cffectivc~icssfactor.
189. In cxperi~iientsby Maisin el al. [M5], 12-weekl e fractionatedold male mice were exposed to s i ~ ~ gor(10 eguill doses separated at daily intervals) doses
from 3 7 ~ ga1111riasrays (4 Gy niin-l) in the dose
range 0.25-6 Gy. The dose-response curve for thymic
lynipho~nawas of a threshold type, the ilicidencc in
irradiated animals rising above that in controls only at
4 and 6 Gy. Si~lgledoses were more effective thanfractionated exposures at 4 Gy by a factor of about 2;
there was no significant difference in response at
6 Gy.
190. Suttlmary. An effect of dose rate on h e
inductio~iof thy~niclympho~nahas been demonstrated
in RFM niale and fen~alemice with DDREFs of about
2.6 and 5.8 for doscs of 2 to 4 Gy and for dose rates
varying by factors or more than 1,000 (Table 8). As
with ovarian tumours there are difficulties inextrapolating these data to man, however, as cellkiili~igappears to be involved in the development of
this lumour.

191. A number of studies have reported that when theradiation dose is fractionated, the incidence of skintunlours decreases in comparison with acute exposures. Hulse et al. [H30] irradiated the skin of threemonth-old CBAM fernale mice with a '% source.
Four different schedules of exposure were used: four
equal doscs at weekly intervals, four equal doses atmonthly intervals, 12 equal doses at weekly intervals
and 20 equal doses five days weekly for four weeks.
Total doses given were large, 60 Gy or 120 Gy. The
tunlours occurring after the different irradiation
schedules were similar to those seen after single
exposures and were mainly dermal tulnours at bothdose levels. Dividing the total dose into four fractions
did not affect tulnour yield, whether the exposures
were spread over 22 days or 1 2 weeks. When 20 fractions wcrc givcn over 25 days, however, the yield wassignificantly reduced (p = 0.02) to about half that witha single exposure. With 12 fractions given over 11
weeks, tlre yield was non-significanlly reduced (p =0.09 for both dose groups; p = 0.06 for 60 Gy). It was
concluded that a reductio~~
ia tunlour yield followed
multiple Cractioeation and protraction over several
wceks o~ilyif the dose per fraction was 5-6 Gy or
less. The reduction factor was about 2. For epidermal
tuniours, of which h e r e were fewer than half thenumber of deniial turnours, there was a much greater
variation i r ~respolrse bctwecn the groups. None of the

A N N W F: INFLUENCE OF DOSE AND DOSE RA

groups with fractionated exposure had a significantly
different tumour yield from tlre single exposure group,and there was no clear evidence that protraction or
fractionation reduced tumour yield. The yield of epidermal tumours was, however, signiticantly less in the
20-fraction groups (at 6 irnd 12 Gy total doses)
compared with Lhc groups give11 4 and 12 weekly
hctions.
192. In a series of studies in male CD rats [B40], skintunlour incidence following acute exposure to attenuated 0.7 MeV electrons (1.6-2.4 Gy min-l) was measured at nine doses (20 rats per group) between 5 Gy
and 23 Gy. A peaked dose-response curve was obtained, with a maximum tunlour incidence at a dose ofabout 16 Gy. At 10, 14.5 and 23 Gy, the exposures
were also split into two equal fractions spaced atintervals of 1, 3 and 6.3 hours. The effect of split
doses on tumour yield depended on the position on thedose-response curve. At the lowest split dose thetumour yield declined with a half-time of about 1.8
hours. At the intermediate dose, an initial increase wasfollowed by a decline, with a half-time of 3-4 hours;
at the highest dose (23 Gy) the tumour yield increased,
presumably as a result of the spacing effect on celllethality. The maximum effect of dose fractionation(14.5 Gy, two fractions, 6.3 hours) gave a reduction intumour yield by a factor of about 2.
193. In a more recent series of papers [ 0 5 , 061, skintumour incidence has been nleasured in female ICR
mice. The backs of the animals were regatedly inadiated with beta particles from " ~ r - Y (2.24 Gy
minm1, surface dose). For doses of 2.5-11.8 Gy per
exposure, three times weekly throughout life, 100%incidence of tumours was observed. At doses of about
1.5 Gy per exposure, however, there was a marked
delay in the appearance of turnoun. In a further studyg 7 ] , p p s of 30 or 3 1 mice were irradiated wilb
Sr- Y three times weekly throughout their life withdoses of 0.75, 1.0, 1.5 and 8.0 Gy at each irradiation.
The study demonstrated that tumoun appeared later inthe groups given 1.0 or 1.5 Gy per exposure than in
the group given 8.0 Gy per exposure, although tumour
incidence was 100% with these two doses. At 0.75 Gy
per exposure, no tumours appeared within 790 days,
although an osteosarcoma and one squamous cell
carcinoma did finally appear. There was no effect on
the life-span of the animals. In a further group of 50
mice given 0.5 Gy per exposure no turnours were obtained 108, T l l ] . This observation of an "apparent"
threshold in response may be accounted for by thesmall number of animals involved, but it is more likely arises as a rcsult of tlie characteristics of thisparticular tumour, in which induction appears to be
more dependent on dose per fraction than on total
dose; single doses of up to 30 Gy alone do not induce
tumours. At the higher doses and dose rates tumour

development is likely to he influenced by radiation
effects on tlre tissue surrounding initiated cells.
194. Surnrnary. A series of studies in rodents has
shown that when irradiatio~lof the skin is fractionatedthe incidence of skin tumours is lcss than with acuteexposure. In the majority of studies, however, the tolaldoses have been Ii~rgc,and dose fractionation has been
seen to have an effect only for doses per fraction ofless than about 5-6 Gy. In general, the effect of dose
fractionation under these conditiorrs has been to reducetumour yield by a factor of about 2. In one study, inwhich fernale ICR mice were repeatedly irradiatedan apparent threswith beta particles from %r-%,hold for tumour induction was obtained at a dose per
fraction of about 0.5 Gy. This may have been the
result of delayed tumour appearance or the influenceof radiation damage to surrounding tissues at the highdoses and dose rates used.
Q Tunlour induction in r u t s

195. In male Sprague-Dawley rats (3 months old)
exposed to %o gamma rays to give 2.83 Gy (304
rats, 2 2 n ~ G ymin-l), 1 Gy (505 rats, 1.3 mGy min")and 3 Gy (120 rats, 1.3 mGy min-I), an effect of dose
rate on overall tumour induction was observed,
although this varied with the turnour type [M43]. At
lower dose rates lhe incidence of radiation-induced
carcinomas (excluding thyroid, pituitary and adrenals)
was lower than at high dose rates for a total dose ofabout 3 Gy. The frequencies of carcinoma were
6 . 8 % 2 1.9%, 10.1% 2 3.8% and 25.8% 2 8.2% incontrols and animals exposed at 1.34 mGy h-' (total
dose: 2.8 Gy) and 78 nlGy h-' (3 Gy), respectively,
implying a reduction in excess cancers by a factor of
about 6 at the lower dose rate. Although the incidenceof most carcinomas showed an increase with inaeasing dose rate, the effect was most significant for thedigestive and urinary systems.

1%. For a group of sarcomas that are poorly inducible in the rat (nervous system, leukaemia, lymphosarcoma, bone and mesothelioma) but frequent in man,no dependence on dose and dose rate was observed.
For a second group of sarcomas (angiosarcomas andfibrosarcomas of internal organs and of soft tissue),which are infrequent in man but colnmon in the rat,
the incidence did increase with dose (from 1 to 3 Gy),although again it was independent of dose rate.
197. Sumntury. The results of chis study in maleSprague-Dawley raLr indicate that, as with the studies
in mice, the effect of dose rate on tumour induction
varies between different tissues. For dose rates varying
by a factor of about 60 and for a total dose of about
3 Gy, DDREFs in the range from about 1 to 6 havebeen obtained for tumours in various tissues. Taken

1993 REPORT

together, the cancer ratc was reduced overall by afactor of about 3.
(I) Uncertainties in the cnlculntion of DDREF

198. A particular problem in estimating dose-rate
effectiveness factors from the ratio of cancer yields
following exposure to acute (high-dose-rate) andchronic (low-dose-rate) irradiations is that very often
the standard errors atlachcd to the linear fits to thedata are relatively large (Table 9). Formulae havetherefore been developed that allow an cstimate to bemade of uncertainties in the calculation of the
DDREF. If a~ and a~represent the yield coefficientsfor high and low dose rates, respectively, then the
DDREF may be estimated by:
DDREF = a,laL [ l + ( o t l a 3 ](I6)

where oLis the standard error on aL.The correction
term exists to represent the skewed distribution of theratio when a~ and aLare both normally distributed[Eli]. The correction is of little importance unless
aL/aLexceeds about 0.3. Examples of calculations of
DDREF that allow for this correction are shown in
Table 10. These values may be compared with thepoint estimates of DDREF for the same studies given
in Table 9. In all cases the values of DDREF thatallow for this correction are larger than the values of
those that do not, although by very variable amounts;
the effect on the estimate of DDREF increases
substantially when the standard error aL exceeds aL.
The central estimates of DDREF given in Table 8 forthe range of tumour types described in this Chapter do
not include this correction.
( n ~ ) High-LET radiation

199. The implication of the results described earlier,i.e. that at low doses of high-LET radiation the effects
of fractionated or protracted exposures on life shortening are very similar to the effect of acute exposures(Section lI.A.l.c), would suggest a similar lack ofeffect on tumour induction in individual tissues. The
effects of neutron and alpha-particle irradiation are
described separately.
200. Neutron irradiafion. The effects of protracted
and fractionated neutron irradiation on the induction oftumours differ in different tissues and have recenlly
been reviewed by Fry FlO]. Grahn et al. [GI21 haveexamined the main categories of cancers found in
B6CFl mice, namely, those of lymphoid and epithelial
tissues. The results obtained so far indicate that mortality from lymphoma and leukaemia is greater after
fractionated exposures than single exposures, whereas~rlortality from epithelial tumours is less after thefractionated than single exposures. Since no dose-fractionation effect is seen on the overall life-span in thedose ralige up to 0.2 Gy, it must be assu~iiedthat thetwo effects cancel each other out.
201. There is littlc Curther information to suggest thatdose ratc influences leukaemogcnesis in experimental
animals. Upton ct al. (U21J did not report any difference bctwecri the cffects of protracted neutron exposures at low dose rates on the induction of myeloid
leukacli~ia in RFM mice and the effect after single
doses. Huiskanip ct al. [H28, H29] reported no effectof dose rate on either the induction of acute myeloid
leukaemia (AML) or survival in male CBA/H mice
exposed bilaterally to fast fission neutrons (meanenergy 1 MeV) at 2, 10 and 100 mGy min-' to give a
total dose of 0.4 Gy. No AML was observed in the
sham-irradiated controls. The observed AML frcquencies in the irradiated groups were 11.4%, 12.3% and9.8%, respectively, indicating that the incidence of
AML was not influenced by a fifty-fold change indose rate. Besides AML, lymphosarcomas were observed in all experimental groups with a suggestion of aslightly higher frequency in the high-dose-rate group,
although numbers were small and with no clear trendwith increasing dose ratc. Although survival was significantly reduced in the exposed animals, it was independent of dose rate.
202. Ullrich [U16] examined the effect of dose rate ordose fractionation on tumour induction in BALB/cmice exposed to total doses of 0.025-0.5 Gy fromz 2 ~ f neutrons. The animals were exposed at highdose rate (0.1 Gy in 20 hours daily), or in two equal
fractions separated by 24 hours or 30 days, or at low
dose rate (0.01 Gy in 20 hours daily). The effect ofdose fractionation and dose rate on the turnorigenic
response depended very much on the tissue. For
ovarian tumours, the response to fractionatedexposures was similar to that obtained for a single
acute exposure; however, at the low dose rate theresponse was reduced. This would be consistent with
the need for tissue damage and hormonal imbalancefor ovarian tumours to manifest themselves. For lungtumour induction splitting the dose into two equal
fractions separated by 24 hours had no effect on the
response, althougti separating the fractions by 30 days
gave a higher incidence of lung tumours at a total
dose of 0.5 Gy (there was no difference at doses up to
0.2 Gy). These results suggest that the number of cells
at risk may have increased in the 30-day interval
between fractions, possibly as a response to cell killingby the first fraction. This might also explain why theincreased effect occurred only when the initial dose
was 0.25 Gy or above. For mammary tumours the
response to dose fractionation was similar to that forlung tumours. For both lung and mammary tumours
the tunlour incidence was greater at low dose rates

ANNIX F: INF1,UENCE 01: DOSE AND DOSE RATE ON STOClbGTIC E F 1 2 C E 01: RADIATION

than with acutc cxposurcs, and the increiise was mostmarked at intermediate doscs of about 0.1-0.2 Gy. In
another study, the induction of Hardcriari tumours was
little diffcrcnt in si~iglccxposurcs and in fractio~isof
25 rnGy up to a total dosc of 0.4 Gy IF9j. I t has also
becn reported that, rclativc to acutc exposures, protraction of ricutrori irradiatio~ladvanccs the time of
appearance of maallnary tunlours in rats [U3].
203. Di Majo et al. ID31 havc rcported dose-response
relationships for liver tunlour induction in BC3FI malemice exposed to fission neutrons. Three-mon~h-old
mice given doscs from 0.17 to 2.14 Gy (0.05-0.25 Gy
min-l) showed an increased tumour incidence in all
the irradiated groups [C29, D3]. A linear model gavea best fit to the dose-response data [I@) = 11.3 t
34.6D], implying that no dose-rate effect would be
expected. Because of the different shapes of the doseresponse curves for x rays and neutrons (Figure XII),the RBE depended on the dosc at which it was calculated, with a value of 1 3 estimated at 0.17 Gy.
204. Summary. These results indicate that there aredifferences between tissucs in the tumorigenic
response following fractionation and changes in dose
rate for neutron irradiation. These differences may
relate to the different mechanisms of tumorigenesis
involvcd in the different tissucs. Taken together,
however, any effects of dosc rate and dose fractionation on tulnour inductio~i in the various animal
experiments that have been reported are small.
205. Alpha particle irradiation. Information is alsoavailable on tunlour induction in experimental animals
following intake of alpha-emitting radionuclides. Theinterpretation of such data is, however, considerably
more difficult than is the case for neutron exposure.
The spatial and temporal distribution of dose throughout a tissue depends on the age of the animal and thepattern of intake, as well as on the radionuclide itself
and the chemical form in which it enters the body.
Thus, even for the same radionuclide given in thesame chemical form, the distribution of dose may bevery different after acute and protracted exposures,and this is likely to affect the turnour yield. This isparticularly the case for alpha emitters deposited in theskeleton, wherc rates of bone turnover that vary bothwith age and site in the skeleton result in a very
heterogeneous deposition of the radionuclide, which inturn can result in quite diffcrent distributions andhence dosc with various patterns of intake. Local
deposition of radionuclides can also produce hot spotsthat could lead to local cell killing, thus reducing thetumour yield [PI 11. Much of the published data hasrecently becn summarized IS28].
206. Two lifetime studies with adult beagle dogs
a give a wide range of radiation
injected with 3 3 6 ~ to65 9doses, cithcr as a single injection (0.22-370 kBq kg-')or fractionated (to give total i~ijcctcdactivities of0.88370 kBq kg*') have been rcported. The data suggcst&at for both mcthods of ad~ninistration,2 2 6 ~ awas
equally effective in inducing skeletal osteosarcomas.
However, 2 2 6 ~ awas more cffcctivc at inducing
osteosarcoma (per unit dosc) at low total doscs than athigh total doses, wherc cell killing and waslcd radiation may be significant (G13, T19].
207. Fabrikant et al. [ F l l ] have compared osteosarcoma inductio~~by alpha-radiation in young malerats given u 9 ~ u(1 10 kBq kg-') by intravenous injection, either as a single dose or fractionated overmonths (37 kBq kg", then 19 kBq kg-' at 2, 4, 6 and8 weeks). Although the number of animals in eachgroup was small (Z),the tumour incidence in the twogroups (52% and 56%, respectively) did not differ
significantly. There was a tendency for tumours inanimals given fractionated injections to occur earlier.
It was notable that in animals given single injectionsof 2 4 1 ~ m
at a similar dose the incidence of bonetumours was about one fourth that in the animals.
is likely to be due to differences ingiven 2 3 9 ~ uThis
the distribution of the two radionuclides in theskeleton.
208. Thc effects of dose protraction on osteosarcoma
induction have also becn examined in female NMRI
mice given cithcr single or repeated injections of
2 2 4 ~(half-life:a
3.5 days) p 4 0 ] . One group received
a single injection (18.5 kBq kg-', corresponding to amean skeletal dose of 0.15 Gy) and the another group
received a similar amount in 72 fractions given twice
weekly over 36 weeks. In the group given fractionatedadministration, lymphomas appeared early (13.5%,
42,1299 mice; controls 1%, 1/98 mice); osteosarcomas
occurred during the second half of life of the animals(7.1%, 211299; controls 3%, 3/98). In contrast, thegroup given a single injection did not develop early
lymphomas and showed a later occurrence ofosteosarcoma with an incidence of 5.8% (171295).
Although the incidence of osteosarcoma was similar
up to 800 days in the two experimental groups, after
that, it was different: no additional cases ofosteosarcoma were observed in the single-injectiongroup, but one third of all osteosarcomas occurred
after 800 days in the fractionated group. Because of
the very short half-life of 2 2 4 ~ administeredain thestudy, much of the dose is delivered while the radiumis on bone surfaces shortly after administration, andthus local doses will havc been significantly higher
than the average bone dosc calculatcd (0.15 Gy). In
contrast, the dose rcceivcd following protracted
administration would have been more uniformly
spread over the skeletal tissues, and this might wellhave accounted for the observed differences in tumour
response.

UNSCEAR 1993 REPORT

660

209. Information is available 011 lung tuniour
this tumour typc a threshold for the response would
induction in rodents exposed to alpha emitters. Sanders
therefore be expected, i~ltl~oitghthis would notnecessarily be tbc case Tor otl~crtumaur lypcs or forel al. IS291 conipi~rcd lut~g tun~our rates in rats
to aerosols of 7 3 9 ~ u 0 2andtulnours occurring i l l mall. I t was concluded that, at
ex osed by i~~halalior~
24BCni02. The dosc distribution Uiroughout t l ~ elung
least in tllc Wistar rat, avcr;lgc lung doscs i s cxcess of
was similar for Uie two r;~dionuclidcs, although
1 Gy (20 Sv assur~iinga ratliation wcigliting factor,
2 4 4 ~ n iis~ 2no re soluble in tllc lung than 2 3 9 ~ u ~ 2 wR, of 20) arc ~iccdcdlo give a signilicarit i~incasein
lullg tualours.
is cleared niore rapidly.
and, as a co~~scquc~icc,
Despite this, Uic dosc response for 1i111gtumour
induction following inhalation of soluble 2 4 4 ~ ~ nwas
0,211. Tlic induction of l u ~ ~cancerg;~ftcrsingle or
protracted irradiation with alpha particles was alsosimilar to that for insoluble 2 3 9 ~ u 0 2up to average
examined by Lundgren el at. [L19] in nlicc exposed toradiation doses to the lung of a few gray. At greater
M9~~
After
0 2single.
or repeated inhalation exposuresradiation doses, rats exposed to 2 4 4 ~ m 0died
2 earliergiving average lung doscs of 2.8 and 2.7 Gy,
from radiation pneumoaitis than those exposed torespectively, lung tumour incidence was about 2.7
2 3 9 ~ u 0 2reflecting,
the differences in dosc ratc andtimes higher after repeated cxposurcs, although the
distribution of activity throughout the lung tissue. The
difference between the groups was not significant
effect of cell killing on tumour induction became(0.05 c p c 0.10). In contrast, a significant difference02
apparent at doses of about 2 Gy for 2 4 4 ~ n ~ andwas obtained in mice receivitig pulmonary doses ofabout 3 0 Gy for 7 3 9 ~ u 0 2Thus,.
at high total doses,
14 Gy in a single exposure or 19 Gy in repeatedexposure from 2 3 9 ~ uappeared more effective for
exposures, the percentage with pulmonary tumours.
tumour induction than exposures from 2 4 4 ~ mSanders
being about 3.5 times greater among the repeatedly
ct al. have also shown IS301 that further protraction of
exposed mice (0.01 > p > 0.025). It seems possible,
the dose from 2 3 9 ~ u by fractionated exposure does not
however, ttiat, as with the study by Sanders et al.
increase the lung tunlour incidence in rats, indicating[S29], the differences in effect could be attributed tothat lung-tuniour promotion is not so much a function
higher dose rates from the sir~glcexposures resultingof the temporal dose-distribution pattern as of thein more cell killing.
spatial dose-distribution pattern.
210. In further studies on tuniour induction in rats
exposed to 2 3 9 ~ u 0 2g,o u p s of animals were exposed
to various levels of activity giving average lung doses
betwcer~0.01 Gy and 62 G (based on initial lungdeposits measured with a ' ~ bmarker and h o w ledge of the retention function for plutonium in thelung). This was a large study involving 1,052 female,
SPF, Wistar, sham-exposed rats and 2,105 rats
exposed in groups to give different initial lungdeposits. The dose from inhaled 7 3 9 ~ uis accumulated
over an extended time because of the insolubility ofthe particles and the long retention time in the lung
[S43, S201. Of the 97 primary lung tumours found in
this study (93% malignant and 80% carcinomas) 1 wasin controls and 96 in exposed rats. Survival was
significantly reduced only in rats with lung doses>30 Gy. Of the malignant lung tumours 49 were
squamous carcinoma arid 22 adcnocarcinoma with theremainder consisting of hacn~ongiosarcoma (9),adcnosquanious carcinoma (7),and fibrosarconia (3).
No squamous cell carcinomas wcre found at averagelung doses less than 1.5 Gy, and for adcnocarcinoma
the threshold dose was 3.1 Gy. The other tunlour types
wcre seen only at higher lung doscs. In this study the
predominant tumour typc was tl~crcfore squamous
carcinoma, which is ~ I I O W I Ito develop in the rat lungfollowing the developtncnt of squamous ~rietaplasia[S44], which occurs mainly in regions of high,t l ~ clocal dose would be
deposition of 2 3 9 ~ uwhere
substantially in cxcess of thc average lung dose. Fori212. Some iriformatiori on t l ~ ceffect of dosc ratc on
the induction of lung tunlours has also been obtained
following intratrachcal instillation of 2 1 0 ~ oin saline[L18]. Protraction of the dosc over 120 days was more
carcinogenic at lower total doscs (0.24 Gy) but lesscarcinogenic at higher doses ( 2 4 Gy), in comparison
with an exposure limited to a 10-day period. However,the developnlent of tuniours was also markedly
enhanced by the weekly instillation of saline alone,emphasizing the importance of other factors in theexpression of radiation-induced cancer.
213. A number of studies have been reported on the
exposure of animals, particularly rodents, to varying
concentrations of radon and its decay products. Studies
at the Pacific Northwest Laboratory in the UnitedStates, which have examined the effects of exposure
to radon under a range of cxposure conditions inexperirnerital animals, have recently been reviewed[C2, C3]. The predornina~~teffect of Ihe inhalation ofradon is turnour induction in the respiratory tract. The
main tumours arisiug are adcnocarcinomas, bronchiotar carcinomns, adcnocarcinoni;~~,epidernioid carcinomas, adcnosquamous carcir~omasand sarcomas. Acutedo not appear toeffects, altllough species-depc~idc~~t,have occurred at exposure levels of less than 1,000
WLM (3.5 J 11 n ~ - ~Excess).
respiratory tract tumours
were, however, produced in rab at exposures well
below 100 WLM. The results of a series of studies inrats exposed at 5 , 50 and 500 WLM per week to give

ANNIX F: INFLUENCE OF DOSE AND DOSE RATE ON S'MCt 1ASnC EFFECIS OF RADlAlON

a range of cumulative exposures are give11 in
Figure XVI. WiUi a few exceptions, the incidence ofadenomas and sarcomas was well below 10%. A decrease in exposure rate, at a given exposure level,
increased the ovcrall incidence of lung tunlours at all
but the lowest exposure level (320 WLM). This increase was specifically the result of an increasing
incidence of epidermoid carcinomas, most of which(>70%) are fatal. In rats, most (-80%) of the tunlours
arc considered to originate peripherally and to occur atthe bronchiolar-alveolar junction. The remaining 20%
are considered to be centrally located in association
with the bronchi. It should be noted that these areinterim results. The shape of the dose-response curve
remains uncertain. Most of the exposures below 100
WLM are not yet complete or analysed. At the lowest
exposure rate (5 WLM per week), the data suggestthat the exposure-rate effcct (but not the risk) tapers
off, and the risk might still best be described by alinear model, at least at low doses (Figure XVI) [C3].
214. A series of studies has also been conducted by
COGEMA in France on the effects of radon exposure[G24, M24j. In these experinlcnts more than 2,000
rats were exposed to cumulative doses of up to 28,000
WLM of radon gas. There was an excess of lungcancer at exposures down to 25 WLM (80 mJ h m9).
Theses exposures were carried out at relatively highconcentrations of radon and its decay products (2 J
m-3). Above 6,000 WLM, rats suffered increasingly
from life shortening due to radiation-induced nonneoplastic causes, thus limiting tumour development.
W e n the dose-response data were adjusted for thesecompeting causes of death, the hazard function for theexcess risk of developing pulmonary turnours wasapproximately linearly related to dose. This suggeststhat apparent reductions in tumour induction at highdoses may chiefly have been the result of acutedamage. Later experiments have, however, found thatchronic exposure protracted over 18 months at analpha energy of 2 WL (0.0042 mJ m 3 ) resulted in
fewer lung tumours in rats (0.6%, 31500 animals, 95%
CI: 0.32-2.33) than similar exposures at a potentialalpha energy of 100 WL (2 niJ m-3) protracted over 4
months (2.2%, 111500 animals, CI: 0.91-3.49) or over
6 months (2.4%, 12J.500, CI: 1.06-3.74). The incidenceof lung tunlours in controls was 0.6% (51800, CI:
0.20-1.49) [M24]. The confidence intervals arc,
however, wide, and the longer period of exposure (18months) would in itself have been expected to resultin fewer lung tumours. It is significant, however, thatno increase in risk was observed with a decrease in
exposure rate.
215. The two-mutation (recessive oncogenesis) modelof Moolgavkar and Knudson [M38] has been used tomodel lung tumour induction in rats exposed to radon.
This model postulates transitions from a normal cell to661

an iatem~ediatccell to a malignant cell with quantifiablc rans sit ion rates and takes account of the growth
characteristics of the nonnal cell and intermediate cell
populations. The model describes well the rat lungcarlccr data followi~~g
exposure to radon [M6].The
f'indil~gssuggest tl~attlle first mutation rate is verystrongly dependent on h e rate of exposure to radon
progeny and the second mutation rate much less so,suggesting that the nature of the two mutational eventsis different The n~odclpredicts that (a) in rats radon
doubles the background ratc of the first mutation at an
exposure rate of approximately 0.005 J h mJ wk-I
(1.35 WLM wk"), an exposure ratc in the range of
exposures to miners; @) radon doubles the backgroundrate of the second mutation at an exposure rate ofabout 1.4 J h m-3 (400 WLM wk-l); consequently, thehypothesis that radon has no eEect on the second
mutation rate cannot be rejected; and (c) tlie net rateof intermediate cell growth is doubled at about 0.12 J
h m 3 wk-' (35 WLM wk-l). The model also predicts
a drop in hazard after radon exposures cease, paralleling the exposure-rate effect noted previously, and thatfractionation of exposure is more efficient in producing tumours, although further fractionation leads to adecreased efficiency of tumour production.
216. Summary. It is clearly difficult to generalize
from these results on the effects of neutrons andalpha-emitting ratiionuclides on tumour induction inexperimental animals. Despite this, there is little
evidence to suggest that, in the absence of cell killing,
there is an appreciable enhancement of tumour
induction when the dose from alpha-irradiation is
protracted or fractionated rather than administered ina single exposure. For the present, the data seem to bereasonably consistent with the assumption of a linear
dose-response relationship, at least at low doses.

(n)Sunlnlary217. A number of studies have been published that
permit the effcct of dose and dose rate on tumour
induction in experimental animals exposed to low-LET
radiation to be examined. The majority of the data arefor external radiation exposure but some informationis also available for incorporated radionuclides. The
data h a t have been reported by various authors covera wide range of dose-response relationships and ingeneral show an increasing risk with incrcasing dosc
and dose rate at low to intermediate doses. Although
the results from a number of studies can be fined bylinear-quadratic functions, this is by no means
universal, and many other dose-response relationships
have been obtained. The assessment of the extent towhich changing the dosc rate increases the effectiveness of the radiation depends, therefore, on the dose
range over which the dose and dose-rate effectiveness662

UNSCEAR 1993 REPORT

factor (DDREF) is calculated. The majority of studies
also show that at high doses and high dose rates, cellkilling beconics significant and reduces tumour yield.
In these circur~~stances
the risk of tumour induction at
low doses may be undcrcstitnated by fitting a linear
function to the data obtained in this region. Estimatesof values of DDREF froni the different studies thathave been reviewed have therefore been made in thedose range in which no cell killing is apparent. The
results of these analyses are given in Table 8.
218. A wide range of DDREFs for tumour induction
in a variety of different tissues has been found, withmost studies being carried out in the mouse. It must
be stressed that some of the tumour types for which
information is available are not found in man (Harderian gland) and others (ovarian tumour, thymic lymphoma) appear to involve substantial cell killing
and/or changes in hormonal status. For other tumoun
thcre is a human counterpart (tumoun of the lung,breast, pituitary and thyroid), although the tumours
involved may not be strictly comparable to the humandisease. In practice, the DDREFs found in these twogroups are little different, falling in the range fromabout 1 to 10 or more for dose rates that vary by afactor of 100 or more, and there was no clear trendwith tissue type. The data reported on myeloid leukaemia induction in different species and sexes also
give DDREFs in the range from 2.2 to >lo. The one
reasonably consistent finding is that DDREFs fortumour induction in mammary tissue tend to be lower
than for tumours in other tissues, although even here
one author [U26] has reported a substantial effect ofdose fractionation and, hence, a relatively high valueof the DDREF (-10) for mice.
219. The main co~iclusion to be drawn from theresults of both the studies on radiation-induced life
shortening (Section Il.A.1) and those on the inductionof specific tumour types is that the tumour response to
low-LET radiation is dependent on the dose rate.
While the absolute value of the DDREF varies withthe conditions of exposure, the animal strain, tissue/
tumour type and the dose range over which it is calculated, there is in general a consistent finding thattumour yield decreases with a substantial reduction in
the dose rate. There is also some evidence that if thedose rate is sufficicnuy protracted initiated tumours
are unlikely to be fatal in the life-span of the animal.
These results may be expected to apply to humantumours as well as to those in experimental animals.
220. A number of the animi~lstudies also indicate thata dose-rate effect cannot riecessarily be inferred fromexposures at high dose rates alone, as the doseresponse data for tumour induction can be adequately
fitted by a linear function. This implies the absence ofa visible quadratic (i.e. multi-track) function in thedose response, which, according to coriventional interpretations, would appear to be o necessary prerequisite
for an effect of dose rate on tumour yield. It is ~ h u s
clear that where infoniiation is available ordy for
exposurcs at high dose riltcs, as is normally the casefor hlrrnali exposure on whicl~risk estirnatcs are based[Cl, 12, Ul], any attcrilpt to assess the effect a t low
doses and low dose rates, a ~ i dhence a value of the
DDREF, by simply attenipting to fit a linear-quadraticor similar function to the dose response is unlikely to
succeed fully. The limiting factor is the aniount of
information available at low doses from which the initial linear term (aL of Figure I) can be accurately
determined. In planning future animal studies it should
be noted that most information is likely to come fromstudies on ariimals exposed at different dose rates
rather than from studies that attempt to obtain information on the risks at very low doses. It is to be
hoped that more work will be carried out to supplement the very limited information presently available.
221. From the limited and somewhat disparate data on
high-LET radiation it is difficult to generalize. Thereis, however, little experimer~taldata to suggest that, inthe absence of cell killing, there is a need to apply a
DDREF to tumour incidence data obtained at highdose and dose-rate exposures to calculate risks at low
doses and dose rates. Simil;irly, there is little evidence
to suggest that thcre is an appreciable enhancement oftumour yield when the dose from high-LET radiation
is protracted or fractionated. Some data suggest that if
radiation exposure is protracted this results in a delayin the appearance of tunlours, and in practice they
may not arise in the life-span of the animals.

B. IN VITRO CELL TRANSFORMATION
222. As has been indicated, oncogenesis is a complex,
multi-stage process that is modified by both environmental and physiological factors. In virro cell transformation systems, which have developed rapidly inrecent years, have been used to study part of thisprocess in single cells free from host-mediated influences, such as hormonal and inimunological factors, andfrom environmental agents. Even here, however, cellcell interaction cannot be discounted. Such systems
have the advantage that they allow the rclative importance of cell killing and transformation to be measured
in the same target population of cells. They can also
be carried out in a much sliorter period of time than
animal studies designed to exaniine tuniour induction,and they can be Illore readily a~ialysed,not having the
problem of cottipetilig health risks, which is inherent
in animal studies.
223. Transformation describes the cellular changes
associated with loss of normal control, particularly of

A N N M F: INFLUIiNCE OF DOSE AND DOSE RATE ON STOCIlA!jTiC EFFECIS OF RADIATlON

cell division, which results in Ule developnient of ar~eoplasticphenotype. Although exact definitions depend on the experimental conditions, enhanced growthrate, lack of contact inhibition and indefinite growthpotential, anchorage-indcpcr~dcntgrowth and the ability to form nialignant tumoilrs when transplanted intoa suitable host are the main features of the transformation systems currently in use [Ol]. Whereas in vivo
models involve the whole process of carcinogenesis,
in vilro cell transformation considers events at thelevel of the initial target cells. However, cell transformation is in itself a complex, multi-stage process
by which a cell acquires progressively the phenotypiccharacteristics of a tumour cell. In practice progression
to complete transformation may not occur [L7, L l l ] .
224. The two nlost common cell lines used in celltransformation assays are the NIH BALB/c3T3 and theC3HlOT'A mouse-embryo-derived fibroblast line.
There are inevitably disadvantages associated with theuse of such cell transformation systems as a model for
carcinogenesis in man. The lack of close intercellularcontact and the necessity for an artificial growth
medium car1 alter the reactions of cells. Cell handlingtechniques, such as the degree of trypinization andchanges in culture medium, may substantially alter the
results obtained (E6, T13]. In particular, in the cultivation of mammalian cells, the properties of serum,
constituting 10% of the growth riledium of C3HlOT'A
cells, can be very variable. Thus Hsiao et al. [H27]found large differences in the ability of serurn tosupport the expression of transformed phenotype of
C3HlOT'A and rat embryo cells. A particular problem
with current work on cell transformation is that it islargely based on fibroblasts of rodent origin, whereas
tumours of epithelial origin are the main radiationinduced cancers in man. Reliance on data from experimental models that utilize cultured rodent cells for
extrapolation to man, without experimental supportcan, and has, led to serious errors of interpretation[S21]. Thus, a correlation between anchorage-independent growth and the tumorigenic phenotype has been
established in rodent cells [FS,0 1 , 5221, which has
allowed for the selection of neoplastically transformed
cells by growth in soft agar. This does not apply,
however, to cultured human cells, as normal human
diploid fibroblasts are capable of anchorage-independent growth when cultured in the presence of highconcentrations of bovine serum. More relevant celllines based ideally on human epithelial cell systems
are needed for studying mechanisms of tumorigenesis.
There are indications that such nlodels can be developed; a recent paper has described transformation ina human colonic epithelial cell line [ W l l ] . A numberof studies have also reported neoplastic transformationof human fibroblasts by ionizing radiation and othercarcinogens using anchorage-independent growth as anassay (see, e.g. [M26, S231).

663

225. Rodent cells sccni to have a much greater ability
than human cells to undergo the ininiortalization stageof transformation in vitro, either sporitancously or asa result of treatment with a whole range of carcinogens. This may reflect a fundamental difference intlleir rcsponte and must be taken into account in any
interpretation of radiation-induced transformation
studies employing the currently available rodent celllines [L9, Lll]. Complete transformation of normal
human diploid fibroblasts by physical or chemical
agents has rarely been achieved [M3, N5]. Immortalization leading to turnorigeriicity is a rare event in
human diploid cells, whereas certain characteristics ofmorphological transformation, such as anchorageindependent growth, may be induced quite easily [LlO,
L1 11.
226. Nevertheless, Uiere are several general characteristics of cell transformation in vuro that support its
relevance as a model system for studying the earlystages of radiation-induced carcinogenesis in vivo andthe effects of dose rate. These have been summarized
by Little [ L l l ] as follows:
(a)

@)

(c)
(d)

the commonly used cell transformation systems
provide quantitative information on the conversion of non-tumorigenic to tumorigenic cells;
there is a high correlation between the carcinogenicity of many chemicals tested in both animals and cell transformation systems. Similarcorrelations hold for a number of inhibitors andpromoterj of carcinogenesis that have beentested both in virro and in vivo;
cell transformation responds to initiation andpromotion similarly to two-stage carcinogenesis
in tissues of experimental animals;
transfection assays have shown that cells
transformed in virro have activated oncogenesthat can be isolated and will transform recipient
cells. The DNA of parental, non-transformed
cells is inactive in such transfcction assays.
These findings are analogous to those withhuman tumours and normal cells in the same
DNA transfection assay.

227. Cell transformation systems currently in use
divide into two main categories. The first one is shortterm explants of cells derived from rodent or humanembryos, e.g. Syrian hamster embryo cells. These havethe advantage that they are normal cells with a normal
karyotype allowing parallel cytogenetic experiments.
As such, they have a limited life-span in culture.
Immortal transformants are identified by their alteredmorphology as suwivors against a background ofsenescing normal cells. Spontaneous transformation ofthese cells occurs at a low frequency (of about 1 0 ' ~per cell), and in these assays cell survival and transformation irequency are measured hl the same cell

ANNEX F: INFLIJENCE OF DOSE AND DOSE A A W ON S M C I l A S n C EFFECTS OF RADIATION

234. It is now recognized that nlcasurcmenls ofradiation-induced transfon~lationneed to be made withcells that have beell allowcd to attain asynchronous
growtll by plating at low density at least 40 hours
before treatment IM9, HlOj. Before 40 hours, transientparasyechronous growth may cause large fluctuatio~uin obscrved transfonnatio~rfrequencies for relatively
small variations in plating time, because the susceptibility of the ccll to transfomlation varies throughout the ccll cycle. This may also be affected by radiation-induced cell cycle delay. The failure to recognize
the importance of allowing cells to achieve asynchronous growth may account for some of the more
complex dose-response relationships that have beer.
observed. For example, Miller et al. [M8, M9]measured the effect on C3HlOTN cells of x-ray doses
down to 0.1 Gy delivered just 24 hours after seeding.
They found a plateau in the incidence of transformants
per surviving cell between about 0.3 and 1.0 Gy(Figure XVIII). With this unusual dose-response curve
there could be substantial ur~dercstimationof the effectat low doses if projecting from high doses alone on
the basis of a linear model.
235. A similarly shaped curve can be fitted to theresults of Borek and Hall [B21], which were obtainedby irradiating fresh explants of golden hamster
embryos either with single doscs or with two fractionsof x rays. Because of the greater sensitivity of thissystem, the apparent plateau in response is at doses
below 0.1 Gy. However, a linear rclationship cannot
be excluded on statistical grounds. Similar doseresponse kinetics have becn observed for experiments
perfomled with asynchronously growing cells and insome cases with cells irradiated in the platcau phase.
236. C3HlOTS cells irradiated at low density 48
hours or more after initial seeding are determined to
be growing asynchronously and increasing exponentially [H9, HlO]. The dose-response data reported for
low-LET radiation, expressed as transformation frequency per surviving cell, can be fined to a linear
model for doses up to about 2 Gy. However, thequadratic model cannot be excluded on statisticalgrounds. For single exposures to *CO gamma rays
(1 Gy min-') Han et al. [H5, H6] reported a linear
response up to 1.5 Gy for transformation in C3HlOTM
cells described by I(D) = 2.58D lo4 G ~ - '(Figure
X E ) , which agrees renlarkably well with the dose
response obtained up to 2 Gy lor acute x-irradiation(4 Gy nlin") of I@) = 2.50 t O.llD lo4 Gy" by
Balccr-Kubinck et al. [ B l ] for 36-hour asyrlchronous
cultures (Figure XX;scc also paragraph 245). In bothof these experiments the lowest dose used was 0.25
Gy. Little [LS]has compared results for two relatedmouse ccll transformation systems: BALBl3T3 andC3HlOT'h cells. Following exposure to up to 3 Gy
from x rays, the shapes of the dose-response curves

665

differed significatrdy: that for C3HlOTH cells
appcarcd to follow a linear-quadratic or quadratic
rclationship, while that for BALBl3T3 cells was nearlylinear (Figure XXI). A linear rclationship was also
obtained lor BALB/3T3 cclls exposed to beta particles
from tritiatcd watcr [ L l l ] .
237. A linear dose-response rclationship for transformation freque~lcywith no suggestion of a threshold
was also obscrved at doscs up lo 1.5 Gy for golden
hamster embryo cclls irradiated 7 2 hours after culture
initiation [W3]. Above this dosc a rather more shallow
increase in transfonnation frequency per surviving e l l
was observcd. By contrast, Bettega ct al. [ B l l ]irradiated asynchronously growing C3H10T1h cellswith 3 1 MeV protons (-2 keV mm-l), finding a transformation frequency per surviving cell that showed amarked change in slope over the dose range examined
but in the opposite direction. Between 0.25 and 2 Gy
the frequency was observcd to increase slowly with
dose, but above 2 Gy and up to 7 Gy it steepened very
sharply.
238. X-irradiated contact-inhibited (plateau-phase)
C3HlOTM cells have also becn used to investigate
induced transfonnation [TI]. A steep increase in transformation frequency up to a dosc of about 0.5 Gy wasobserved with a doubling dose of about 0.2 Gy, followed 'by a slower increase over 1-4 Gy with adoubling dose of 1 Gy and a plateau above 6 Gy. For
plateau cclls the Do was 1.53 Gy. Contact-inhibited
cells are perhaps closer to the state prevailing in vivo.
However, there are technical problems associated withthe cell density of plating that may affect the resultsfrom confluent cultures, as well as with the more
widely used technique of low-density plating of asynchronously growing cells.

2.

Dose rote nnd fractionation

239. Early results for the exposure of C3HlOTh cells
to fractionated doses of x rays H4 and for exposures
aCo gamma rays [H5,to high and low dose rates of lH6] using an experimental system involving irradiationof established asynchronously growing C3HlOT'hcells, which had been in culture for at least 40 hours,
indicated that transformation frequency per surviving
cell was reduced significantly with fractionated or
protracted exposure as cornpared with single acutedata suggested
exposures. Analysis of the cxpcrin~cl~tal
fractionation allowed the error-free repair of subtransformation damage.
240. When considering protracted or fractionatedexposures to low-LET radiation, the relative times ofcell plating and irradiation are important Conlplcx
dose-response relationships have been shown in the666

UNSCMR 1993 REPOR'T

region of 0.3-1.5 Gy when C3I-I10T'h cclls arc irradiag
XVIII). Approxialate
ted soon after s c c d i ~ ~(Figured o u b l i ~ ~ofg the tra~rsfornlatio~~
frequency per irradiatedccll call Ilc ob~crvcdWIICII doscs in this range are
given ill two fraclio~~sIM81. I ligllcr r~ur~lbcrs
of cqual
fr;tctio~rs,up to hrcc or four, sl)rc;ld over 5 hours leadto an almost prc~porlional incrc;~scin the obscrvcd
tra~uform;~tionfrcqucr~cy[ H 1 1. This c ~ t h a n c e ~ l lwasc~~talso obscrvcd when freshly pl;~tcd C3HlOT'A cells
werc irradiated with gamlna rays to a dosc of
1 Gy delivered over 6 hours rather than 10 minutes[Hl]. Above a dosc of about 1.5 Gy, no cnl~anccmentat reduced dosc rate was observcd. Thus using thisparticular cxpcrir~~enlal
approach in h e dose range ofabout 0.3-1.5 Gy, the transfonnation frequency can beenhanced either by splitting the dose into a number offractions or by protracting the dosc over a similarinterval. At 2 Gy, no effect was observed. A similar
enhancement in the observcd lransfonnation frequency
per surviving ccll has been observed with freshly
seeded Syrian hamster embryo cclls irradiated withfractionated doses of 0.5 and 0.75 Gy [B21, B23-1, forsimilarly treated BALBnT3 cclls at doscs below 2 Gy
[L8] and for C3HlOT'h cclls exposed to 2 J 4 ~ m
alphaparticles giving doses in t l ~ erange 2 mGy to 3 Gy
[B43].
241. This enhance~ncat in tr;iasfonuatio~~withfractionation of the (lose has not been observed forother biological effects of low-LET radiation either invitro or in vivo, and the ex~)lanationappears to lie in
Lhc shape of the dose-rcsl)o~ise curve for cells
irradiated soon after seeding, when parasynchronizalion effects may apply. In the plateau region between
0.3 and 1.5 Gy, where the effect is roughly independent of dosc (Figure XVIII), irradiation with two
fractions that are assumed not to i~~teractwill
approximately double the transforn~ation yield. In
addition, from this curve, extrapolation from intermediate and high doses will substa~ltially underestimate the true transfonnation freque~~cy
at low
doses, particularly when dclivcrcd at low dose rate orin several fractions. These results are in contrast lo
radiobiological expectations, and in view of theinterest surrounding Ihcrn, further, nlore extensive
experiments havc been conducted [ B l , B2, H6, H9,HlO].
242. Han ct al. [ H 6 ] havc coml)ared t l ~ ctransformation frequency in C3H1OT1h cclls exposed to either
single doscs (0.25-1.5 Gy: 1 Gy III~II-')of 6 0 ~ ogamma rays or five equal frections (0.5-3 Gy; 0.5 Gymill-') separated by 24 hours. T r a ~ ~ s i c ~parasyn~tly
chronous cells werc incubi~ted for at least 40 hours
before h e begiru~ing of irradiation to ensure asynchronous growth. For both patterus of exposure thedose response could be fitted with a linear function,
but for fractionated exposures the tra~~sfonliation

frcqueilcy for surviving cclls (0.8 lo4 Gy-') was
d acute exposurc (2.6
about a third of th;11o b t a i ~ ~ caftcr
lo4 Gy-l), iadicatiag a DDREF of 3.2 (Figure XIX).
ill t l ~ cslope wit11 fractio~~atedcxposure
The reductio~~
indicates tl~at s u b t r ; ~ ~ ~ s f o r ~ a ; ~dnnlagetion
can be~transformation
repaired cvcr~ill the dosc r c g i o ~wl~crc
is apparcatly li~~carlyd c p c ~ ~ d c nont the dose. This isclearly contrary to the auto~lomoussingle-hit intcrpret;ltion of the l i ~ ~ c dose-resl)onscarrelationship. However, it is possible Illat linear and quadratic terms areboth present, but thi~tthe datii iirc insufficient to allowh e m to be resolved.
243. Similar results have been obtained by Terasima
et al. [TI], who compared the illduction of cell transforxnation and cell killing in plateau-phase C3HlOTS
mouse cclls by single doses or two fractions separated
by intervals between 3 and 15 hours. On the linear
component of the dose-response curve (up to 4 Gy)
with total doses of 0.9 and 1.9 Gy, fractionation
decreased transformation frequency by about 50%,
allhough very variable results were obtained. At thehighest dosc uscd (3.7 Gy) the decrease was by afactor of a b o h 2. Walanabc ct al. [W3] have reported
that for asynchro~~ouslygrowing golden hamster
embryo cells exposed to x rays at various dose rates,
lower dose rates (0.5 Gy min-l) were less effective ini ~ ~ d u c i at gr a ~ ~ s f o r ~ n n t thani o ~ ~ highsdose rates (6 Gymin-l) by a fhctor of about 2.

244. The use of C3HlOTS cclls in plateau phase also
demonstrated the repair of potential transfornlation
damage. Results obtained by Tcrasima et a]. [TI, TI31
showed that a rapid reduction of transformation
freque~~cy
occurred over a period of 6-7 hours aftcr asingle dose (3.7 Gy) of 200 kVp x rays, if the irradiated cultures were kept in a confluent state before
plating cells at a low density for transforniation assay.
In two of the three media uscd, the overall
transforniation Gequcncy was reduced to about one
fourth'of that obtai~~edwith IIO post-irradiation period
of incubation. The results indicated the rcpair ofpotential transforniation damage had a half-tirne ofabout 3 hours. At times longer than about 7 hours thetransformation Gequency t e ~ ~ d cto
d increase again,
although the results were widely variable.
245. B;llccr-Kubiczck et al. [ B l ] studied the dose-rate
effect ill C3HIOT'A cclls in some detail, using
protracted exposure to x rays of transforn~cdand nontransfor~ucd cells. In ill1 i r l i t i ; ~ l study on 36-hourasynchroaous cultures, siniili~rsurvival curves for both
ccll types at doscs up to 2 Gy (0.4 Gy III~II-')were~ ~ g repair capacity of transobtained, i ~ ~ d i c a t isi~nilar
formed and non-lransforrned cclls, a result consistent
with hat of Hill et al. [Ha]. In a second series ofexperiments, ccll transformation from acutc exposure
was comparcd with that fronl protracted exposure. For

ANNFX F: INFLUENCE 01: DOSE AND DOSE RATE ON STOCIlA!XIC EI:t.7'.CTS OF RnD112710N

667

c x p o s u r c ~t11c c f f c r ~ i v c ~ ~ofc s high-LETsradiation OII
prolraclcd cxposurc the dosc ratc was ~)roportio~laltotransfor~nation i ~ ~ d u c l ifollows
o ~ ~ a pattern sinlilar to
UIC total dosc, giving a coestant cxposurc time, so thatthal for C I ~ ~ O I I ~ O S O I I Iaberration~II
induction, ccll killing
the repair timc was cqual at all doses Icvcls. Thc doscand otllcr cellular end-points 116, S121. 111a rcvicw ofrcsponsc curvcs for oncogcnic tra~~sfor~nationin thcpublished data, Barendscn [B9] suggcstcd that a niaxilow-dosc range bctwccr~0.25 and 2 Gy wcrc consistrnum RBE valuc of bctwccn about 10 and 20 is typicnt with a lincar rcspoasc, giving paralncters of 2.5 t
0.11
1.5 1?. 0.03
a ~ ~0.87
t l t 0.05 lo4 G ~ - ~cally fou~ld for 0 . 4 1 McV ncutrons. Thcsc RBE
values tcnd to bc highcr than thc equivalc~~tvalues forfor acutc ( 4 min) and 1-hour and 3-hour protracted
ccll rcproductivc death by a faclor of 2-3 [I71 but
cxposurcs. respcctively (Figurc XX). Thcsc results
similar to those found for diccntric aberration inducindicate that in thc linear dose-respoase range between
tion [I6, L12, S12j and so~n;~tic
ccll gene mutation by
0.25 and 2 Gy, oncogcnic transforniatio~~is reduced byhigh-LET nionoc~~crgcticions [Cl I]. Barc~~dscn[B8]
a factor of up to about 3 with protraction of cxposurc.
interprctcd this difference as bcing duc to the rclaA linear-quadratic model could also bc fittcd to thetivcly large linear componcnt found for ccll reproresults, but without a cornmon l i ~ ~ ctcr~n.
a r The results
ductive death i ~ ~ d u c cby
d low-LET radiation, in comarc consistent with a reduction in slopc of the doseparison with the corresponding valuc for ccll transforresponse as the exposure time is increased.
mation. In a reccnt review of data on oncogenic transfonnation of C3HlOTS cells Miller and Hall [M46]246. 111an extension of this work, Balccr-Kubinck ct
noted that irradiation of cells with monoenergetic
al. [B2] cxamined the effcct of dosc protraction in thc
neutrons l i a v i ~ ~ericrgiesg
betwecn 0.23 and 13.7 MeV
range 0.25-2 Gy with acute cxposurc and protracted
to doses of 0.05-1.5 Gy resulted in a linear rcsponse
cxposures over 1, 3 and 5 hours. Rcsults similar tofor both transfonnation and cell killing. When comthose of the prcvious study were obtaiucd for comparpared with rcsults obtaincd with 250 kVp x rays, allable exposure conditions (2.33
1.55 lo4 andricutroll cncrgics wcrc Inore cffcctivc at both cell1.01 lo4 G ~ for- acute,~ 1-hour and 3-hour exposures,
killing a l ~ dillduction of transfonnation. Valucs of therespectively). For protraction of thc dosc ovcr 5 hours,
maximu~nbiological effcctivc~~css,
RBE,, were calcu- ~a transfomlation frcqucncy of 0.56 lo4 G ~ waslatcd fro111 the initial lincar tcrln ( a , , cquation 11) for
obtained. Thus, the overall reduction in o~lcogenic
a linear-quadratic modcl fit to data on low-LET
transfornlatiori with protraction was by a factor 4.5.
radiation such that
Based on an analysis of thc dose-rcsponsc data using
a linear-quadratic function, a rcpair half-ti~nefor ccll
RBE, = a,/%(17)transfonnation of 2.4 hours (95% CI: 1.8-3.0) wasthat is, the ratio of the i~iitialslopes for ccll transestimated. Intercstingly, this compares well with aformation followi~~g
exposurc to ncutrons, a,, andof about 2
typical value for chronioso~nalaberratio~~s
x rays, a,. Both cell survival and the induction ofhours [PSI.
transfor~nationshowed an i~iitialincrcase in effcctiveness with i~lcreasingneutron cncrgy, reaching a maxi247. Thc effect of dosc ratc on tra~lsfonnation
lnuni at 0.35 MeV, followed by a subsequent decline
frequency has also been cxamincd in golden hamster(Figure XXII). This pattcrn of response is gcncrally
embryo cells exposed to x rays at diffcrc~rtdose ratcs
c o ~ ~ s i s twith
c ~ ~microdosinietrictpredictions, in that the(0.05 Gy min-', 0.75 Gy min-I and 6 Gy min-I), givneutron-induccd recoil protons are shiftcd to lower
ing total doses up to 4 Gy. The transformation free s the neutron energy increases, and thelineal c ~ ~ c r g ias
quency increased steeply with increasi~~gdosc at alleffcct of heavy recoils is lessened by saturationdose rates up to a total dose of 1.5 Gy, with theeffccts. The results obtair~cdwith hcavy ions gavehighest dosc ratc giving a transfonnation frequency
RBE values, relative to "CO gamma rays, of 3.3 forabout 1.5 times that of thc lowest dose ratc at doses of'%I (530 kcV ~ I I I - ' ) 2.4, for 4 ~ ionsc (36 keV p n - l )about 1 Gy. At highcr doses the i~lcrcasein transforand 3.3 for 4 ~ ionse with a 100 pin A1 absorber (77mation frequency was less stccp, a ~ ~at d4 Gy thekcV p~ll-l)[S24].
transformation frequency at thc highest dose rate wasabout twicc (hat at the lowcst dosc ratc [W3].
249. As ~)rcviouslydescribed, fractionated and lowdose-rate cxposurcs to low-LET radiation generally
show a dccrcasc i n cffectivcncss for ccll transformation. For high-LET radiation, howcvcr, such a doseratc cffcct is not usually observed, lcading to higher
248. An cxtcr~sivcserics of studies has cxarni~~cd
thevalues of RBE for low-dosc-ratc or fractionated cxpoeffects of high-LET radiation on ccll trarrsfonnation.
sure co~~ditions.
Thus, for fission spcctruln ncutrons at
Thcsc studics havc bccn conlincd largcly to neutrons,
high dosc ratc (0.1-0.3 Gy min-I), thc RBE for transcovcring a wide range of cncrgics, although some dataf o n n a t i o ~of~ C3HIOTH cells was about 2.5 whenon the effects of hcavy ions (95 MeV "N, 22 MeV
co~~lparcd
with high dosc rate (1 Gy min-')gamma-ray
4 ~ e have)also bccn publishcd 15241. For acute668

UNSCFAR 1993 REPORT

exposure from 6 0 ~ o . With protracted exposure(0.86 mGy min-l) or fractionated exposure (fivefractions over 4 days at high dose rate) the RBE wasabout 20. Higller values of RBE might be expectedwith fractions given at low dose rate [Hll]. Some celltransformation experiments have, however, indicatedan inverse dose-rate effect, with certain energies ofneutrons giving a greater tra~lsformationfrequency at
low dose rates than at high dose rates v 8 , H10, H11,
M l l ] , although others have not [B3, B4, B12, H7,
H201.
250. Hill el al. [H8, HlO] first described an inverse
dose-rate effect for oncogenic transformation in
C3HlOTfl cells exposed to fission spectrum neutrons
produced by the Janus reactor al~dsuggested that irradiation times of at least 50 minutes were necessary forenhancement of transformation. At low doses, fission
neutrons administered either in dose fractions over 5
days [ H l l ] or continuously for 5 days [H8] induced
higher frequencies of transformation than cells
exposed to single doses (Figure XXIII). Thus at dosesin the range 0.025-0.1 Gy, a linear fit to the data at
0.38 Gy min-' gave a transformation frequency of 5.96
lo4 G~-',while at lower dose rates (0.86 mGy min")the frequency of transformation was 5.3 l o 3 G ~ - ' .
Thus the incidence of transformation increased at thelower dose rate by a factor of about 9, corresponding
to a DDREF of 0.11 [HlO]. Later studies intended toclarify this effect have failed to find a factor of thismagnitude. A two- to threefold enhancement at low
dose rates of fission spectrum neutrons has been
observed for transformation of fresh cultures of Syrian
hamster embryo cells [J2], and a similar response has
been found by Redpath et al. [R2, R16] with a
HeLa x skin fibroblast human cell hybrid system
exposed to fission neutrons from both the Janus and
TRIGA reactors. An enhancement in transformation
frequency has been found by Yasukawa et al. [Y5].
For C3HlOT'h cells exposed to 2 MeV neutrons froma Van de Graaff generator, fractionation of a dose of
1.5 Gy (two fractions of 0.75 Gy at a 3 hour interval)
increased the transformation frequency by about 50%,although with 13 MeV neutrons from a cyclotron thetransformation frequency was reduced by about 30%
with a similar exposure schedule. Enhancement oftransformation was also seen by Yang el al. [Yl], who
irradiated confluent cclls with accelerated argon ions(400 MeV amu"; 120 keV pn-') and iron ions (800
MeV amu-l; 200 keV p " ) and found an enhancement of transformation at low dose rates. Thisenhancement was found to be greater at lower doses.
251. Several laboratories have reported no inverse
dose-rate effect with C3HlOT'h cells for other highLET radiations, such as 2 4 4 ~ nalpha1
particles [B12]and 2 4 1 ~ alphamparticles [H7]. Balcer-Kubiczek el al.
[B3, B4, B39] examined the dose-rate effect in somedetail, using fission spectrum neutrons from a TRIGA
reactor to irradiate experientially growing or stationary
cultures of C3HlOTYi cells. No significant inverse
dose-rate effect was obtained following exposure to
0.3 Gy at dose rates from 0.005 to 0.1 Gy min-l.
These data argue strongly against the hypothesis thatdifferer~cesin proliferative status of C3HlOT'A may
play a role in the dctennination of any dose-rate
effect. In a second series, consisting of nine experiments, the induction of trans for ma ti or^ in actively
growing C3HlOT'h cells at neutron doses from 0.05 to
0.9 Gy at dose rates of 0.0044 or 0.11 Gy min-' wasexamined. Again, no discen~ibledose-rate effect was
obtained [B39]. In a third series, concurrent with thesecond and with the same exposure parameters, mutagenesis at the lrprt and a ] in AL cells was measured,and again no dose-rate effect was observed [B39].
252. Hill [H20], using both 30- and 46-MeV protons
on beryllium failed to observe enhancement of transformation for low-dose-rate exposures. No differencein transfornlation frequency of rat tracheal epithelial
cells was obtained in exposures to neutrons at 0.1-0.15
Gy min-' and 50.18 mGy min-'. There was also no
difference in Ihe induction of metaplasia and tumoursin tracheal cells exposed at high and low dose-rates.
The exposure times for the low-dose irradiation were
between 18 minutes and 3 hours [T14].
253. Saran et al. [S35] examined the effect offractionation of the dose of fission-spectrum neutrons
on exponentially growing C3HlOTh cells. With total
doses of 0.11, 0.27, 0.54 and 1.1 Gy given either assingle doses or in five equal fractions at 24-hourintervals, no significant difference in either cell
survival or neoplastic transformation was obtained. Infurther studies. C3HlOT'A cells were exposed to 1 and6 MeV neutrons giving doses of 0.2.5 and 0.5 Gyeither as single doses or in five fractions given at
2-hour intervals. Again, IIO significant difference
between acute and fractionated exposures was obtained
for survival or neoplastic transformation [S36].
254. Miller et al. [ M l l ] , investigated the effects ofdose fractionation for monoenergetic neutrons of various energies generated by a Van de Graaff particle
accelerator. Comparison of C3HlOTfl cells exposed to
low doses of neutrons given either in a single acuteexposure or in five equal fractions over 8 hours
showed th;~t,of the wide range of neutron energies
studied (0.23, 0.35, 0.45, 5.9 and 13.7 MeV), sig~ificant enhancement of transformation occurred onlywith 5.9 MeV neutrons. Of the rleutron energies
examined, 5.9 MeV neutrons had the lowest doseaveraged lineal energy and linear energy transfer.
255. From these studies and a comparison of theavailable transformation data for C3HlOTLA cells irradiated with neutrons, a dose-rate enhancement factor

ANNI:X F: INFLUENCE OF DOSE AND DOSE RATE ON STOCllASTlC EFITCB OF RADlA'llONof about 2-3 at low doscs lcss than 0.3 Gy) and dosc
rates below 0.01 Cy s l i l l s was saggested [M12]. It
was concluded tliat Uic c~ihiinccmcntof tra~isformatio~iby fractio~~atcd
or low-dose-rate exposures to n e u l r o ~ ~ sappciirsto depend on radiatio~~
quality, wit11 some neutron e~icrgiesboth i~bovcand below 5.9 MeV showing
110 dose-rate effect (Figure XXIV).
256. In a furlher study, Miller ct al. [M28, M46]
in C3HlOT'A cells
e x a r ~ i i ~ ~transfonnationed
inductio~~
cxposcd lo gradcd doscs of 5.9 MeV neutrolis given asa s i ~ ~ g acutelc
cxposurc (30 mGy mia-') or in fiveequal fractions 2 hours apart, or continuously over an
8-hour period at low dosc rates (from 0.21 to
1 mGy min-I). Although cell survival studies showed
no differences in effect with a change in dose rate,
oncogcriic transformation was enhanced by a factor of
2-3 when the dose rate was reduced (Figure XXV).
When the neutron dose was divided into five fractions
given over 8 hours, the cffect was inter~nediatebetween that for acute and low-dose-rate exposures.
Further irradiatio~lwas given with dcutero~iswitb a
LET of 40 keVPm-', approximati~~gthe rneasured
dose-mean lineal energy deposited in the nucleus of
C3HlOT'A cells by 5.9 MeV monoenergetic neutrons.
An inverse dose-mte/dosc-fractionation effect for the
induction of transfonnation by these high-LET deuterons was observed when the tirne between each of
three fractions for a 0.3 Gy total dosc was at least 45
minutes. AlUiough the t r a n s f o r ~ i ~ a t i ofrequency~~
increased by a factor of about 2, no further enlrancement was seen for longer friictionatioa periods, suggesting h a t very protracled exposures of high-LET
radiation would produce no additional cnhanccmetlt
257. A variety of results have thus bcen reported on
the effects of dosc rate on ccll ~ra~ufoniiationin vilro.
The consistent features that have emerged on the
response of C3HlOT'A cells to various patterns ofneutron exposure have recently been su~nmarized[B30, H311:
(a)
@)

(c)

(d)
(c)

(9

enhanccment of vansformation with dose protraction is not observed with low-LET radiation;
the greatest cnhancemc~~t
for fission neutrons
occurred at dosc rates below -10 mGy niin-l:
for fission (and all other) neutron irradiation atdose rates abovc -10 nlGy I I ~ ~ I I - ' , little or noenhancement is apparent:
monocnergctic ncutro~lsproducc a significantly
smaller enhanccmcnt tl~ando fission neutrons;
charged particles wit11 LET much ahove 140 keV~ 1 n - producellittle or no enhancc~ncnt;
the effect appears ~ r ~ o spro~ninentt
at dosesaround 0.2 Gy, with less c v i d c ~ ~ cofc e ~ ~ h a n c e merit at doscs much abovc or bclow this.

258. A nun~berof biophysical ~nodclshave bcen proposed to account for this inverse dose-rate effect. The

669

rclcvallcc o r diffcrc~~tialradiation sensitivity throughd by Oftcdal 1021, and its
the ccll cyclc was p o i ~ ~ t coutapplicatio~~to the i ~ ~ v r r dose-ratesceffect observed intransfor~nationstudies was first f o n i ~ i ~ l i ~by
c d Rossi
and Kcllcrer [R5],wlio postulated tl~alcclls in a particular " w i ~ ~ d o wof" [heir cyclc may be more sensitive
to radiation (for tlic end-point of i~~tcrcst)
than cells in
lbc rest of the ccll cycle. IC this is the case, an acuteexposure of cycling cells to high-LET radiation will
result in some fraction of these sensitive cells receiving (on average) very large deposits of energy, muchgreater than required to produce the damage that may
ic
On the other hand,lead to o ~ ~ c o g e n transfonnation.
if the exposure is protracted or fractionated, a larger
proportion of sensitive cells will be exposed, althougb
to smaller (on average) amounts of energy depositcd;
the tolal energy deposition per ccll would still be sufficient to produce a poterltially oncogenic change inthe cell. T o the extent that this latter postulate may not
apply to low-LET radiation, the inverse dose-rate
effect would not be expected to apply. T o account forsuggesting
the data first published by Hill ct al. [HlO],
e~thancc~ncnt
by a factor of up to 9 with fractionatedcxposurcs, a rather short "windown of only about 5
minutes duration was proposed. With the exception ofthis early report, the data on enhancement due to dose
protraction now all suggest an enhancement factor ofup to about 2 or 3, and on this basis the model framework proposed by Rossi and Kcllerer IR5] has beenrevised by Bre1111crand Hall [B30] and Hall et al.
[H31], as su~nmarizedbclow.
259. The probability that a particular cell will be
exposed to a given number of tracks is given by the
Poisson distribution. Thus the probability, P, that a ccll
will receive at lcast one track will be
p = 1 -c-N

(18)

where N is the a v c r a g nunibcr of tracks, which at adose D (givcn in Gy), delivered acutely, will be

N, = S D ~ ' / ~ ,(19)where yF is the (frequency) average lineal energy (the~ n i c r o d o s i ~ ~ ~ correlate
etricof LET (given in kcV pm-l)
depositcd in the nucleus, which is assumed to be
spherical with dia~neterd (given in pm). It is assumed
that the entire nucleus is the target. Not all the cells
will be in the sensitive phase during a short acuteexposure; the proportion in the sensitive phase, Q,,
will beQ, = T / S(20)

where t is tile durittion of tlic sensitive period of thecell cyclc a ~ s~ isd tile total I c ~ ~ g tofh the cycle. Now,a s s u n ~ i ~that~ g any I I U I I I ~ C of~
high-LET tracks isequally likely to produce the damage that can lead totransfom~ation,the ovcrall probability will be

UNSCEAR 1993 REPORT

670

where Pa is given by equations 18 and 19. Thus, thetransformation rale due to this process will be
T = KQ,Pa(22)

where K is a constant. It seems unlikely that cells in
the rest of the cell cycle will be conipletely insensitive
to thc induction of transformation. Based on the lowLET dose response where the effect of the sensitive
phase should be less evident, the dose-response relationship for cells damaged in phases other than their
sensitive phase can be approximated by a linear-quadratic function. Thus, the total transfornlation rate isIf the dose is not delivered acutely but at a dose rate

D over a time t (= DP), then the average number oftracks through each nucleus in the sensitive phase will
decrease from N,to N,:

N, = N,r/(t

+ r)

(24)

However, the proportion of cells exposed in thesensitive phase will be increased from Q, to Q,:
Q, = (t + t ) / s(25)

For t + t c s, the overall transformation rate will be

where PC is given by equations 18 and 19. Finally, for
an irradiation that is divided into n equal fractions,where the time behveen fractions is longer than r, theexpressions become

Nf = N,/n

and

Qf = n t / s

(27)

and

where Pf is given by equations 18 and 19.
260. Based on the critical assumption of a target sizeof 8 ,um (corresponding to the average size of thenucleus of a C3HlOTlA cell) and a value forof
0.29 lo4, determined from experimental data [ M B ] ,the parameters a l , K and t were determined as a bestparameter fit for the experinlental data shown in
Figure XXV for 5.9 MeV neutrons. The model fit totbe data was obtained with a period of sensitivity of
61 minutes and values for al of 4.0 2 2.1 lo4 G ~ - 'and for K of 1.3 2 0.19. This rather longer period ofsensitivity, t , is more reasonable in terms of the periodof the entire cell cycle. A fcature of the model is thatthe time between fractions needs to be longer than r ,the length of the sensitive window, for a dosefractionation effect to be observed. As the time

betweell fractions decreases, the exposure will become
increasingly sinlilar to an acute exposure. The model
appears to give a reasonable fit to much of thereported experimental data on the C3HlOTH syste~nand predicls liltle eahancement of effect for alphaparticle irradiation, as is observed. For intermediateLET r;tdiation, such as fission neutrons, the effectwould be c o ~ ~ f i ~tol e intermediateddoses, as the modeltransformalion
predicts that both acute and conti~~uousrates will have the same initial slopes.
261. The hypothesis that there is a narrow window(about 1 hour) of sensitivily to oncogenic transfornlation requires that cells be cycling for the inverse doserate effect to be observed and therefore predicts noeffect for plateau-phase cells. In a further study, Miller
et al. [MI71 investigated the LET-dependence of theinverse dose-rate effect using charged particles ofdefined LET. Parallel studies were conducted withplateau-phase and exponentially-growing C3HlOT'A
cells exposed to single or fractionated doses ofchaked particles with LETS between 25 and 2.50 kV
pn". Doses were delivered in three dose fractions,with various intervals from 0.3 minutes to 150 minutes
between the fractions. Dose fractionation with prolonged time intervals enhanced the yield of transformed cells, compared with a single acute dose for arange of LET values between 40 and 120 kV p - l .
Radiations of lower or higher LET did not show thisenhancement. This enhanced effect for cycling cells in
log phase was not seen for cells in plateau phase,
lending strong support to the model by Brenner et al.
[B30]. These data by Miller et al. [MI71 have also
been analysed by Brenner et al. [B16] in the context
of their model, but with the additional modificationthat tbe constant K was varied to reflect the specificenergy deposition in the nucleus wilh varying LET.
They concluded that tbe observed LET effects were
well explained by the model, assuming a period ofsensitivity within the cell cycle of about 1 hour. The
inverse dose-rate effect disappears at very high-LET
because of a reduction in the number of cells being hit
and disappears at LET below about 40 kV ,urnm1
because the majority of the dose is deposited at low
values of specific energy insufficient to produce thesaturation phenomenon central to the effect. At evenlower LET danlage repair will produce a characteristic"sparingn associated with protraction of x- or gammaray doses.
262. In a further analysis, the predictions or the model
were ccsted by Harrison and Balcer-Kubinek [H34].
Their analyses, based on unweighted least-squares
techniques, suggested that there is no unique solution
for t and that its value is critically dependent on the
nuclear diameter. There were also difficulties applying
the model to other neutron data on cell transformation.
It is clear that the model proposed by Brenner andA N N M F: INFLUENCE OF DOSE AND DOSE RA

Hi111 [B30], or some future derivative of i t , will ticcd
to be tested for different doscs, dose ratcs ;lnd doscfractionation schemes to fully cxaniille its gcncral
applicability. Ultimately a coniplctc undcrstatlditlg of
the inverse dose-rate effect Inust dcpc~idon experimental studies designed to elucid;ite thc rncchaaistic
basis of the observations [B45].

263. Cell trallsfor~nationstudies can yield itiforniationof practical use in radiation protection in addition togiving insight into the initial rncclianisl~~sof carcinogenesis. At present, the most quantitative data can bederived from cell systems that are not typical of theepithelial cell systems irivolvcd in niost Iiunral~cancers. The niost commonly used ccll lines irrcludc
cultured embryo cells and the mouse fibroblast celllines C3HlOTS and BALBfc3T3. Thus, when altempts
are made to extrapolate to cancer induction in cpithelial tissues in man, the biological limitations ofthese assay systems must be considered. 111 addition
cell transformation studies have proved to be very
difficult to standardize and there are tech~ricaluncertainties which must be taken into account inassessing the results of any studies. These illclude theeffects of changes in response during the ccll cycle, of
plating density and of promoters and suppressors,some of which may be normal componet1t.c of thegrowth medium, particularly the serum, and therefore
difficult to control.

264. Nevertheless, in carefully controlled cxpcri~nents
where asyncl~ronouslydividing cells or, in so~liccases,
non-dividing plateau-phase cells have beet1 irradiated,
the resulting observations of dose or dose-ratc cffccts
for low-LET radiation are in general agreement withthose relating to other cellular effects, such as cellkilling and the induction of mutations or chromosomal
aberrations. Dose-response curves per cell at risk havea number of features in common with tumour induction in vivo, showing an itlitial rise in transformation
frequency with increasing dose to a niaxiaiuln atidthen a decline. When plotted as transformants per surviving cell, the dose response for low-LET radiation
generally shows the expected lincar or linear-quadratic
relationship tailing off to a plateau at higher doses.
When low doses of x rays or ganinia rays are dclivered at low dose rate or in fractionated intervals, a doserate reduction factor of between 2 and 4 is corntiionly
found. It is noteworthy that sonic e x p e r i a ~ e ~ ~datatalsuggest that the linear tenn in the dose response mayalter with dose rate, but this may be accoulited for by
the lack of precise data at low doses.
265. Exposures to high-LET radiatioli results in ahigher transformation efficiency with a tendency

tow;ircls a liricar rcli~tiotlship, in litic with data forcllrotliosoliial aberrations and again tending to aplalcau at high doscs. As expected from this pattern of
response, there is no tcndcncy for the responsc to
decrease at low dosc rilles or with fractionation, and inpractice, a nuliiber of studics have shown an enhanced
cl'l'cct. Tlic main cvidctlce for an inverse dose-rate
effect with high-LET radiation seenis to be limited to
5.9 MeV or tiision spectrum neutrons, and over the
past few years estimates of the magnitude of theil~crcascdeffect Iravc been reduced, from factors of
about 9 to factors of about 2 or 3. Results reported
fro111a eumber of laboratories have become reasonably
coesistctit, and it has been possible to develop a modelthat call satisfactorily predict many experimental
results. The rnodcl is based on the assuniption that the
targct ill the cell, taken to be the nucleus, has a"window" in t l ~ ecell cycle during which it is moresensitive to radiation.
266. Wilh protracted or fractionated exposures there
is a greater opportunity for this particular "windown tobe hit by at least one track and thus make possible anenhancement of Iransfor~nation frequency with arcductioll in dose rate. The magnitude of any effectwill dcpe~ldon the lineal energy, and with alphaparticle irradiation little enhancement would be
expected, as is in fact observed. Although such amodel appears to be consistent with much of the
expcrilnestal data, it will need to be tested at different
doscs, dose rates and dose-fractionation schedules tofully exaniine its general applicability. Ultimately acomplete understanding of the inverse dose-rate effectmust depend on experimental studies designed toelucidate the mechanistic basis of the observations.
267. Despite this apparent explanation for the inverse
dose-riite effect, there remains the problem that it islargcly based 011 the results obtained with theC3HlOT'h ccll syste~nand may well have only limitedapl)lic"ion to human carcinogenesis. The dcvclopmer~tof epithelial ccll systems that arc of much more direct
rclcva~lceto human carrcer should be a research priority. Wtrilc some qualitative information is becoming
avai1;tble from such cell systems, no quantitative
assays iIl)l)ear to be available at present.

268. 11 is getierally believed (and pointed out inAnl~cxE, "Mechanisms of radiation oncogenesis") thatthe principal mecl~anismresulting in a rlcoplastic initiatillg evetit is iliduccd dalriage to the DNA moleculethat redis is poses target cells to subscquenl malignant
dcvcloplnent. There is also strong evidence linking atiunlbcr of tuniours to specific gene mutations. Aficr
Ute ~~rilnaryi~litiatiligevent many gcactic, physiologifactors will influence the devecal atid ~~~virolil~ictit;llUNSCEAR 1993 REPORT

672

lopment and subsequent nlanifestation of a tumour.
There is, however, a clear need to u~lderstandthe roleof both dose and dose rate in this initial genetic
change. Studies on somatic and germ cell mutations
boll1 in viva and in virro are directly relcvanl to thisquestion, although the results obtained have beensomewhat variable. The effect of dose and dose rate
on radiation-induced mutation in mammalian cells has
been reviewed by Thacker [T5], and a review of
specific locus mutation rates in rodents was also
prepared by the NCRP [Nl].

1. Somatic mutations
269. A number of mutation systems have been described in the literature, but only a few are sufficiently
well defined for quantitative studies. Mutation of asingle gene is a relatively rare event; the majority ofexperimental systems are therefore designed to selectout cells carrying mutations. Commonly used systems
employ the loss of function of a gene product (enzyme) that is not essential for the survival of cells in
culture. Thus, cells may be challenged with a toxic
drug that they would normally metabolize with fatal
consequences. If mutation renders the gene producing
the specific enzyme ineffective, the cell will survive,
and thus the mutation frequency can be obtained bymeasuring the survivors. A frequently used example ofsuch a system is that employing the loss of the
enzyme hypoxanthine-canon phosphoribosyl transferase (HPRT), which renders cells resistant to thedrug 6-thioguanine (6-TG), and of the enzyme thymidine kinase (TK) which gives resistance to trifluorothymidine (TFT).HPRT activity is specified by an Xlinked gene hprt, while T K is specified by anautosoma1 gene tk, and therefore has to be used in theheterozygous state.
270. There are a number of difficulties witb suchsomatic cell systems, and these have been reviewed[TS].In particular, the mutation frequency of a given
gene is to some extent modifiable, depending on theexact conditions of the experiment. There may also bea period of time for the mutation to manifest itself. In
the unirradiated cell the enzyme would normally be
produced and thus will be present for some time in theirradiated cell, even if it is no longer being replenished
as a result of a specific mutation. An expression timeis therefore normally left after irradiation before a cellis challenged by the specific drug. Ideally the mutation
frequency would increase with time after irradiation toreach a constant level. This is not always the case,however, and tile mutation frequency may reach apeak arid subsequently decline. Thus the true mutation
frequency may be difficult to determine, and this canpresent difficulties in studies of the effect of dose rate
when exposures can be spread over varying periods oftime.

271. Several established cell lines, derived frommouse, hanistcr or hu111a11tissue, have been used tomeasure mutant frequencies at different dose rates.
The cells lines used cxperilnentally can havescnsitivilies that depend on the stage of the cell cycle;
therefore, to ensure as consislent a response as
possible, it is preferable to use a stationary culture inplateau phase in which only a limited number of thecells will be cycling in the confluent monolayer [H21,
M30]. The range of published data encompasses botha lack of cffect of dose rate and a marked effect on
induced mutant frequency [T5]. The data presented
here are intended to illustrate the range of results
available.
272. The first report on the effect of dose rate on
hamster cell lines at low dose rates used hamster V79
cells and the 11prt locus system [T2]. The cells were
irradiated at dose rates of 1.7 Gy mid1 and 3.4 mGymin", with exposures taking up to five days at the lowdose rates. A reduction in mutant frequency was
obtained at low dose rates with a reduced effectivenessof between about 2.5 and 4 at total doses between
about 2 and 1 2 Gy. The dose-response relationship formutation and survival was approximately the same.
Further studies [C17] used growing V79 cells andcompared dose rates of 4 Gy mid1 with 8.3 and 1.3~ n G ymin'l. The authors reported that 8.3 mGy min-'reduced the mutant frequency compared with the highdosc-rate exposure, and that, surprisingly, 1.3 mGymin-' increased it.
273. A series of studies in Japan on a number ofmouse ccll lines [F6, N6, N7, S25, U29] reported that
mutation frequency in growing cells was substantiallyreduced with decreasing dose rate over a range of dose
rates from about 5 Gy min-' down to 0.8 mGy min''.
Thus, for mutation resistance to both 6-TGand methotrexate a reduced effectiveness by a factor of about 2,
was obtained at low dose rates for L5178Y cells when
the linear term (al)of the linear-quadratic model fit tohigh- and low-dose-rate data were compared [N6].
Similar results were also found with Ehrlich ascites
niouse tumour cells used in plateau phase with theliprr gene locus system. At a dose rate of about 11
mGy min-' compared with 10 Gy min-l, there was a
reduction in effectiveness by a factor of about 2,
although the extent of the reduction varied wilh
experimental conditions [IS]. It was noteworthy in alllhese studies that change in mutant Gequency withdose rate was parallelled by changes in cell inactivation, which might reflect mechanisnls of DNA
damage processing (TI 71.
274. Further studies were reported by Furuno-Fukushi
et al. [F7],who used the hprt assay for 6-TGresistance and nleasured cell killing in growing mouse
L5178Y cells exposed to 0.5 Gy min", 3.3 mGy min-'ANNEX F: INFLUENCE OF DOSE AND DOSE M

and 0.1 nlGy mine'. A marked increase in cell survival
was observed with decreasing dose rate. At the lowdose rate no reduction in the surviving fraction of cells
was found up to a dose of 4 Gy, although only about
10% survival was obtained for the same total dosedelivered at high dose rate. The induction frequency
for mutations found at 3.3 mGy min-' was less thanthat obtained at the high dose rate (0.5 Gy min") by
about a factor of about 2. Surprisingly, there was little
decrease in mutation frequency at the low dose rate
(0.1 mGy min-') compared with that at 0.5 Gy min-'up to a total dose of about 3 Gy, and at the highest
dose (4 Gy) the reduction was between that found at
the high and intermediate dose rates. These results
therefore suggest an inverse dose-rate effect for the
low dose rate compared with the intermediate dose
rate.
275. In a subsequent study, LX830 mouse leukaemia
cells, which are more sensitive to cell killing by x rays
than U 1 7 8 Y cells and 2-4 times more sensitive tomutation induction, were also exposed to
0.5 Gy min-l, 3.3 mGy rnin" and 0.1 mGy min-' F8].
A slight, but significant increase was observed in cell
survival with decreasing dose rate up to a dose ofabout 1 Gy. Beyond that, increasing doses at thelowest dose rate (0.1 Gy min-l) did not reduce
survival further, although the higher dosc rates
continued to show an exponential decrease in survivalwith increasing dose. The mutation frequency
increased linearly with dose at all three dose rates, but
no significant difference in response was foundbetween the different dose rates. This is consistent
with the finding that the LX830 cells are deficient inrepair and that this produces a nearly dose-rateindependent response for mutation [E4].
276. A very different sensitivity has been reported by
Evans et al. [ES],who assayed for the hprt genemutant frequency in the radio-resistant L5178Y-R
cells. At very low dose rates (0.3 mGy min-' fromx rays), there' was little difference in mutation
frequency compared with that at 0.88 Gy mid1. The
results also indicated the progressive loss of slowgrowing mutants.
277. Evans et al. [E7] also compared the effects ofdose rate (0.88 Gy min-' and 0.3 mGy min-l) on
mutation frequency in two strains of LS178Y cellswith differing radiation sensitivities. The induction ofmutants at the heterozygous tk locus by x-irradiation
was dose-rate-dependent in W178Y-R16 (LY-R16)
cells, but very little dose-rate dependence wasobserved in the case of L5178Y-S1 (LY-S1) cells.
This difference may be attributed to the deficiency in
DNA double-strand break repair in strain LY-R16.
Induction of mutants by x-irradiation at the
hemizygous hprt locus was dose-rate-independent for

both strains, suggesting that in these strains, themajority of mutations at this locus are caused bysingle lesions.
278. Suspension cultures of human TK6 cells assayedf rf loci after exposure tofor mutations at the l ~ p rand
nlultiplc acute doscs of 10-100 mGy min-' for 5-31
days showed no significant cell inactivation but linear
dose-response functions for mutation. The induction
frequency was very similar to that following acuteexposures. Similar results were obtained by Koenig
and Kiefer [K4], who found no changes in mutant
frequency in human T G cells at low dose rates (0.45
and 0.045 mGy mine').
279. In recent experinlents Furuno-Fukushi et al. [F2]examined the induction of 6-TG resistance in cultured
near-diploid mouse cells (m5S) in plateau and log
phase following exposure to gamma rays at dose rates
of 0.5 Gy min-', 3 mGy min-' and 0.22 mGy min-'.
In plateau-phase culture, lowering the dose rate from
0 5 Gy rnin" to 0.22 mGy min" resulted in an
increase of cell survival and a marked decrease in
induced mutation frequency. A reduction factor of
more than about 3 was obtained at 2 Gy from dataobtained for high- and low-dose-rate exposures. The
frequency at 0.22 mGy min-' was not higher than thatobtained at 3 mGy mid1, contrary to previous findings
on growing mouse b-178 cells PI. In contrast, in
log-phase culture, the magnitude of the dose-rate
effect was not marked, and up to about 5 Gy almost
no differences in mutation frequency were found at thethree dosc rates examined. These results, together withthose indicating an inverse dose-rate effect in growing
mouse I5178 leukaemia cells [F7], show that cell
growth during protracted irradiation significantly
influences the effects of gamma rays, particularly formutation i~iduction.

2.

G e m cell mutations

280. The measurement of germ cell mutation rates
presents additional difficulties, as animal studies areneeded to demonstrate the mutational response. The
effect of dose rate on the induction of specific locus
mutations has been reviewed by Searle [ S E ] , by the
NCRP [Nl] and by Russell and Kelly [Rll]. No
repair of radiation damage has been demonstrated inmature sperm [ N l , R6], reflecting the lack ofcytoplasm and e~lzynlicactivity. A series of studies
involving in vifro fertilization and embryonic cultureof mouse oocytes has demonstrated, however, that
x-ray-induced damage in mature sperm following
exposure to 1-5 Gy can be repaired in the fertilized
egg. Assay of chromosome aberrations in fertilized
eggs treated with various DNA inhibitors has demonstrated that DNA lesions induced in sperm comprise

674

UNSCEARmainly double-strand breaks arid base damage. It
remains to be deterniined if the specific involvementof repair of a particular type of DNA damage leads tocl~romosomcaberrations arid mutations in fcr~ilizcd
eggs, and whether there is a dose-rate effect for suchdamage. No dose-rate effects appear to have beendenionstrated so far [M48, M49, M50, MS1). Unlike
mature sperm, sperniatogonial cells are metabolically
active, and repair proccsscs can modify the yield of
mutations or chromosomal aberrations with protracted
irradiation. Mouse sperniatogonial stem cell studies
provided the Erst demonstration of a dose-rate effectfor mutational changes.
281. Russell ct al. [R6, R l l ] first showed that specificlocus mutation frequencies after chronic exposures toI3'cs gamma rays (58 mGy mid1) were lower thanafter comparable acute x-ray exposures (0.72-0.9 Gymid1) at doses up to about 6 Gy (Figure XXVI).
Similar results were reported by Phillips [P6]. The
data available have been summarized by Searle [S26].
For chronic exposures the dose-response data werefitted with a linear function, but for acute cxposures apeaked response was obtained; thus, the relative effectivcncss of acute and chronic exposures (i.e. themagnitude of the dose-rate effect) varies with theexposure level considered. By comparing the linear fitsof the data from 0. 3 and 6 Gy points following acute
x-ray exposures with all the data obtained following
chronic exposures (at 0.01 and 0.09 mGy min-l),Russell [R7] obtained a ratio of 3.23 2 0.62. Alternatively, fining a linear function to the acute dataobtained up to 3 Gy, on the assumption of a cellkilling function being present at higher doses, gives aratio of 4.0 [S26].
282. More information on the dose-rate cffect for
mutation frequencies in spermatogonia has been obtained with various dose rates and fractionation regimes. Russell et al. [R7, R11, R17] reported that
mutation frequency decreased markedly as the dose
rate is reduced from 900 mGy min-' to 8 mGy min",although there appeared to be no further reduction atdose rates down to 0.007 mGy min-l. Because this independence of dose rate had been shown over a morethan one thousand-fold range, it was thought unlikelythat mutation frequency would be further reduced ateven lower dose rates. The mutation frequenc
obtained at dose rates from 720 to 900 mGy min- ,with total doses up to about 6 Gy, was compared withthat obtained at low dose rates, on the basis of linear
fits to the data, to give a DDREF of 3.0 2 0.41, inclose agreement with previous estimates [Rl 11.

ray exposlire was split into 60 equal fractions of
100 niGy, given daily at 170 mGy min-l, the mutation
freque~~cy(4.17 10" per locus) was less than one thirdof that froni a si~lgle amma-ray exposure at the same
dose rntc (15.39 10' per locus) and similar to thefrequency obtained after giving a coriiparable dose at
0.08 niGy mia-' over 90 days (3.15 10.' per locus).
However, if 12 weekly doses of 0.5 Gy from x rays
were given acutely the mutation frequency was similar
to that found after a single acute exposure (12.61 loJ
per locus). It may be concluded that repeated small
doses, even if given at a moderately high dose rate,
have less mutagenic effect than the same dosc given
at one time. With fewer fractions (he. larger doses per
fraction) the effect is iritcnnediatc between the
response for an acute exposure and chronic exposurc(Table 16).

S

284. These results are very similar to those obtained
for lung tunlour induction in mice by Ullrich et al.
[U26] (Section II.A.2.b), where the incidence oftuniours for a given dose again depended on the dose
per fraction. A similar explanation can be invoked,
namely that with small doses per fraction, in this case-100 mGy given at a moderately high dose rate, theeffect of each fraction will lie predominantly on thelinear portion of the dose-response curve, and thus theoverall response is similar to that for low-dose-rate
exposure. With larger fractions (0.5 Gy) the quadratic
function makes an increasing contribution to the
response, and thus an effect between acute and chronic
exposure conditions is obtained.

285. Based on the above results of dose-rate effects
on mutation rates in spermatogonia, a DDREF of 3
has bee11 applied by the Committee since the
UNSCEAR 1972 Report [US] for assessing the risksof hereditary disease at low dose rates. This value of
DDREF was also applied in the UNSCEAR 1988
Report [Ul].

1286. It is also possible to examine the effects ofradiation on translocations induced in spermatogonial
cells by subsequent examination of the spermatocyte
stage. Clear evidence of dosc fractionation effects
have been observed in the mouse, and these werereviewed by the NCRP [ N l ] and more recently by
Tobari ct al. [Tg].
Dose-rate reduction factors from 3
to >10 have been obtained.

283. To examine further this dose-rate effect, Lyon etal. [L17] compared the effects of single doses of about
6 Gy from x rays or gamma rays with those of various
fractionation regimes. They found that if the gamma-

287. In a rccclit study [T9], the induction of reciprocaltranslocations in the spern~atogoniaof the adult crabeating nionkey (Macaca fascicrrlaris) was examinedfollowing chronic gamma-irradiation to total doses of
0.3, 1.0 arid 1.5 Gy (0.018 mGy min", about 0.024
Gy in 22 h d-I). Two or three monkeys were used foreach dose level, and in each testis reciprocal translocations were scored in 1,000- 1,250 spennatocytes.

ANNEX F: 1NFL.IJENCE OF DOSE AND DOSE RA;ZE ON STOClLrZSIlC EFFECTS OF RADIATION

The dose-response relationship for the frequency oftranslocation per cell could be represented by a linear
function I@) = 0.09 + 0.16D, wliere I(D) is thefrequency of translocatiol~s(%) and D is the dosein gray. After acute exposurc to x rays at high dose
rates (0.25 Gy min-') the dose response was also
found to be linear, at least below 1 Gy, and fitted by
the equation I@) = 1.08 + 1.79D [M18]. Thus, at highdosc rates the incidence of translocations was higher
than at low dose rates by a factor of about 10.
288. In contrast, van Buul et al. [B24] found that,when the testis of the rhesus monkey was exposed toa gamma-ray dose rate of 0.2 mGy min-' to give a
total dose of 1 Gy, the yield of translocations was
0.38%, about one half the yield obtained at the same
x-ray dose delivered at 0.3 Gy min" (0.83%). If a
correction is made for the RBE of gamma rays, whichis possibly about 0.5-0.7, the translocation yield would
become more than one half that at high dose rate. It
would appear from these results that the dose-rate
effect is less pronounced in the rhesus monkey than in
the crab-eating monkey.
289. These results suggest that a wide range of doserate effectiveness factors nlay be obtained, dependingon the species and strain used for particular study.
Reciprocal translocations are, however, two-hit
aberrations, and the yield will be very dependent on
recovery processes occurring between successive
events. The marked difference in dose-rate effects
between species may be accounted for by variable
rates of repair in different species.
290. Effects of dose rate have also been studied insome of the germ-cell stages present in female mice.
Mature and maturing oocytes have a much larger
dose-rate effect than that found in spermatogonia[R18], and unlike the situation described earlier for
spermatogonia one study has reported that the size ofthe dose-rate effect continues to increase when thedose rate is lowered below 8 mGy mine'.
291. Selby et al. [S38], using the specific-locus
method, examined the effect of dose rate on mutationinduction in mouse oocytes irradiated just before birth.
Female mice were exposed to 3 Gy of whole-body
x-irradiation at dose rates of 0.73-0.93 Gy min-' and7.9 mGy m i d l at 18.5 days after conception. The
frequency of specific-locus mutations was assayed in
the offspring of both control and exposed animals. The
radiation-induced mutation frequency decreased from
6.1 lo-' to 4.2 lom6n~utationsper gray per locus, i.e.
by a factor of about 14, between acute and chronically
exposed animals. Although the confidence limits ofthis estimate of the magnitude of the dose-rate effectare wide with an upper bound of infinity, the results
indicate that mutational damage in females irradiated675

just bcforc birth has a pronounced dose-rate effect.
The mutation rate following exposures at low dose
rates did not difler significantly from that in controls.
Similar calculations, based on rcsults of irradiating
nlature and maturing oocytes at the same dose rates(0.8-0.9 Gy min-I and 8 mGy min-l) [R18, R191,
suggest an approximately fourfold reduction in the
induced mutation frequency in the adult. With protracted exposure and lower dose rates (0.09 ~ n G ymin-I),
a further reduction in mutation frequency was obtained. It was concluded that although the confidence
limits on these estimates of the reduction factor at low
dose rates were large, the results suggested thatfemales irradiated just before birth had a more
pronounced dose-rate effect for mutational damage tooocytes than those irradiated later [S38].
292. Irradiation of mice with high-LET radiation fromfission neutrons has shown average values of RBE of
about 20 (range: 10-45), relative to chronic irradiation
with gamma rays, both with spermatogonial andoogonial irradiation [I6,S121. Spermatogonia show
little or no dose-rate effect with fission neutrons [R8]except at high doses (>2 Gy), where there is asuggestion of a reduced effectiveness, presumably due
to selective cell killing of the spermatogonial
population [B32, R8].

3.

Summary293. Studies on somatic mutations in virro and germ
cell mutations in vivo are relevant to assessing theeffect of dose and dose rate on the primary lesion in
DNA involved in tumour initiation, although subsequent tumour expression will depend on the influence of many other factors. The results obtained indifferent studies on somatic cell mutations in mice
have been somewhat variable, but the overall extent of
the dose-rate effect indicates a maximum value ofabout 2-3. A DDREF of about 3 for specific-locus
mutations has also been found in mouse spermatogonia for dose rates that vary by a factor of more than
1,000, and for reciprocal translocations DDREFs up to
about 10 have been reported, although there appear to
be considerable differences between species. Based onthese results, a DDREF of 3 for damage to spermatogonia has been applied by the Committee since
the UNSCEAR 1972 Report [U5]for assessing therisks of hereditary disease at low dose rates. The
DDREF in mature and maturing mouse ooeytcs
appears to be larger than that in spermatogonia, w i h
the main difference being that the mutation ratecontinues to decrease when the dose rate decreases
below 8.0 mGy min-l. Mouse oocytes present justbefore birth appear to show a more pronounced doserate effect than mature or maturing oocytes, with a
DDREF of about 14.

676

UNSCEAR 1993 UEPORT111. DOSE AND DOSE-RATE EFFECTS IN HUMAN CANCER
294. In general, cpidemiological studies OII the induction of cancer in human populations following exposure to low-LET radiation do not provide information
on exposures at different dose rates that allow estimates to be made of dose-rate effectiveness factors.
Furthermore, dose-response data are generally notavailable at the low doses needed to make good estimates of the linear component of the dose response(slope a ~Figure,I). There are, however, some humandata that can be used to assess likely dose-rate effects;
these have been reviewed by the Committee [Ul, U2].
295. In the UNSCEAR 1986 Report [U2] it was
concluded from a review of dose-response relationships for radiation-induced tumours in man that for
low-LET radiation the data available in some cases(lung, thyroid and breast) were consistent with linear
or linear-quadratic models. For breast cancer linearity
was considered more probable, as the incidence islittle affected by dose fractionation. The Committee
considered that for low-LET radiation linear extrapolation downwards from effects measured at doses ofabout 2 Gy would not overestimate the risk of breastand possibly thyroid cancer, would slightly overestimate the risk of leukaemia and would be likely tooverestimate the risk of bone sarcoma (see paragraph16). For radiation-induced cancers of most otherorgans only experimental data from animals wereavailable 011 dose-response relationships, for which
upward concave curvilinear dose-response relationships with pronounced dose-rate and fractionation
effects are commonly found. The Committee concluded that if similar curves are applied to cancers inhumans, a linear extrapolation of risk coefficients fromacute doses in the intermediate dose region (0.2-2 Gy)
to low doses and low dose rates would very likely
overestimate the real risk, possibly by a factor of up
to 5. Although some reference was made to the dataon the survivors of the atomic bombings in Hiroshima
and Nagasaki, the data were not fully utilized becauseof the uncertainties regarding the revision of thedosimetry. It was also noted that bone sarcoma induction after intake of radium isotopes shows a pronounced inverse relationship of latency to dose,
resulting in an apparent threshold at low doses. For
assessing the risk of lung cancer from exposure toradon the flattening of the response at higher
cumulative exposures could result in an underestimation of the risk by linear extrapolation to low doses.
296. In the UNSCEAR 1988 Report [ U l ] epidemiological data on the effects of low-LET radiation
relevant to assessing risks at low doses and dose rates
were also summarized. The Committee considered thethen most recent data on the atomic bomb survivors inJapan [P4,S9, SlO], which took account of the new@S86) dosimetry. For Icukaemia, a significant
differcncc in the excess relative risk per Gy of organ
absorbed dose among survivors exposed to 0.5 Gy or
more, as opposed to lhose exposed to lower doses(5.53 versus 2.44, rcspcctively) was noted, suggestinga curvilinear dose-effect relationship for haemopoietic
malignancies. For all cancers except leukaemia theexcess relative risk associated with higher doses does
not differ significantly from that at lower doses (0.41
versus 0.37, respectively) suggesting a linear response.
No significant excess risk was observed at doses
below 0.2 Gy, however. The scatter of the data points
in the low dose region was such that they could be
fitted almost equally well by a quadratic, linearquadratic or linear dose-response relationship [Sg].
297. The Committee also reviewed epidemiologicalstudies of individuals exposed to l3'1, which suggested
that radiation doses from chronic internal exposuresarc less carcinogenic than similar doses of acuteexternal radiation by a factor of at least 3 [N2] andpossibly even 4 [Hl5], although non-uniformity ofdose distribution within the thyroid gland may be acontributing factor. Breast cancer studies involving
fractionated exposures provide some information on
low-dose and low-dose-rate effectiveness factors. No
fractionation effect was evident in a Massachusetts
study of breast cancer following n~ultiplefluoroscopic
examination [B15]. However, in a similar but larger
Canadian study, a non-linear dose response, especiallyat high dose, appeared to have been found. This would
suggest a low-dose and low-dose-rate effectivenessfactor greater than 1.
298. From examination of bolh experimental andhuman data the Committee concluded that reduction
factors will vary with dose and dose rate and withorgan system but will generally fall within the range
2-10. No dose or dose-rate reduction factor wasconsidered necessary for high-LET radiation at low
doses.
299. Since the publication of the UNSCEAR 1988
Report [Ul],more information has become available
from cpideniiological studies that relate to considerations of dose-rate effects for low-LET radiation. The
relevant studies are reviewed below.

A. LEUKAEMLA AND
ALL OTHER CANCERS. ~ the atomic bombings in Japan
1. S u w i v o ~ of300. The follow-up study on the survivors of theatomic bombings in Hiroshima and Nagasaki continues
to provide the main source of information on theeffects on a population of exposure to ionizing radia-

ANNW F: INFLUENCE OF DOSE AND DOSE RATE ON STOCIIASIIC EI~FECTSOF RADlAlON

tion. Information is available from 1950 to 1985 on
mortality in just under 76,000 survivors for whomrevised estimates of doses based on the new DS86
dosimetry system [R4] have been calculated [S9, SlO].
301. The dose-response relationship for cancer
mortality anlong t11e survivors of the atomic bombingsin Japan has been examined by Pierce and Vaeth [P2,P3]. Their aim was to determine the degree of
curvature in a linear-quadratic dose-response modelthat is consistent with the data. From this, possible
values for a linear extrapolation overestimation factor(LEOF), which is equivalent to the dose and dose-rate
effectiveness factor (DDREF), were derived.
302. Figure XXVII gives dose-responses for Ieukaemia and all cancers except leukaemia on the assumption of an RBE for neutrons of 10. For both sets ofdata any estimates of dose above 6 Gy (shielded
kenna) have been reduced to 6 Gy. In both cases thedata indicate a levelling off in the relative risk atdoses above about 3 Gy. This apparent plateau at highdoses may be due, at least in part, to cell killing, asappears to be the case in a number of animal studies(see Chapter 11) and other human studies [S45],
although it may in part be attributed to errors in
exposure estimates.
303. Because of uncertainties as to the reason for thisplateau, two approaches were taken by Pierce andVaeth [P2, P3] in evaluating the dose-response data,
namely:(a)@)

the dose range was limited to 0-4 Gy as well as
0-6 Gy. While this restriction in the range of
exposures studied reduces the statistical power instudying the dose response, it should alleviate
any bias in this relationship due to errors inestimates of high exposures. The linear-quadraticmodel assumption is also less critical if madeover a restricted range of exposures;
adjustments were made for random errors in thedosimetry of about 35% across the whole rangeof exposure estimates. Again, such errors could
bias the shape of the dose-response curves andwould lead to risk estimates higher by about
10%. Results of the unadjusted analysis were
given for comparison.

The model fit adopted for all cancers except leukaemia
was taken with excess relative risk constant in age-atrisk, but depending on age-at-exposure and sex.

categories. Estimates of the LEOF from analyses
based on the range 0-6 Gy were lower than those
based on the 0-4 Gy range. However, even after
allowing for random errors in the exposure cstirnatcs,
there is an indication that the analyses based on the
0-6 Gy range are i~ndulyaffected by the lcvellirlg off
in the dose response beyond 4 Gy. Hence, the analyses
based on the 0-4 Gy range are likely to be more relevant for the extrapolation of risks to low doses.
305. For the grouping of all cancers other than
leukaemia, the maximum likelihood estimate of LEOF
was 1.2, with a 90% confidence interval (CI) ranging
from less than 1 to 2.3. However, after adjusting for
random errors in the dose estimates, the best estimateof LEOF was 1.4 (90% CI: <I->3.1). Thus the data
for all cancers other than leukaemia are fitted well bya linear dose-response model, although they are also
consistent with a linear-quadratic model for which thelinear extrapolation overestimation factor is between 1
and 3. For leukaemia, the maximum likelihood estimate of the LEOF from the Japanese data was 1.6(90% CI: 1.0->3.1) without adjustment for random
dosimetry errors and 2.0 (90% CI: 1.1->3.1) withadjustment for these errors. Thus, these data forleukaemia suggest that a linear dose-response model
does not provide a good fit and that a linear-quadraticmodel with an LEOF of the order of 2 is to be preferred. For all cancers together an LEOF of 1.7 (90% CI:
1.1-3.1) was obtained with adjustment for random
errors. Pierce and Vaeth [P2, P3] emphasized that theuse of LEOFs much above 2 would need to be based
upon infornlation from experimental studies and that
their inferences depended strongly on the assumptionthat a linear-quadratic model is appropriate forextrapolation to low doses.
306. It is clear that there are a number of limitationsin the analysis of these data. The plateaus in the dose
response at intermediate doses (Figure XXVII) imply
that analyses of the shapes of the dose-response curves
that include groups exposed at doses much above
3 Gy are likely to underestimate the contribution of
the quadratic component to the dose-response function.
Yet it is these same groups that make a significant
contribution to the overall assessment of risk at highdoses and high dose rates. A further problem lies indetermining the initial slope of the dose-response
function when only limited data are available at low
doses.
2.

304. Estimates of the LEOF were obtained based on
the exposure range 0-4 Gy (DS86), with or without
adjustment for random errors in dose estimates [P2].
Data were given for leukaemia, for all cancers otherthan leukaemia as a group and for combined inferences, assuming common curvature in these two disease

677

Exposures from the nuclenr industry

307. Several studies have been conducted of nuclear
industry workers. In the United States, Gilbert [GI41performed a joint analysis of data from about 36,000
workers at the Hanford site, Oak Ridge National
Laboratory and Rocky Flats weapons plant. Neither for

678

UNSCEAR 1993 REPORT

the groupilrg of all cancers nor for leukaemia wash e r e an indication of an increasing trend in risk withdose. The upper limit of the 90% confidence interval
for the lifcti~rie risk corresponded to a value of
8.2
SV-I for all cancers and 0.6 1 0 ' ~SV" forleukaen~ia.
308. A recent stildy of just over 95,000 individuals in
the National Registry for Radiation Workers (NRRW)
in the United Kingdom cxa~ilirredcancer mortality inrelation to dose [Kll]. For all malignant neoplasms,
the trend in the relative risk with dose was positive
but was not statistically significant (p = 0.10). Basedon a relative risk projection model, the central estimateof the lifetime risk based on these data was 10 lo-'SV" (90% CI: c0-26 lo-*).For leukaemia (excluding
chronic lymphatic leukaemia, which does not appear
to be radiation-inducible), the trend in risk with dose
was statistically significant (p = 0.03). Based on a
BEIR-V type projection model [Cl], the central estimate of the corresponding lifetime risk was 0.76
SV-' (90% CI: 0.07-2.4 10.~1.The NRRW therefore provides evidence of a raised risk of leukaemia
associated with occupational exposure to radiation,but, like the combined study of workers in the Untied
States [G14], is consistent with the risk estimates for
low-dose, low-dose-rate exposures derived for workers
by ICRP [I21 from the Japancse survivor data (4SV" for all cancers and 0.4
SV-' for leukaemia)
which include a DDREF of 2. In particular, combining
the results of the NRRW and the United Statcs studies
produces ccntral estimates for the lifetime risk of 4.9
lo-* SV-I (90% CI: c0-18
for all cancers and 0.3
SV-' for leukaemia (excluding chronic lymphatic
leukaemia) [Kll]. These values are similar to the
ICRP [I21 risk estimates, and generally support the useof a low DDREF in assessing risks at low doses anddose rates from high dose and dose-rate studies.
309. Information has recently become available froma number of low-dose-rate studies in the former
USSR. Kossenko et al. [KlO] have followed up the
population of about 28,000 persons exposed as a resultof the release of radioactive wastes into the Techa
river in the southern Urals. The study shows a statistically significant increase in the risk of leukaemia
estimated to be 0.85 (CI: 0.24-1.45) per lo4 PY Gy.
This is substantially snialler than the value of 2.94 per
lo4 PY Gy derived for the atomic bomb survivors[S9]. Some risk estimates are also available forcancers in a number of organs arid tissues that are
similar to those obtained fro111 the atoniic bomb survivors, but the confidence i~rtervalsare wide. The risk
estimates for leukaen~iatherefore suggest a reduction
in risk at low dose rates by a factor of about 3,
although the data must be rcgarded as preliminary.
Further extended analyses are planned. Data are alsoavailable on the incidence of leukaemia among theworkers at the Chelyabiask-65 nuclear weapons plarit[K12]. Filrii badge data arc available on 5085 men in
two facilities. Avcrage cu~iiulativc doses varied
between 0.49 and 2.45 Sv. When corriparcd with
USSR natiorral rates for tlrc period 1970-1986, therelative risk of Icukaeaiia :~pl)caredlo be illcreased
with a ~.elativerisk of 1.45 G ~ " ,which is about 2.7
times less than that based on ttle atomic bomb
survivors (220 ycars, excess RR = 3.92 Gy" [Sg]).

310. A substantial nuniber of studies have reported
excesses of thyroid cancer in populations exposed toexternal radiation. Many of Uiese studies were summarized in the UNSCEAR 1988 Report [ U l ] and by
the NCRP p 2 ] . The information summarized in [N2]suggested risks of radiation-induced thyroid cancer are
greater in children than in adults, by about a factor 2,
and that females appear to be more sensitive thanmales by a factor of 2 to 3. Radiation-induced thyroid
cancer risks in a population were calculated to be 7.5
lo4 G ~ - 'and in adults to be about 5 lo4 Gy-'.
311. Information on the dose-response relationship forradiation-induced thyroid cancer is available fromstudies by Shore et al. [ S l l ] on about 2650 persons
who received x-ray treatrncnt for purported enlarged
thymuses in infancy. The 3 0 thyroid cancers detectedin the irradiated group (el expected), when allocatedto 5 dose groups, coilld be fitted by a linear doseresponse relationship (Figure XXVIII) I@) = 3.46 ?
0.82 per lo4 PY Gy (21 SE, p < 0.0001), although alinear-quadratic relationship could not be excluded.
312. Shore et al. [ S l l ] also examined the effect ofdose fractionation, as the number of dose fractions
ranged from 1 to 11, with most subjects having 3 or
fewer. Three semi-independent variables were tested:number of fractions, dose per fraction, and averageinterval between fractions. No evidence was obtained
for a significant sparing effect for thyroid cancer
associated with any of these three fractionation
variables, although numerically the excess cancer risk
per Gy was grcater in the lowest dose-per-fractiongroup (0.01-0.49 Gy) than in the higher dose-pcrfraction groups (0.5-1.99 Gy and 2-5.99 Gy), namely
by a factor of 2-3, again possibly reflecting an effectof cell killing.
313. Data on thyroid canccr illduction also comesfrom patients given 1311 for diagnostic reasons [H13,
H15, H35]. Holni et al. [HI31 reported a retrospective
study of 10,133 subjects given 13'1 for suspected
thyroid disease. The population (79% fcniales) had amean age of 44 years. For the 9,639 adults (>20 yearsof age) the mean calculated thyroid dose was 0.6 Gy,

ANNEX F: INFLUENCE OF DOSE AND DOSE RATE ON SSTOCt LASIIC E17ECTS OF RADIATION

whereas in the 494 younger subjects the mean dose
was 1.6 Gy. Patients were followed for a mean timeof 1 7 years after exposure to l3'1. Only patients diagnosed more than 5 years after I3l1 exposure were included in the analysis. No excess of thyroid cancer
was found, although the number of observed cases
was small (8 observed, 8.3 expected).

679

radiation, although these studies mostly involved
adults who appear to be less sensitive to the inductionof thyroid cancer tl~ariyoung persons.

C.

BREAST CANCER

318. Since the publication of the UNSCEAR 1986
Report [U2] further information has become available
on possible effects of dose rate on breast cancer
induction. Miller et al. [M32] have reported data froma number of provinces in Canada on mortality frombreast cancer in tuberculosis patients irradiated during
fluoroscopic examinations. Mortality data have beenobtained for 31,710 women treated at sanatoriums
between 1930 and 1952, known to be alive in 1950
and followed to 1980. A substantial proportion(26.4%) had received doses to the breasts of 0.1 Gy or
more from repeated fluoroscopic examinations during
therapeutic pneumothoraxes. The principal difference
315. Further information on thyroid cancer induction
among sanatoriums was that in Nova Scotia theis available from groups given 1311 for the treatment
patients usually faced the x-ray source, whereas inof hyperthyroidism. Although a number of studies
other provinces they were usually turned away from it.
have been reported, no evidence for radiation-induced
Various dose-response models were fitted to the data.
cancer in these groups has been obtained. Treatment
The best fit was obtained with a linear dose-response
for hyperthyroidism, however, involves the adrninistration of large quantities of l3'1 giving substantial doses
relationship, and it was nolable that a greater effectper unit dose was found in Nova Scotia than in theto the thyroid (>20 Gy), which would be expected toresult in substantial cell killing [H32].
other provinces. Thus, the increases in relative risk
~ Scotia and the otherwere 1.80 and 0.53 G ~ for- Nova
provinces, respectively. In the BEIR V Report [Cl]316. An increased incidence of thyroid nodules has
the difference in relative risk was given as a factor ofbeen seen in the inhabitants of the Marshall Islands
who were exposed to weapons fallout [C19]. However,
6. Even allowing for the differences in orientation
during exposure this difference in response isalthough a large proportion of the dose was contributed by short-lived isotopes of iodine (132.133*135~), surprising, and the authors considered that it could be
due to a dose-rate effect. Although the mean numbers
there was also a contribution from external radiationof fluoroscopic exposures were similar in the two
with only a small proportion of the dose coming fromgroups, the dose rate in Nova Scotia was higher by
It is therefore difficult to use the dam to assess
more than an order of magnitude, although not higher
any effect of dose rate on turnour induction.
than that in the atomic bomb survivors. These results
would
therefore be consistent with a dose-rate
317. There are some uncertainties regarding dosimetryeffectivenessfactor greater than 1.
in the studies of Holm et al. [H14. H15, H221. The
main factors influencing the calculated thyroid dose
are the mass of the gland and the initial uptake of 1311.
Animal studies suggest differences in distribution
D. SUMMARY
throughout the gland will be of less importance (see319. The human data that are available for assessing
Section II.A.2.e). The mean thyroid weight wasestimated on the basis of information in the records
the effects of dose rate on tumour induction from lowand available thyroid scintigrams to be <30 g in 42%
LET radiation are limited. In general, the in for ma ti or^of the patients, 30-60 g in 38%, and >60 g in 12%. In
available is from exposures at high dose rates, andlittle information is available at doses of less than
8% of patients the thyroid weight was not assessed.
No information is given in the paper on the uptake ofabout 0.2 Gy. Analyses of dose-response relationships
for solid tumours in the atomic bomb survivors are
1311 by the gland, but the calculated doses suggest
generally consistent with linearity but also with a
30% has been used, in line with recommendations bysmall reduction in the slope of the dose-response at
the ICRP [I3]. Both these parameters may affect thelower doses. For leukaemia among the atomic bomb
dose calculations, but taken together are unlikely tosurvivors, however, the data are inconsistent withalter the average doses calculated by more than alinearity, and the central estimate of the DDREF atfactor of 2 The studies therefore suggest that 1311 is
low doses is about 2. Model f i t to the dose-response
less carcinogenic than acute exposure to external314. For 35,074 patients in Sweden examined forsuspected thyroid disorders between 1951 and 1969
the mean follow-up was 20 years [HIS, H22]. The~
44 years; 5%mean age at administration of 1 3 1 waswere under age 20 years and the mean dose to thegland was about 0.5 Gy. Persons with a history of
external radiotherapy to the head and neck region, or
who had been given internal emitters, were excluded
from the study. No overall excess risk of thyroid
cancer in this group was observed.

UNSCEAR 1993 REPORT

690

data for the atomic bomb survivors over the dose
range 0-4 Gy kerma for all cancers combined, suggests a DDREF in the range of about 1.7 (when adjusted for randoni errors). For solid cancers alone,
however, li~learilyprovides a good fit, althougt~thedata are also consistent with a DDREF of the order of
2. This interpretation of the data depends on theassumption that a linear-quadratic model is appropriate
for extrapolation to low doses and that the linear term
can be adequately resolved. Information on thyroid
cancer induction by acute external irradiation compared with low dose-rate exposure from intakes of l3'l
are consistent with a DDREF of about 3, although
therc is some question over the contributions thatheterogeneity of dose and uncertainties in the dose
estimates as well as the effect of age make to thein risk. For female breast cancer theoverall reductio~~
information is conflicting. Dose-response relationships
for acute exposures and for fractionated exposures athigh dose rates ;Ire consistent will1 a linear doseresponse rcl;~tionsl~ip.
However, comparative data from
Nova Scotiii and from other Canadian provi~lcessuggest a DDREF greater than one may be appropriate forassessi~lgcancer risks at low dose rates. Althoughepideniiological studies of low dose-rate exposure
should be more relevant for the purposes of radiological protection than studies at high dose rates, thefornler type of study at present lacks sufficient
statistical power to allow risks to be estimated withtight confidence limits. Howcver, the results of studics
such as thosc of radiation workers are consistent withlow values of DDREF.

IV. DESIGNATION O F LOW DOSES AND LOW DOSE RATES
320. The choice of bounds for low and high doses of
low-LET radiation that are appropriate for decisions
on whether to apply dose and dose-rate effectivenessfactors (DDREFs) is not straightforward, as it is essential to understand both the physical and biologicalfactors involved and theirinteractions. The
physical factors, unlike the biological factors, are wellunderstood as a result of the advances that have takenplace in recent years in microdosimetry at the cellularand subcellular levels [B18, B20, G6, P1, R14). This
Chapter reviews the physical, experimental and epidemiological data that can be used as a basis forassessing either the doses or the dose rates below
which it would be appropriate to apply a DDREF.

A.

PHYSICAL FACTORS

321. The microdosimetric approach to defining low
doses and low dose rates uses fundamental microdosimetric arguments that are based on statistical considerations of the occurrence of independent radiation
tracks within cells or cell nuclei (Section I.A.3).
Photons deposit energy in cells in the form of tracks,
comprising ionizations and excitations from energetic
electrons, and the smallest insult each cell can receiveis the energy deposited from one electron entering or
being set in motion within a cell. For *CO gamma
rays and a spherical cell (or nucleus) assumed to be
8 p n in diameter, there is on average one track percell (or nucleus) when the absorbed dose is about
1 mGy [B18, B20]. This dose, corresponding to one
track per cell, on average, varies inversely withvolume and is also dependent on radiation quality.
being much larger for high-LET radiation [G4, 141.

322. If the induction of cancer by radiation at low
doses depends on energy deposition in single cells,with no interaction between cells, there can be no
departure from linearity, unless there have been atleast two independent tracks within the cell. The
number of indcpendcnt tracks within cells follows a
Poisson distribution, as illustrated in Table 17, withthe mean number of tracks being proportional to dose.
For average tissue doses of 0.2 mGy from 6 0 ~ gamo
ma rays, spherical cells (or nuclei) of diameter 8 p
each receive, on average, about 0.2 lracks (Figure 111).
Hence, Table 17 shows that, in this case, just 18% of
the cells receive a dose and 90% of these cells receive
only one track. Thus less than 2% of cells receive
more than one track. Halving the dose will simply
halve the fraction of the total cells affected, and s o atsuch low doses the dose-effect relationship should be
linear. There sllould be no dose-rate effect, because
this only affects the time interval between energy
deposition in different cells (Section I.A.3). This
argument applies to all biological effects where theenergy deposited in a cell produces effects in that celland in no other cell. It is generally thought to apply tocell killing, chromosome aberrations and mutations. I u
applicability to transformation and cancer is less certain. It would need modification, for example, if theprobability of effect were so enhanced by a second
track at a later time that the small minority of suchcells were doniinant. This could conceivably bc thecase for multi-stage carcinogenesis if more than one
essential stage was likely to be caused by radiation.
323. To employ h e microdosimetric argument forassessing low doses, a knowledge of the autonomous
sensitive volume within a cell is required. BiologicalANNEX F: INFLUENCE OF DOSE AND DOSE RATE ON STOCIIASTIC EFFECTS OF RADIAION
effects are believed to arise predominantly fromresidual DNA changes that originate from radiation
damage to chromosomal DNA. It is the repair response of the cell that determines its fate. The majority of damage is repaired, but it is the remaining
unrepaired or misrepaired damage that is then considered responsible for cell killing, chromosomal
aberrations, mutations, transfornlations and cancerouschanges. The link between DNA damage and cellulareffects leads to the notion that the cell nucleus is thecritical volunle that should be used for these microdosirnetric estimations of a low dose. A sphere of
8 p diameter is representative of some cell nuclei;
others may be smaller or larger. On this basis a low
dose would be estimated to be less than 0.2 mGy. Ifpart of the nucleus alone responds autonomously toradiation insults and repair, then a smaller volume
may be appropriate, and the estimate of a low dosewould increase. Conversely, if the entire cell or
adjacent cells can be involved in a cooperative
response, a larger volume may be appropriate.
Figure XXIX shows, for various volumes and radiations, the doses that would correspond to thismicrodosimetric definition of a low dose. The mostfundamental corresponding criterion for a low dose
rate is that the dose should not be exceeded in a
lifetime (say, 60 years), so that there should be
negligible scope for radiation to cause multiplechanges in a single cell or its progeny. By thiscriterion, a low dose rate would be less than aboutmGy min-'. A less cautious criterion, applicableto single-stage changes only, is that a low dose should
not be exceeded in a time characteristic for DNA
repair, say a few hours. In this case, a low dose ratewould be less than about 10'~mGy min".

B. BIOLOGICAL FACTORS
324. A second approach to estimating a low dose andlow dose rate is based on direct observations in animal
experiments. The results of animal studies designed to
examine the effect of dose and dose rate on tumour
induction (see Section 1I.A and Table 8) suggest thatan average dose rate of -0.06 mGy min-I over a few
days or weeks may be regarded as low. The choice by
the Committee in the UNSCEAR 1986 Report [U2] ofa low dose rate to include values up to 0.05 mGymin-' appears to have come directly from dose rates
used in animal studies. If it is assumed that dose-rate
effects arise when sufficient damage accumulates in acell within repair times characteristic for DNA damage(a few hours), then a rounded value of 20 mGy may
be regarded as a low dose.
325. It should be noted, however, that experimental
studies at "highn dose rates were mainly carried out inthe range from about 100 to 800 mGy min-' (Table 8),681

i.e. dose rates more tllan a thousand times those at the"lown dose rates for which a DDREF between 2 and10 has been obtained. It seems likely that a reduction
in tumour ield similar to that obtained at about 0.06
mGy inin-'would have been obtained at dosc rates a
few times higher, or lower, than this. There are analogies here with the data on mutation yield in mouse
spermatogonia, for which a threefold reduction in yield
was obtained at 8 ~ n G ymin-' compared with 720-900mGy min-' (Section II.C.2), with no further reduction
at 0.007 nlGy min-' IRIS]. It may be concluded,
therefore, on the basis of animal experiments that a
low dose rate can be taken to be 0.1 mGy min-' when
averaged over about an hour.

326. A third approach to estimating low doses comesfrom parametric fits to observed dose-response datafor cellular effects. As described in Section 1 . k 2 , theeffect can be related to dose by an expression of theform

in which al and a2,the coefficients for the linear andquadratic terms fitted to the radiation response, areconstants and are different for different end-points.
This equation has been shown to fit data on the induction of chromosome aberrations in human lymphocytes, for example, and also data on cell killing andmutation induction. For some types of unstable chromosome aberrations in human lymphocytes, the al/%quotient is about 200 mGy for *CO gamma rays
[L12], and thus the response is essentially linear up to
20 mGy, with the dose-squared term contributing only
9% of the total response. At 40 mGy the dose-squared
term still only contributes about 17% to the overall
response. On this basis it could, therefore, be estimated that 20-40 mGy is a low dose.
327. A fourth approach to estimating a low dose isbased on the analysis of data from epidemiologicalstudies, in particular from data on the survivors of theatomic bombings in Japan. Analysis of the dosc
response for mortality from solid cancers in the range
0-4 Gy (adjusted for random errors) has suggested anall- quotient from a minimum of about 1 Gy with acentral estimate of about 5 Gy p2, P3]. An all%quotient of 1 Gy suggests that at a dose of 100 mGy
the dose-squared term contributes less than 10% to the
response and at 200 mGy the contribution of the dosesquared term is still less than 20%. This would suggest that for tumour induction in humans a low dosecan be taken to be less than 200 mGy. There is, inpractice, little evidence of a departure from linearity
up to about 3 Gy. In the case of leukaemia in theatomic bomb survivors, where there is significant
departure from linearity at doses above about 1.5 Gy,
the central estimate of all? has been calculated to be

682

UNSCWR 1993 REPORT

1.7 Gy, with a niinimun~value less than 1 Gy [P2,P3]. On the basis of this central estiniate the dosesquared tern1 would contribute about 10% to the
response at a dose of 200 mGy and about 23% at
500 n~Gy.

328. A number of approaches based on physical,
experimental and epiden~iologicaldata have bccn examined for assessing either doses or dose rates for lowLET radiation below which it would be appropriate toapply a dose and dose-rate eITectiveness factor(DDREF). The fundamental ~nicrodosirnetricargument
indicates that a low dose, at which fewer than 2% of
cells receive more than one track (assuming a cell
diameter of 8 pm), is about 0.2 mGy. Since halving
the dose will simply halve the fraction of cells
affected, at such low doses the dose-effect relationshipshould be linear. This fundamental microdosimetricapproach would have severe practical limitations inradiological protection, and there do not appear to be
any experimental or epidemiological data that suggestthat it should be applied.

329. Dose-response studies for cells in culture suggestthat doscs of less Ulan about 20-40 niGy are low;
however, epidemiological studies on the illduction ofsolid tumours in the survivors of the atoniic bombingsin Japan iridici~tca li~leardose respollse up to about
3 Gy, which suggests that for turnour induction a low
dose would bc at least 200 mGy. For leukacnlia induction there is a signific~ntdeparture from linearity atdoses above about 1.5 Gy, hut again a low dose canbe taken to be less than 200 mGy.
330. Infom~ation on low dose rates for tumour
induction can at present be obtained from animalstudies. The results of a series of studies in experimental animals that arc summarized in Table 8 suggestthat a low dose rate can be taken to be less than about
0.1 mGy minml given over a few days or weeks.
331. The Committee concludes that for the purposesof assessing the risk of tunlour induction in man adose-rate effectiveness factor (DDREF) should beapplied either if the total dose is less than 200 mGy,
whatever the dose rate, or if the dose rate is below
0.1 mGy min-l (when averaged over about an hour),whatever the total dose.

CONCLUSIONS
332. Information on dose and dose-rate effects onradiation response has been reviewed in this Annex
with the aim of providing a basis for assessing therisks of stochastic effects at low doses and low dose
rates from infomiation available at high doses andhigh dose rates.

333. The conventional approach to estimating both theabsolute and the relative biological effectiveness of agiven radiation at minimal doscs is based on theassumption, derived here in general terns of target
theory, that the induction of an effect can beapproximated by an expression of the formI@) = ( a l D + ?D 2, e -<P ID PP4(30)

in which a, and 9 are coefficients for the linear andquadratic terms for the induction of stochastic effects
and p1 and P2 are coefficients for linear and quadratic
terms for cell killing. This equation has been shown togive a fit to much of the published data on the effectsof radiation on cells and tissues, including cell killing,
the induction of chroniosome aberrations, mutation insomatic and germ cells, cell transforniation andtumour induction. For tumour induction it is generally
assumed that at sufficiently low doses al will be con-stant and independent of dose rate. In practice, however, tumour induction has rarely been observed either
in experirncntal animals or in epidemiological studies
at acute doses of much less than 200 mGy.

334. The reduction in effect per unit dose observed at
low doses and low dose rates, compared with effects
at high doses and high dose rates, is termed a doseand dose-rate effectiveness factor @DREF), although
the terms dose-rate effectiveness factor @REF), linear
extrapolation overestimation factor (LEOF) and lowdose extrapolation factor (LDEF) have also been used.
At sufficiently low doses, when cell killing can bedisregarded, the DDREF can be defined from theprevious equation as
DDREF = ( a , D + %D 2 ) / a l ~== 1 + (%/al)D(31)

where D is the dose (in gray) at which the effect ismeasured.
335. In the absericc of clear information on lhe shapeof the dose-response curve for tumour induction at low
doses, the initial slope, a l , of the response at low
doses can be determined, in principle, from exposures

ANNFX F: 1NFLUI:NCE OF DOSE AND DOSE RATE ON STOCIMSTIC EFFECTS OF RADIATION

at low dose rates. There are, however, limited data on
dose-rate effects on tumour induction iii human populations and no information on the mechanisms influencing tunlour development from which qi~antitative
estimates of dose-rate effects can be inferred. Animalstudies and experinlents on ccll transfomlation and on
somatic and gem1 cell liiutation rates are therefore
needed to provide insight into the likely effccls ofboth dose and dose rate on turnour induction. Biophysical models of radiation action also provide a n
approach for understanding how the fundamental interactions of radiation with cells can play a part in doserate effects.
336. Models of radiation action. Guidance on
expected effects at low doses and low dose rates canbe sought from radiobiological and epidemiological
data in terms of the quantitative models that have beendeveloped to describe thern. Radiobiological data for
effects on single cells under a variety of conditions
have led to the development of maliy quantitativemodels, mechanistic or phenomenological, for single
radiation-induced changes in cells. Multi-stage modelsof radiation carcinogenesis, based on epidemiologicalor animal data, assume that one or more changes are
required before a cell becomes malignant and thatradiation can induce at least some of these changes(see Annex E, "Mechanisms of radiation oncogenesis"). The biophysical concepts underlying thedifferent models are described in terms of generalfeatures of target theory, based on the insult of
ionizing radiation always being in the form of finite
numbers of discrete tracks. In this way fundamental
expectation can be sought on the nature of overall
dose responses, their dcpendence on dose rate andtheir features at the low doses of practical importance.
337. Dose-response relationships can be subdivided
into regions. In region I a negligible proportion ofcells are intersected by more than one track, and hence
dose responses for single-stage effects can be confidentiy expected to be linear and independent of dose
rate. In region II many tracks intersect each cell, but
multi-track effects may not be observed in the experimental data, and hence independent single-track action
is commonly assumed, although true linearity anddose-rate independence hinge on the validity of thisassumption. In region Illmulti-track effects are clearlyvisible as non-linearity of dose response and hence
dwe-rate dependence is likely. The simpler forms ofdose response can be expanded as a general polynomial, with only the dose and dose-squared terms
being required to fit most experimental data, althoughsometimes a separate factor is added to account forcompeting effects of cell killing at higher doses. In
this approach it is common to regard the fitted linear
coefficient as being constant and fully representativeof the response extrapolated down to minimally low

683

dose and dose ratc. However, the literature conpins
data from numerous studies that violate illis simple
expectation, for both low-LET and high-LET radiation.
Many of these imply that mulli-track effects can occur
in the intermediate-dose region (II) and that evenwhen the dose response appears linear it may exhibit
dose-rate dependence and non-linearity at lower
doses.
338. Low-dose and low-dose-rate expectations basedon rnulti-stage processes of carcinogenesis depend
crucially on the radiation dcpcndence of the individual
stages and on the tissue kinetics. Expectations could,
in principle, readily range between two opposite
extremes. On the one hand there could be the total
absence of a linear term, implying vanishing risk as
the dose tends to zero, as should be the case if two (ormore) tinie-separated radiation steps were required. On
the other hand, there could be a finite slope of thedose response down to zero dose, and this could evenincrease with decreasing dose rate, as may occur ifeither of the stages can occur spontaneously and if
there is clonal expansion between thern (see Annex E,"Mechanisms of radiation oncogenesis").
339. Lge shortening in experi~nenlal animals.
Radiation-induced life shortening in experinlental
animals following exposure to both low- and highLET radiation at low to intermediate doses is mainly
the result of an increase in tumour incidence. There islittle suggestion that there is a general increase inother causes of death into the lethal range, althoughdegenerative diseases in some tissues may be increased at higher doses. On this basis, life shortening
can be used to assess the effect of dose fractionationand protraction on tunlour induction.
340. The majority of comprehensive studies on theinfluence of fractionation of low-LET radiation onlife-span have used the mouse as the experimental
animal. The effect of fractionation appears to be very
depende~iton the strain of mouse and the spectrum of
diseases contributing to the overall death rate. For
example, in some strains thymic lymphoma incidence
is increased by fractionation. Where this is a major
contributor to the fatality rate, fractionation can leadto a greater loss of life expectancy than acuteexposures. Overall there is no clear trend, and theresults from a number of studies suggest that, whencompared with acute exposures, the effects offractionation on life-span shortening are small and, a1
least for exposure times of about a month, simple
additivity of the injury from each dose increment canbe assumed. For fractionation intervals over a longer
time there is a tendency to a longer life-span with anincreasing interval between the doses, but the increases
in life-span observed are generally less than thosefound with protracted exposures.

341. When the effects in nlice of acutc exposures to~OW-.LETradiation arc con~paredwith chose of protracted irradiation given more or less continuously, thecffectivcncss of the radiation clearly decreases withdecreasing dosc rate and increasing time of exposure.
With lifetime exposures Illere is some difficulty
assessing the total dose contributing to t l ~ closs oflife-span. However, the res~lltsavailable suggest thatwith protracted exposures over a few months to a year
the effect on life-span shortcning is reduced by factors
between about 2 and 5 compared with acute exposures. The effcct of dose ratc on tumour induction andlife-span shortening has also been examined in rats
and beagle dogs, although no significant differences
have been found. In these two studies dose rates
varied by factors of 60 or less, whereas in the studies
with mice they varied by factors of 100 or more.
342. A number of early studies suggested that fractionated exposures to high-LET radiation induced
more life shortening than single exposures. Morerecent studies have shown, however, that when total
doses are low and the dosc per fraction is small, there
is no significant difference in life shortening between
fractionated and acutc exposures. Although the data
are limited, the available information suggests that
protraction of exposure docs not affect life shortening.
343. Turnour induction in experimental animals. A
number of studies have been published that permit theeffect of dose ratc from low-LET radiation on tumour
induction in experimental anirnals to be examined. The
data that have been reported by various authors covera wide range of dose-respol~se patterns, and withdifferent dose ranges, differing values of DDREF may
be calculated. A wide rangc of DDREFs for tumour
induction in different tissues has been found for dose
rates generally varying by factors between about ahundred and a thousand or more. Some of the tumour
types for which information is available have a humancounterpart (myeloid leukacmia and tumours of thelung, the breast, the pituitary and the thyroid),
although the tumours involved may not be strictly
comparable to the human disease. Other types either
have no human counterpart (Harderian gland) or
require for their development substantial cell killing
and/or changes in hormonal status (ovarian tumour,thymic lymphoma). In practice, the DDREFs found inthese two groups arc little different, falling in therange from about 1 to 10 or more, and there is noclear trend with tissue type.
344. Myeloid leukacmia has been induced in lZFM
and CBA mice, although there are differences insensitivity between the strains and between the sexes.
DDREFs between about 2 and more than 10 havebeen obtained, but with no consistent trend withchanging dose rate. A reasonably consistent finding isthat DDREFs for tulnour induction in manllnary tissue~ one
in rodents tend to be low, although c v c ~hereeffect of dose fracauthor bas reported a s~~hslantial
tionation on the tumour rcspollse in mice. DDREFs forlung turnour induction also tel~dto be low, with values
falling in the range of ahout2-4 following exposure lo
both external radiation at different dose rilles and toinhaled insoluble radionuclides with different effective
half-times in the lung. The results of the principal
studies that l ~ a v ebeen reviewed are given in Table 8,
together with the dose ranges over which the DDREFs
have been estimated.
345. It has also been dernonstratcd that the effect offractionation on tumour response depends on the dose
per fraction. With small doses per fraction, which lie
predominantly on the linear portion of the doseresponse curve, the tumour response is similar to thatobtained at low dose rates. At higher doses per
fraction, the response approaches that obtained forsingle acute doses.
346. The main conclusion to be drawn from theresults of the studies on radiation-induced life shortening and those on the induction of specific tunlour
types following exposure to low-LET radiation is thattunlour induction is dependent on the dose rate, witha reduction in incidence at low dose rates. While theabsolute value of the DDREF varies with the conditions of cxposure, the animal strain and gender,
tissue/tumour type and the dose range over which it iscalculated, there is a consistent finding of a differencein tumour yield per unit dose for dose rates varying by
factors of between about 100 and in excess of 1,000.
347. The animal studies also indicate that the presenceof a dose-rate cffect could not necessarily be inferredfrom dose-response relationships obtained at high dose
rates alone, since for a number of studies the doseresponse data for tumour induction up to a few graycould be adequately fitted by a linear function. This
would imply the absence of a visible quadratic (i.e,multi-track) function in the dose response, whichaccording to conventional interpretation would appear
to be a prerequisite for an effect of dose rate on
tumour yield. Clearly, when information is available
only for exposures at high dosc rates, any attempt toassess the effect at low doses and low dose rates, andhence a value of the DDREF, by simply fitting alinear-quadratic or similar function to the dose
response is unlikely to be fully successful. The lirniting factor is the amount of information available at
low doses from which the linear tenn (a,of equalion30) can be accurately defined. For planning future
animal studies it is clear tl~at tilost information is
likely to come from studies on animals exposed at
different dose rates, rather than fro111 attempting toobtain information on the risks at very low doses. It isANNEX F: 1NI:LUENCE OF DOSE AND DOSE WTE ON STOClIASllC E F E C E Of: RADIATION

to be hoped that more studies will be carried out tosuppleliient (he infonnation presently available.

348. From the limited and somewhat disparate data on
high-LET radiation it is difficult to generalize. Thereis, howcvcr, little cxpcrin~cntalsupport for applying a
DDREF to high-dose or high-dose-rate cxposurcs to
calculate risks at low doscs and dose ratcs. Sin~ilarly,
thcrc is ii~tlcevidcncc to suggcst that, in the absenceof cell killing, thcrc is an appreciable cnhancement oftumour yield when the dose from high-LET radiation
is protracted or fractionated.
349. Cell fransforrndion. Cell transformation studies
can yield infonnation of practical use in radiation
protection in addition to giving insight into the mcchanisms of carcinogenesis. At present, however, the mostquantitative data is derived from the least physiologically relevant cell systems, such as cultured embryo
cells or the mouse fibroblast cell lines C3HlOT41 andBALBIc3T3. Thus, when attempts are made to extrapolate to cancer induction in man, which occurs
mainly in epithelial tissues (lung, gastrointestinal
tract), the biological limitations of these assay systems
must be considered. In addition there are a number oftechnical uncertainties that must be taken into account.
These include the effects of cell cycle time, of plating
density and of pronioters and suppressors, some ofwhich may be nonnal conlponcnts of the growth
medium, particularly the serum, and therefore difficult
to control.
350. Nevertheless, in carefully controlled experiments
where asynchronously dividing cells or, in some cases,
non-dividing plateau-phase cells have been irradiated,
the resulting observations on dose or dose-rate effects
for low-LET radiation are in general agreement withthose relating to other cellular effects, such as cellkilling and the induction of mutations or chromosomal
aberrations and to tumour induction in animals. Doseresponse curves per cell at risk have a number offeatures in common with tumour induction in vivo.
showing an initial rise in transformation frequency
with increasing dose to a maximum and then adecline. When plotted as transformants per surviving
cell, the dosc response for low-LET radiation generally shows the expccted linear or linear-quadratic
relationship tailing off to a plateau at higher doses.
When low doscs of x rays or gamma rays are delivered at low dosc rate or in fractionated intervals, a
DDREF of bctwccn about 2 and 4 is obtained. Bccause of the liniiti~tionsof the cxperin~cntalsystem,
the range of dose rates applied i n experimental
animals has not been used, with the maximum range
being a factor of about 40. It is noteworthy that someexperimental data suggest that the linear term mayalter with dose rate, but this may be accounted for by
thc lack of precise data at low doses.

685

351. Exposures to high-LET radiation result in aya tendency
higher transfor~natiori c f i c i c ~ ~ c withtowards a linear relationship, in line with data forchromosomal aberrations and again tending to a platcau at high doscs. As cxpcctcd fro111this pattern of
response, Uierc is no tendency for the responsc to
decrease at low dosc ratcs or with fractionation, arid inpractice, a number of studies havc shown an enhanced
effect. The main evidcncc for an "inverse" dose-rate
effect with high-LET radiation sccnis to be limited to
5.9 MeV or fission spectrum neutrons, and over the
past few years cstimatcs of the magnitude of theincreased effect have been reduced from factors ofaround 9 to about 2 or 3. Resulls reported from anumber of laboratories havc become reasonably
consistent, and it has been possible to develop a modelthat can predict many experimental results.
352. The model is based on the assumption that thetarget in the ccll, taken to be the nucleus, has a "window" in the cell cycle lasting about 1 hour during
which it is more sensitive to radiation. With protracted
or fractionated cxposurcs there is a greater opportunity
for this particular window to be hit by at least one
track, and thus the possibility for an enhancement oftransforniation frequency with a reduction in dose rate.
The magnitude of any effect will depend on the lineal
energy, and with alpha-particle irradiation little
enhancement would be cxpcctcd, as is in factobserved. Although such a model appears to beconsistent with much of the experimental data and has
been tested in onc series of studies, it is criticallydependerit on the target size and will need to be
examined at different doses, dose rates and dose-Gactionation schedules to fully examine its general applicability. Ultimately a full understanding of the inverse
dose-rate effect must depend on experimental studies
designed to understand the mechanistic basis of theobservations.

353. Despite this possible explanation of the inverse
dose-rate effect, there remains the problem that it islargely based on the results obtained with theC3HlOT?4 mouse-embryo-derived fibroblast cell line
and may well havc only limited application to humancarcinogenesis. The development of epithelial cellsystems that are of much more direct relevance tohuman cancer should be a research priority.
354. Mutagenesk in sonzatic and genn cells. Studies
on soniatic mutations in virro and gcrlll ccll mutations
in vivo are relevant to assessing the effect of dose anddose rate on the primary lesion in DNA involved intumour initiation, although subsequent tumour
expression will depend on the ir~fluenceof many otherfactors. The results obtained in different studies onsomatic cell mutations in mice have been somewhat
variable, but the overall extent of the dose-rate effect686

UNSCEAR 1993 REPORT

indicates a ~naximurnvalue of about 2-3. A DDREF
of about 3 for specific-locus mutations has been foundin nlouse spennatogonia for a dose rate of 8 mGyn~in-'compared with a dosc rate of about 900 niGymin", although no further reduction in effect was
obtained at lower dose rates down to 0.007 mGy
min-l, i.e. an overall range in dose rates in cxccss ofa factor of 10'. Based on these results, a DDREF of
3 for damage to spcrmatogonia has been applied by
the Committee since the UNSCEAR 1972 Report [US]when assessing risks of hereditary disease at low dose
rates. For reciprocal translocations, DDREFs up to
about 10 have been reported, although there appear to
be considerable differences between species. Reciprocal translocations are, however, two-hit aberrations,and the yield will be very dependent on recovery processes between successive events. The marked differcnces in dose-rate effects between species may be theresult of variable ratcs of repair. The DDREF in
mature and maturing mouse oocytes is larger than thalin spermatogonia, wilh the main difference being thal
the mutation rate continues to fall when the dose rate
decreases below 8 mGy min-'. Mouse oocytes present
just before birth show a more pronounced dose-rate
effect than mature or maturing oocytes, with a
DDREF of about 14.
355. Epidemiology.
The human data that areavailable for assessing the effects of dose rate on
tumour induction from low-LET radiation are limited.
Ln general, the information available is from exposuresat high dose rates, and little information is available atdoses of less than about 0.2 Gy. Analyses of doseresponse relationships for solid tumours in the atomic
bomb survivors are generally consistent with linearity
but also with a small reduction in the slope of thedose-rcsponse at lower doses. For leukaemia anlong
the atomic bomb survivors, however, the data areinconsistent with linearity, and the central estin~atcof
the DDREF at low doses is about 2. Model fits to thedose-response dab for the ato~nicbomb survivors overthe dose range 0-4 Gy kerma for all cancers combined, suggests a DDREF in the range of about 1.7(when adjusted for random errors). For solid cancers
alone, however, linearity provides a good fit, although
the data are also consistent with a DDREF of theorder of 2. This interpretation of the data depends on
the assun~ptionthat a linear-quadratic model is appropriate for extrapolation to low doses and that the linear
term can be adequately resolved. Information on
thyroid cancer induction by acute external irradiationcompared with low dose-rate exposure from inlakes ofl3'1 are consistent with a DDREF of about 3, although
there is some question over the contributions thatheterogeneity of dose and uncertainties in the dose
estimates as well as the effect of age make to theoverall reduction in risk. For female breast cancer the
information is conflicting. Dose-response relationships

for acute exposures and for Gnctionated exposures athigh dose ratcs are consistent with a linear doseresponse relationship. However, comparative data from
Nova Scotia and fro111other Canadian provinces suggest a DDREF greater than onc may be appropriate forassessing cancer risks at low dose rates. Althoughepidcniiological studies of low dose-rate exposure
should be more relevant for the purposes of radiological protection than studies at high dose ratcs, theformer type of study at present lacks sufficient
statistical power to allow risks to be esti~natedwith
tight confidence limits. However, the results of studies
such as tl~oseof radiation workers are consistent withlow values of DDREF.
356. Dose criteria. The designation of low doses andlow dose rates below which it is appropriate to apply
dose and dose-rate effectiveness factors @DREFs) inassessing risks of human cancer resulting fromradiation exposure have been considered by theCommittee. A number of approaches based on physical, experinlental and epidemiological data have beenreviewed. It was concluded that for assessing the risksof cancer induction in man a DDREF should beapplied either if the total dose is less than 200 mGy,
whatever the dosc rate, or if the dose rate is below
0.1 mGy min-I (when averaged over about an hour),whatever the total dose.
357. Sutttmary. The dose-response information on
cancer induction in the survivors of the atomic
bombings in Japan provides no clear evidence forsolid tumours for a DDREF much in excess of 1 forrisk estimation at low doses and low dose rates of
low-LET radiation. For leukaemia, the dose responsefits a linear-quadratic relationship with a best estimateof the DDREF of about 2. There is only limited support for the use of a DDREF from other epidemiological studies of groups exposed at high dose rates,
although for both thyroid cancer and female breast
cancer some data suggest a DDREF of possibly 3 may
be appropriate.
358. The results of studies in experimental aninlals
conducted over a dose range that was similar, althoughgenerally sonlewhat higher, than the dose range towhich the survivors of the atomic bombings in Japan
were exposed, and at dosc rates that varied by factors
between about 100 and 1,000 or more, give DDREFs
from about 1 to 10 or more with a central value ofabout 4. Sonic of the aninial tumours have no counterpart in human cancer. Similar results to those obtainedwith arri~naltumour rnodcls have been obtained lor
transforniation of cells in culture, although the
DDREFs obtained have 1101been as large. In a numberof these experimental studies linear functions would
give a good fit to both the high- and low-dose-rate
data in the range from low to intermediate doses. This
indicates that if the cellular response can, in principle,

ANNEX F: INFLUENCE 01; DOSE AND DOSE RATE ON STOCIIASTIC ET;m.CISOF RADIATIONbc fittcd by a lincar-quadratic dose rcsponse, in practicc it is not always possiblc to rcsolvc tl1c colnlnon
linear tcrnl for cxposurcs at different dosc ratcs.

359. If the hurnan response is similar to that in
cxpcrimcntal animals, then it can be c~lvisagcdh a t at
lowcr dose rates than were cxperienccd in Hirosl~ima
and Nagasaki, a DDREF grcater than that suggcslcd
by analysis of the dosc-rcsponsc data could bc
obtaincd. Howcvcr, inforn~ationfrom human populations cxposed at low dosc rates suggcsts risk cocfficicnts that arc not very different from those obtaincd
for the atomic bomb survivors, although the risk
estimates have wide confidcncc intervals. Takcn together, lhe available data suggest that for tumour
induction the DDREF adoptcd should, on cautious
grounds, have a low value, probably no more than 3.
Insufficient data are available to make recomn~cndations for specific tissues.

687

360. For dlc purposes of applying DDREFs forasscssirlg cancer risks ill man, thc Conirnittcc concludcd citller that dosc ratcs less dial1 0.1 n ~ G ymin"(avcragcd ovcr about an hour) or acutc doses lcss than
200 rnGy rnay be regarded as low.
361. For high-LET radiation, a DDREF of 1 is at
prcscnt indicated on thc basis that cxpcrin~cntaldata
suggcst littlc cffect of dosc ratc or dose fractio~lation
on tumour rcsponse at low to intermediate doses. It isnoted that a DDREF of somewhat lcss than 1 issuggested by some studies, but the results areequivocal and cell killing may be a factor in the tissue
rcsponse.
362. In the case of hcreditary disease, the adoption of
a DDREF of 3 is supported by cxpcrimental data inmale mice, although a somewhat higher value has
bccn found with one study in female mice.

UNSCEAR 1993 REPORT

688

Tnble 1
Summary o l reductlon ftrctors for esLirnutlng cancer risk 81 low dose t ~ n dlow dose rat= for low-LET radinlion

Hduoiunfi~ror

SourceYear

Aircrnaitr
condiriuru for npplyhr aredwrbrr farror

Dare

(GY)

Dare rareRc/.

BDR InBElR V
Lukrania
Solid canmr

1960
1990

Intcrnatimd Commissim rm Radidog'cal
Prdcaion

ICRP

1911
1991

2

b

b

2

~0.2

c0.1 Gy h"

Natiod b a l on Radiation Rotutim
and Meuurcrnents (United S h t u )

NCRP

1980

2-10

42

4.05 Gy y-'

PI1

National Radidogicd Prdeairn Board(United Kingdan)

NRPB

1988
1993

3
2

4.1
4.1

4 . 1 Gy d.'c0.1 mGy mine'

IS311
W36j

United N a t i o ~Scientific Committee
cn the Effccls of Alanic Radiation

UNSCEAR

19n
1986
1988

2.5
up to 5
2-10

cO.2
4.2

e0.05 mGy min"
4 . 0 5 mGy min"

United Stales Nudear Rcgulalory
Commission

hUC

1989
1991

3.3
4.2

c0.05 Gy d.'
4 . 1 Gy h"

Gmmittec on Ihc Bidogial EIfear
d lmidng Radiation

225
2
2-10

2

Not specitid

Far radiological proteaion purpcncr.

' C d d be higtru. as d i s a u d in Annex G of h e WSCEAR 1977 Rcpon [W] (paragaphs 314 and 318).

1~41
ICll

4.1
4.1

1111

p7-1

0

IU41
1~21

[A61
[A101

A N N W F: INFLUENCE OF DOSE AND DOSE ILATE ON STOCHASTIC EFFECTS OF RADIATION

689

Table 2
Ionizetion clusters produced directly In a DNA-relnted target by a slngle radiation track a[G6, G21]

AWage number of iorizaiionrinRodhion rypc"

DNA scgmenr of length 2 nm

Nuclearome

Chromnrin segmnu of lcngrh U nm

Gamma rays

1 (0 to >a)2 (0to >20)

2 (0to >45)

Alpha partidca

2 (0 to ~15)

10 (0 to 90)

50 (010 >2W)

A similar, a slightly largcl, n m b c r d excitstim~are produced, in additim.
Estimated range in parcnth-.

Table 3
Damage products Ln a single-cell nucleus traversed by tl single radiation track a[G6, G21]

Rodhion iypc

Avaagc number of induced br&

Atwage number ofionira~ionr

D M singlrsrrad k c a h

DNA d o u b l e - s n d breaks

Chromatin

Gamma rays

70 (1-1500)

1 (0-20)0.04 (0-few)

0.01 (0-few)

Alpha partided

VOOa (1-100,ooo)aM,(0400)

35 (0-100)

6 (0-20)" Nurnba d t h e breaks, based m linear extrapolation to low dose of a s c l d m of u;perirnalal data, and the range estimated from the minodosirnulie Variatim
d single tracks.
Estimated range in parentheses.

Table 4Age at death of RF female mice exposed at 10 weeks of age to whole-body gamma-radiation

W81
C u e of &arh

All caurcs

All cauaes aha than neoplsstic" Study terminated at 799 days cf age.
Dab for conlrds from [U21].

Dare

Nwnbcr of(GY)~ i m k

0

232

1

95

3
0
1
3

Adjured mean age ai dcarh(days) 2 ST 'Difference /ram controh

92

577 r 8552 r 13473 2 17p c 0.02
p c 0.001

104
29
20

611 r 10650 r 18657 r 30

p > 0.20
p > 0.30

690

UNSCMR 1993 RIiPORTAJWEX F: INFLUENCE OF DOSE AND DOSE RATE ON S T O C M C EFW:CX OF RADlATlON

691

Table 6
Mean lifespan and incidence of melignancles In C57BI mlce exposed at 3 months or age lo single andIractionakd doses of ganrrne rodlallon[MU)]
Exposure parrnn

Peamcrekc

PY)

8 /rcurionr
m 3-how t r r dSI~&

I 0 /rarrimr

m 24-how inrm&

hfean lifc+pan (d t SO

SUM^

606 2 29

0576 r 38
540 2 36
S32 2 38
478 2 43

0.25
1
2
4

600 ? 60
610 z 59

611 t 62
Ml r 22545 t 55

609 t 59
516 :51

D~HMC
incidence (%)'Ihymoma

1.27

0
0.25

1
2
4
All leukacmia

:.65
0
23
13.29

20.93

0
0.25
1
2
4

Cardncmaa and .arcanas

16.16

15.04

24.07
24.14
22.61
35.59

20.75
30.11
32.17

13.62
2657

16.3

0
0.25

1
2
4

All malipandu

4.63
0.66
0
23.7

1.89
5.38
7.83

14.04
8.94
14.29
16.08

19.44
16.1
19.13
2034

26.42
27.96
24.39
33.19

0
0.25
1
2
4

28.51
21.95
26.37
39.16

39.81
36.2
36.52
54.24

45.28
51.61
51.3

Table 7
Life shortening fmm single, fraclionatd and continuous gamma-ray exposure of mice[nl
Corff;icnr o/

D P of~ =w=

life sharcninr( d q s lasf pcr Gy)

TLK panen

Rc/.

I

I

I

24 once p a we&
60 m u p a wak
For 23 week
For 59 w+ck

II

22.6 r 2 2
17.5 2 3.3
15.8 r 2 2
7.7 r 0.2

I

I

IT101
IT121

17sl

WTs]

UNSCEAR 1993 REPORT

692

Table 8I h m and dose-rate elfertiveness facton (DDREFs) for tumour Induction by low-LET radlntion In expcrlrnental
nnlrnab
DDREF

e r a c ( m ~ min-I)yhUpper range of dare for
rvdu01l“m (Cy)Animal siudiai

Eflecl

tlixh

Rc/.

Low

V&

Hixh
d m rarednse rareLow

h d a i r n dud
hrmurrs

RFM f d e mice

450

0.06

2

2

-3

[vl& ul4.
UlS]h

BALBIc f d c mice
BALBlc fanale m i a

4W
350

0.06
0.06

2
2-3

2
2-3

28
3.2-4.2[vl% u l s ]
[U61

-3

[GI01
[u61
~ 1 5 1
[G71
F"J21

g
adcnmrdnanrr

lung o n mBeagle dogr

Mnmary turnoun

BALBIc mice
Spngw-Dawlcy rats
Spngue-Dawlcy rau
BALBic mice
WAGlRU ntr

350
100
10-30
450
(2 GY)

0.07
0.3
0.M-0.14
0.06(2 GY)

0.25
0.9
1.8
2
2

0.25
27
0.5
2

11.4
-1
1.6-1.7
1.9-1

Munmary
rdcnmranan.r

Spnguc-Dawley tau

100

(L3

0.9

27

4

[ s151

Mydad Icukrania

RFM rndc mice

800

(BAM rmlc mice
RFMNn f m l c mice
RF frmdc mice

2M
450
67

0.04-0.6
0.04-0.11
0.06
0.00d0.7

1
1.5-4.5
3
3

3
1.54.5
2
6

5.1
22-5
9.7-8

[UZl]
[MI31
PIS)
Lu2ll

[Bul

RFM fanrlc m i a

450

BALBlc fandc mice

400

0.06
0.06

2
2

2
2

-5.5
6.7

[UlSl
[vlsl

Pltuiluy lumoun

BALBIc mice

450

0.06

3

2

-6

[U14, U 151

Skin tumoun

LBA/H fcrmle r n i a

<

6

6

-2

Thymic lymphana

Rrm fcrmlc mice
RFM male m i a

450Onrim tumaurr

Thynid turncurs'(BA r n i a

Lmg E n n r rau
R.U

T d ~moun''

2

Spngue-Dewley
male rats

ILgh dose rstc from "Y; low d a e rate from '"G CT %r.
Ten frodims d 0.2 Gy each.
*ll source (fractimatcd exposure).
tiigh doc rnte ban x rays; low dose rate from "'1.

0.06
O.M-O.6

2
4

2
4

5.8
26

(U12, UlS]

800
(15 Gy)2sW(11 GY)(64-160 Gy)(03-85 Gy)(100 GY)

15
0.94-10.6
1164-160
0.845
100

2-10
-1
-10

rW2l

1.3

0.022

28

3

-3

[M431

wll

PI
1~41

ANNEX F: IN17LUENCE OF DOSE AND DOSE RATE ON S M C I IASTIC EmCE 01: RADIATION

693

Table 9Tumour Incidence in mice and evaluation of dose and dose-mte efrecUveness facton (DDKEF)for exposure to
gamma-radiation

[ml
DDREF

LOU' dose rare

Ifigh dan rare

U p p e range o/ dare fa cvaluarwn
Dare rMge

Incidcncc.

Dore r m g c

Inciduuc,

(Gyf

an

(GY)

a~
(96 pr Gy)(% pcr GY)
+I SE

(GY)

'

V ~ U CHigh dare rnrc

=lsb

Low dasc r u e

21 SE
Myeloid leuhernia (RF male micc) [U21]

0-1
0-15
0-3

14.4 r 3.2
17.4 ? 21
14.3 z 1.7

0-3.080-3.290621

28 z 0.8
26 z 0.7
0.87 r 0.53

3.08

5.1

3.8-7.0

5.8
6.14

6.5
9.6

4.5-9.6
6.3-15

2
2

4.6
8.1

1.8-1 1.5
3.3-201.5

2

22

1.5-3.1

2

2

3.8

27-5.3

2
2
2

6.8
5.8
4.1

3.7-12
359.7
256.9

2

5.8

3.5-9.6

1

Myeloid Itukarmi* (RF lemde mice) [U21]

0-3
0-5

6.8 r 2.0
3.7 z 1.2

(L3.1
0-5.8
06.14

0.99 r 0.47
1.01 z 0.38
0.71 2 0.31

33

Piluibr y tumoun (Whl fcmmlc mice) [Ulq

0-2
0-3

2 2 r 0.8
3.9 r 0.7

0.48 :0.70

0-2

2
3

Hmrdtrian dand tumoun (RM Iemalc mice) [UlS]

0-1
0-15
0-2
0-3

3.8 2 1.2
3.3 r 0.9
5.7 r 1.2
5.4 z 0.7

0-1
0.2

1.5 z 0.9
1.5 r 0.5

Ovarian tumoun (RFM female mice) [Ulq

0-05
0-1
0-2

42 r 72
36 r 925.6 r 5.4

0-1
0-2

1.7 r 3.5
6.2 r 3.9

0.5
1
2

Thymic lymphoma (RFM female mice) [U15)0-2'16.7 r 1.8

0-2

29 r 1.9

B s s d m linm fil w a d a c range speaficd f a mlurt~io n(i.e. a+&
Estirnsrcd ban thc fraaicmd standard errors in the acute and chronic incdeaccr.

2

UNSCMR 1993 REPORT694

Tahlc 10CalculaUons or 1)I)REF nllowlng for unccrialnlles In the dose-t-csponsc for gammtr-rndl~ctlon81 high and low
dase rates[FBI
Upper range of dare fa cvalunrion
(G,)
Eficr

Aninvrl

Mycloid lculuaoir
Myeldd lcuhania
Pituitary lumoun
Hardaim gland rumours&rim tumcura

High dose rare

Low dose rorc

1
3
3
2

3.08
6.14
2
2
2

Male mice
Fcmdc miceFemale mice
Fcmde mice
Fcmdc mice

1

DDREF a+ I SE

Hc/:

5.6
11.4

3.8-8.1
6.3-203-=
274.3
3.5-18

[u211
Iu2ll
P151
1~151
[ u 151

25
4.2
8

Table 11
Acute myeloid leukacmia In male CBNH mice exposed to gamma radiatlon[MI31
Chronic a p o s w e

Arwe ~ p a n v c

f o r d darc
ICY)

Nvmbrr of m'ce

L a h e m i n (5)N u m b of mice

1.5
3.0
4.5

99
83
105

11
17

143 (72/11)
131 (65166)
131 (65166)

25

'

DDREF
LerVtacmia (%)
5
6
5

22
28
5

Dcsc rate 0.25 Gy min.'.
Dcsc rate 0.25 Gy mino' in 20 rractionr. 5 days w d y for 4 wceb: or 0.044.11 mGy m i d l lor 28 days conrinucurly.
Two groups of mice wed uirh numbers in parcnrhau.

Table 12Lung adenocarclno~nalncldence In BALRlc mice exposed to single, fractlonatcd and prolrscted gemma mdiatlon
P261
7

Groq
1
2
4
5

2
2
2
2
2

6

2

3

'

f o r d dare
(GY)

ErpMyr regimen

Darc r a e(Gy mi7-l)

Ohrenod incidcncc(961

Erpcrlai incidence

0.35
0.083~
0.35
0.35
0.35
0.35

38.6 r 5.4
21.4 z 2 6
21.3 2 3.3
27.9 r 4.5

37.3
21
21

30.3 r 6.4
32.9 z 6.8

29

I&& dae ralc
Low dose rrrc
0.1 Gy per f r a d i m
0.5 Gy p a fradim
1 Gy p a f r a d i w 'I Gy per fracriw 'Inddcnce r SE.
Expected incidence b . 4 m I = 11.9 t 4D + 4.30' (D in Gy).
Two fnaicna ~cparalcdby m c day (&cup 5) and 30 days (Grurp 6).
0.083 Gy d.' (0.06 mGy min-I).

@)

25
29

ANNFX F: INFLUENCE OF DOSE AND DOSE RATE ON STOCllkTnC EI:FECTS OF RADIATION

695

T ~ ~ b 13
lc
Lung adenocarcinorna Incidence in UALBlc nlice eslimalcd lmni niodel fits lo experimenhl data for
gamnin-rndialion exposun:["261
Tunuw incidcnce (SJ

Low dare r u e(0.1 Gy p a Jrocrion)

Hixh dose role
(0.35 Gy I&.')

Dosc
(GY)

0.1
0.2
0.3
0.5
0.93
1
2
3

DDREF

Toral

ExcersToral

Dcers *

12.34
12.87
13.49
14.98
19.34
20.20
37.1
62.6

0.44
0.97
1.59
3.07
7.44
830
25.20
50.70

1230
1270
13.10
13.90
15.60
15.90
19.90
23.90

0.40
0.80
1.20
2.00
3.72
4.00
8.00
12.00

1.1
1.2
1.3
1.5
20
21
3.2
4.2

Expeaed incidence bsed m I = 11.9 + 4D + 4.3~' (D in Gy).

Table 14
Mammary adenocarcinoma Incidencx! In BALBlc mice exposed to single, frnclionated and protracted gamma
rndiation
[U261

Group

Torn1 dose
(GY)

1
2
3
4
5
6

0.1
0.2
0.25
0.25
0.25
0.25

Expsure regimen

lii& Q.c rate
High dosc rate
High dosc rate

Low dose rate
0.01 Gy daily hacliom
0.05 Gy duly f n a i m s

Dosc rere(Gy mine')O b d incidence '(46)

kpecrcd incidence

0.35
0.35
0.35
0.1
0.05
0.05

9 r 3.2
15 r 4.8
20 r 4.6
7.9 2 2.1
7.5 2 2.3
17 r 4.1

9.6
14.4
18.0
8.5
8.5
18.3

(%)

r SE
* lnadcoce
Expected incidence bared m 1 = 7.7 + 3.SD + 1 5 0 ~ '(D in Gy).

a0.1 Gy d" (0.07 mGy mine').

Table 15
Mammary adenocarcinoma incidence In BALBlc mice estimated fmm model fils to experimental data for
gamma-radiation expcrrure[U261
Tumolu incidcncc 1%)

0.0s
0.1
0.15
0.2
0.25

Low dose role
(0.1 Gy per frocrian)Iligh dcue role
(0.35 Gy min-')

Dose
(GY)

DDKEF

Toral

ficrs fTord

Exccrf

8.27
9.55
11.60
14.40
17.96

0.57
0.65
3.9
6.7
10.26

7.89
8.05
8.23
8.40
8.9

0.19
0.35
0.53
0.70
0.88

Expecced inddmcc l a a d an I = 7.7 + 3.SD + IMD'(D In Gy).

3
5.3
7.4
9.6
11.7

UNSCWR 1993 WPORT

696-

Table 16
Spclflc-locus mutations In adult spermatogonle of mice expnsed to x- or gantma-radlnllon[Ll'l,EsfImrc c m d i r i w
mCn gamma rays, 12 fractions wcddy@CO pmma rayr, 60 fractions daily

X ray4 12 hadims weckJy
mCo gamma rays, acute"Co g a m rays, acutegr a p , chronic (90 days)

Tord dateI)arc r a c~CY)(mGy "&-I)

6.15
6.26
6. 15
6.36
6.70
6.18

0.6
170
600-700
170
720
0.08

Frcgrcncy p a locw

6.26 10"
4.17 10.'1261 '01
13.07 10"15.39 1 ~ '3.15 10.'

Table 17
Proportions of a cell population traversed by tracks at various levels of track density

MCM masks
per rcU

0.1
0.2
0.5
1
2
5'
10 "

Pcrccnmge of re/& in populaion suflcring
0 tracks

1 nark2 aarks

3 narks

905

9
16.4
30.3
36.8
27.1
3.4
0.05

0.5
1.6
7.6
18.4
27.1
8.4
0.2

0.015
0.10
1.3
6.1
18.0
14.0
0.8

81.9
60.7
36.8
13.5
0.7
0.005

4 nncks>5 n a c h

P m c m g c ofhir c d kwirh only I track

0.4
5.3
56.0
97.1

95.1
90.3
n.1
58.2
31.3
3.4
0.05

0.2
1.5
9.0
17.5
1.9

At Ihae vdua appreciable poportims of the a l l populatioo uill incur more than 5 track.

Table 18
Alternallve criteria for upper limits of low dose and low dose rate for assessing risks of cancer induction In man(for low-LET radiation)
LOW'dose

Low dare rare(~GY)

(mGy m x l )UNSCE4R 1966 Repat IU2j

200

?his Annex

200

0.05
0.1 '

Mcrhod tf enimnrion

Lincar tmn dominant in parametric tits lo dngleo*l do= rcsponscr
Miaodaimaric nnluntioo of minimal multi-track coincidences in cell nucleus

20 - 40
0.2

0.M

Obacwcd dosc-rate cKcas in animal carcinopncsia
Epidcmidogid slud~esof rurnvorc of the atomic banhngs in Japan*

Averagd over about an hcur.

10" (lifetime)
1u3 (DNA rcppir)

200

A N N M F: INFLUENCE OF IIOSE AND DOSE RATE ON STOCI IASnC EFFE.'E(JISOF RADlAnON

A - lligh absorbed doses and high dose rnles
I3 - Linear, no threshold, slope aH
LOW-LETC - Low dme rate, slope aL
D - Limiting slope Tor low & rate, slope a~

ABSORBED DOSE (Gy)Figure I.
h e - r e s p o n s e relationship for rndiatlon-induced cancer.
Possible lnii?renres are iliustraled in extrapolating data availnble at high do= and high dose rates
to response a1 low doses and dme rates for low-LET radiation.
[Nil

'1

Data from w l 4 ]0 Data from [D?]Figure 11.
Incidence of myeioid leuknemln In male CBA/H mice lollowlng brief exposum to x rays.
InZ MI41

697

2

1

3

4

ABSORBED DOSE (Gy).......

C

Epidemiological or cxpcrimcntal data

I I10.001 -I

111
Dose regions (gamma rays)

I

I

I

I

I

I

I

1

0.001

0.01

0.1

1

10

100

1000

10000

TRACKS PER NUCLEUS

I

---+

11

-+

111

I

I

I

I

I

0.0001

0.001

0.01

0.1

1

1
10

GAMMA-MY DOSE (Gy)II-+tIIi -41I

I0.0001

0.001

I
0.01

I

I

0.1

1

NEUTRON DOSE (Gy)

0.001

0.01

0.1

1

ALPHA-PARTICLE DOSE (Gy)Figure 111.
Schematic dose-tpsponse relatlonshlps for Induction of stochastlc blologlcal effects
by hlgh-LET (slow neutrons and alpha particles) and low-LET (gamma rays) radhtlon
on llnear (upper plot) and logarlthmlc (lower plot) scales.
These example curves do not refled all types of observed response,and In some in v i w systems alpha particles may be less eKective than neutrons.
[CZS, GS]

ANNEX F: INFLUENCE OF DOSE /\ND DOSE RAIE ON STOClmrIC

I

I

b

699

b

DOSE

WSE

I

EFFECTS OF RhDlATlON

I

b

b

DOSE

DOSE

Figure 1V.
Various shapes of dose-mponse curves for turnour induction.

w21

Figure V.
Expected cumulative lncldence of radlatlon-Induced cancer according to a Ilnear-quadratlc model wlth cell kllllng.
Cell survlval tuncUons S
deflned by= 0.1 Gy-I and= 0.08 Gy-2,$1 = Od Gy-1 and Pz = 0.08 Gy-2.
Smi, deflned
Incidence (upper plot) normalized to 150 104 at 3 Gy.
Helallve rfsk (lower plot) wllh normallzaUon lo the same value of a,.

>

w21

Single exposure (error bars in the centre of the symbol)

0 Fractionated exposure (error ban lo the lcft of the symbol)

Figure VI.
Lire-span rcduclion In male BALBlc m e lollowing exposure to single o r fractionated dosesor
gamma rays.

Figure VII.
Llle shortening Ln fen~uleRFM mice following exposure l o 1 J 7 ~ gammasrays
at hlgh and lnlermediale dose rates.
IS131

U N S C M R 1993 REI'OIIT

702

FEMALES0.067 G min-1
0 0.004-0.rmGy min-1

E 40W

4
I

I

I

I

Figure VIII.
Mycloid leukaemltr lncldcnce In FW mice lollowing exposure to x rays at high and lntermcdlatc dose rates.
w121

Flgurr 1X.
Lung ~~dcnocurclnomu
incidence In female BAI,B/c mice (nge-adusted)following exposure to 137C.5 gamma rays at hlgh nnd intermcdlnte dose rates.

WlS, u26l

ANNIIX I:INFLUENCE OF I>OSli AN11 DOSE RATE ON STOCl IASfIC EFFECIS 01: RADIATIONTIME A F E R INFIALATION MI'OSURE (d)Figure X.
Theoretical beta-radlaUon dose rates to l u n g of beagle dogs
for various inhaled radionuclides incorporated In fused aluminosilicate particles.
Thc dose rates have been normalized to an IniUtil dose rate of 1 Gy d-1.
[Mil

Figure XI.
Memmnry tumour lncidcnce in female DALllIc mice (npe-ndjuskl)
following exposure to 13'Cs gamma rays at h l ~ hend intermediak dme nib.
lUlS1

703

UNSCMR 1993 ItEl'Olrr

704

100-

NEUTRONS

80-

h

E
,.,

60-

f

E a-

t

20 -

0
0

I

I

I

I

0.5

1

1.5

2

1
2.5

DOSE (GY)
Flgure X11.
Incidence of liver tumours in 3-month-old BC3FI mule mice (age-adusled)following exposure to 250 kVp x rays (upper plot) and llsslon neutrons (lower plot).
P31

ANNEX F: INFLUENCE OF DOSE AND DOSE MllJ ON STOCIiASTlC EI:I-TCTS OF RADJAnON

Flgure XIII.
Herderinn gland lumour lncldence In female RFM mice (age-adusted)followlng exposun? to 137Cs gamma rays at high and intcrmcdiate dare rates.
w121

Figure XIV.
Ovarian tumour Incidence in female RFM mice (age-ncUusted)followlng exposure to InCs gamma rays nt high and intermediate dme rates.
w121

705

0

1

I

I

I

I

I

0.5

1

1.5

2

25

3

DOSE (Gy)Figure XV.
Thymic lymphon~aincidence in lemale RFM mice (age-aausted)lollowing exposure tn lnCs gamma rays at high and Inkrnicdiate dme ram.

[U121

0

500 WLM per week
50 WLM per week
5 WLM per week

-

-

I

to1

12

I
ld
EXPOSURE (WLM)

I
1o4

1
I$

Figure XVI.
LireUme risk cocmclents for tunlour Induction in rats exposed Lo radon nt various exposure ram.

la1

Figure XVII.
General characteristics or incidence o r cell transformation per latcd cell induccd hy low-LET radiation.
Pammetcn al = 104 Gy-1, a2 = 104 Gy-2,= PO-1 G y l and P2 = 10.' G y 2have bccn selected (o illustralc the inlporlance of lincnr and quadratic Lcrn~sin the induction of transformnUons
and or cell rcproducllve death. The broken line rcpmenls the inltiiil siopc, dekrmlned by al.
P91

PI

Singlc doses

0

Fractionated do=

Figure XVIII.
TMnsformation frequency In C3HlO'I?4 ells roll ow in^ exposure to single o r rrnctionlitcd dmes or x rays
berore Ule establishment of asynchronous growth or cells.
In the case of lracllonated doses, the radIaUon was delivered in two equal expacures separated by flve hours.
[MXI

'1

Single exposure, 1 Gy min-1

0 Five Iractions, 0.5 Gy rnin-lFlgure XIX.
'ItaasformaUon fmuencv In CJHlOTH cells
foUowlng exposure to slngle or fkctio&eted doses of 6@Co gamma rays.
H6l
--

-

-

~

~

ws,

Flgum XX.
nPruformaUon f q u e n c y In C3HlOTH cells
following exposum to rlngk or protracted doses of x rays.
Llnea am flu b the data wllh a Ilnenr dwe-rwponse funcUon.

PllANNEX F: INFLUENCE OF 1)OSE AND DOSE RA'111 ON STOCl IASflC IiFFECE OF RADIAnON

Figure XXI.
Transformallon lrequency In C3HlOT35 and BALB-313 cells
following exposure to single dm= o l x rays.

L111
Neoplastic transformation
Survival

I

0
12

NEUTRON ENERGY (kcV)

N~UR
XXlI.
Maxlmal mlallve blologlcal elfectlvenesr (RBEM) for rurvlval andneoplasllc transformallon as a luncUon of rnonoenergetlc n e u h n energy.
RE& repr~senlr the raUo of the inlllal slopesof h e dose-response curves (44lor each energy.

IMW

709

Figure XXIII.
Transbrmatlon Itxqurncy in CJHlOTH cell. exposed to Ilsslon spectrum n e u h n s at hloh *nd In"-Urn.. but I=s.
Ilmken Ilni

*-9

-a

I

0

03 Gy reactor-produd neutrons
0.3 Gy aurlcntor-produd neutrons
0.21 Gy reactor-produced neutrons

W S E RATE (Gy min-1)
Flgure XXIV.
Inverse dose-rate e f k t In (UHIOTH cells irradlaled wlU1 Ilsslun spcclrum and 5.9 hleV neutrnns.

[MI21

rah.

Single doses

0 Five frictions equally sprcad over 8 h
6

-

4

-

Con~inuousexposure for 8 h

2-

I

I

I

0.3

0.4

0.5

0
0

0.2

0.1

DOSE (Gy)Figure XXV.
lkansformalion lrcquency in C 3 H l W cells following exposure
to single, lractlonated o r conllnurd dmesof 5.9 hleV neulmns.
The equations and pnmmelcrs of the flttcd curves am given in paregraphs 259 and X O .
IB30, M B I

0

I

I

I

I

1

2

3

4

I
5

I
6

I
7

I

I

8

9

DOSE (Gy)
Flgun! XXVI.
Mutation rate in mouse spermetogonla lollowing acute end chrunlc exposures.
S h l g h t lines of best n t by the method or maximum likelihood lor specific-locus data.
IR111

UNSCEAR 1993 REPORT712

EQUIVALENT DOSE IN BONE MARROW (Sv)

2.5 1

0

CANCERS OTHER THAN LEUKAEMIA

I
1.1

I
I
I
I
I
3.3
4.4
2.2
EQUNALENT DOSE 1N INISI'ESTINES (Sv)
I

I

I

1
5.5

Figure XXVII.
Excecs relatlve risk of morlallty from leukaemla and cancers other than ieukaemla i n the Life Span Study.
(m86dmlmetry, both citles, both sexes, age a1 e x p u r e gmups 0-19, 20-34 and r35 yean. 1950-1985).
Points are estimalcd relative risk i n each equivalent dme intcrvt~l,averaging with equal weights over six
age-atexposure and sex grnup. RBE Is assumed equal lo 10. U n a a m smoothed avenge of the points.
Error ban refer lo lhe smoothed values.

IP9

ABSSORBED DOSE IN THYROID (Gy)
Flgure XXVIII.
AcUusted thymld cancer Incidence in relatlon to radlation dme In the thymld gland.
IS111

UNSCMR 1993 11E1'01t1'

714

GAhfMAS

9 McV ALI'IIA

IJM'I1CIESMONOENEIIGETIC NEUlRONS
plus 1096 gamma rays

MONOENERGEJlC NEUTRONS

0
8 pm

0

12 urn0.1

1

NEUTRON ENERGY (MeV)

10

0.1

1

NEUTRON ENERGY (MeV)

Figure XXIX.
Upper limit of a low dose for various assumed sensitive volumes within a cell.
[G41

Ib

ANNI:X F: INI'LUENCE 01: DOSE AND DOSE RATE ON STOCIlASTlC EFE(JIS 01: WIATION

Ainsworth. BJ.. R.J.M. Fry, P.C. Brcnnan ct al. Life
shortening, ncoplasia and systematic injuries in micealter single or fractionated doses of neutron or gamma
radiation. p. 77-92 in: Biological and Environmental
Effects of Low-Level Radiation, Volume 1. Sr11/PUIJI
409. IAEA, Vienna, 1976.
A2 Alper, T., C. Marshall and C.B. Seymour. Reply toletter by Elkind et al. Int. J. Radiat. Biol. 53: 961-963(1988).
A3 Archer, M.C. Chemical ~3rcinogencsis.p. 89 in: The
Basic Science of Oncology. (1.F. Tannock and R.P.
Hall, eds.) Pergamon Press, Oxford, 1987.
A4 Aghamohammadi, S.Z., D.T. Goodhead and J.R.K.
Savage. Produdion of chromosome aberrations,micmnudei and sister chromatid exchanges by
24-keV epithermal neutrons in human Go
lymphocytes. Mutat. Res. 211: 225-230 (1989).
N Andersen, A.C. and L.S. Rosenblatt. The effect ofwhole-body X-irradiation on the median lifespan of
female dogs (beagles). Radiat. Res. 39: 177-200(1969).
A6 Abrahamson, S., M. Bender, C. Book ct al. llealtheffects models for nuclear power plant accident
ansequence analysis. Low LET radiation. Part 11:
Saentific bases for health effects models. NUREG/
CR-4214 SAND85-7185, Rev. 1, Part 11 (1989).
A7 Alper, T. Cellular Radiobiology. Cambridge
University Press, Cambridge. 1979.
A8 Armitage, P. and R. Doll. The age distribution ofcancer and a multistage theory of carcinogenesis. Br.
J. Cancer 8: 1-12 (1954).
A9 Armitage, P. and R. Doll. A two-stage thmry ofcardnogenesis in relation to the age distribution ofhuman cancer. Br. J. Cancer 11: 161-169 (1957).
A10 Abrahamson, S., M. Bender. B.B. Boecker et al.
Health effects models for nuclear powcr plant accident
ansequence analysis. Modifications of models
resulting from recent reports on health effects ofionizing radiation. Low LET radiation. Part 11:
Sdentific bases for health effects models. NUREGI
CR-4214, Kev. 1. Add. 1 and LMF-132 (1991).
A l l Aghamohammadi, S.Z., D.T. Goodhead and J.R.K.
Savage. Induction o l sister chromatid exchanges(SCE) in Go lymphocytes by plutonium-238 aparticles. Int. J. Radiat. Biol. 53: 909-915 (1988).
B1 Balcer-Kubiczek, E.K. and G.H. flarrison. Survival
and oncogenic transformation of C31llOT45 cells after
extended x irradiation. Radiat. Res. 104: 214-223(1985).
B2 Balcer-Kubiaek. E.K., G.H. Harrison and B.W.
Thompson. Repair time for oncogcnic transformation
in C 3 H l O m cells subjected to protracted x-irradiation. Int. J. Radiat. Biol. 51: 219-226 (1987).
B3 Balcer-Kubiczek. E.K.. G.H. Harrison, G.11. Zeman el
al. Lack of inverse dose rate effect on fission neutron
induced transformation of C3fllOTM a l l s . Int. J.
Radiat. Biol. 54: 531-536 (1988).
B4 Balcer-Kubiuek, E.K., G.H. Harrison and G.H.
Zeman. The relationship between dose ratc and trans-

A1

715

formation induction in C31110TH cells by TRlCjA
reactor fission neutrons at 0.3 Gy. p. 529-538 in: Imw
Dose Radiation: Biological Bases of Risk Assessment.
(K.1:. Baventock and J.W. Stather, eds.) Taylor andFrancis. London. 1989.
B5 Barendsen, G.W. Radiosensitivity of tumoun and rclatcd cells in culture. Biomedicine 26: 259-260 (1977).
B6 Barendsen, G.W. Dose fractionation, dose ratc andiso-effect relationships for normal tissue responses.
In!. J. Radiat. Oncol. Biol. Phys. 8: 181-197 (1982).
B7 Barendsen. G.W. Dosc-cfled relationships for various
responses of mammalian cells to radiations ofdifferent linear energy transfer. J. Soc. Radiol. Prot. 4:
143-152 (1984).
B8 Barendsen, G.W. Do fast neutrons at low dose rateenhance cell transformation in vitro? A basic problemof microdosimetry and interpretation. Int. J. Radiat.
Biol. 47: 731-734 (1985).
B9 Barendsen, G.W. Physical factors influencing thefrequency of radiation induced transformation of
mammalian cells. p. 315-324 in: Cell Transformation
and Radiation Induced Cancer. (K.11. Chadwick et al.,eds.) Adam Hilger. Bristol. 1989.
B10 Beer, J.Z., E. Budzicka, E. Niepokojaycka et al. Lossof tumourigenecity with simulbnmus changes inradiosensitivity and photosensitivity during the in vitro
growth of L5178Y murine lymphoma cells. Cancer
Kw. 43: 4736-4742 (1983).
B l l Bcttcga, D., P. Calzolari, P. Pollara et al. In vivo celltransformations induced by 31 MeV protons. Radiat.
Res. 104: 178-181 (1985).
B12 Bettcga, D., P. Calzolari. A. Ottolenghi et al.
Transformation of C31i10W with Cm-244 alphaparticles at low and high dose ratcs. p. 333-340 in:
Cell Transformation and Radiation Induced Cancer.
(K.11. Chadwick et al.. eds.) Adam Hilger, Bristol,
1989.
B13 Birnboim, I1.C. and J.J. Jevcak. Fluommetric method
for rapid detection of DNA strand breaks in humanwhite blood cells produced by low doses of radiation.
Cancer Rcs. 41: 1889-1892 (1981).
B14 Book, S.A., D.A. McNeill, N.J. Parks et al.
Comparative effects of iodine-132 and iodine-131 in
rat thyroid glands. Radiat. Res. 81: 246-253 (1980).
B15 Boice, J.D. and R.R. Monson. Breast cancer inwomen after repeated fluoroscopic examinations of
the chest. J. Natl. Cancer Inst. 59: 823-832 (1977).
B16 Brenner, D.J., E.J. Itall. G. Randers-Pehnon et al.
Mechanistic considerations on the dose-rate/LET
dependence of oncogcnic transformation by ionizing
radiations. Radiat. Res. 133: 365-369 (1993).
017 Bond, V.P., E.P. Cronkitc, S.W. Lippincott et al.
Studies on radiation-induced mammary gland
ncoplasia in the rat. 111. Relation of the neoplastic
response to dose o l tobl body radiation. Radiat. Res.
12: 276-285 (1960).
B18 Bond. V.P.,L.E. Feinendegen and J. Booz. What is a"low dose" of radiation? Int. J. Radiat. Biol. 53 (1):1-12 (1988).

716

UNSCEAR 1993 REPORT

B19 Boot, L.M., P. Dentvelzcn, J. Calafat et al. Interactionof x-ray treatment, a chemical carcinogen, hormonesand viruscs in mammary gland carcinogenesis. p. 434440 in: Oncology. Volume 1. (K.L. Clark et al.. cds.)
Yearbook Medical Publishers, Chicago, 1970.
B20 13002, J. and L.E. Feinendegen. A miaodosimetric
understanding of low-dose radiation effects. Int. J.
Kadiat. Biol. 53 (1): 13-21 (1988).
B21 Borek, C. and EJ. Hall. Effect of split doses of x-rays
on neoplastic transionnation of single cells. Nature
252: 499-501 (1974).
B22 Borek, C. Neoplastic transformation following split
doses of x-rays. Br. J. Radiol. 52: 845-846 (1979).
B23 Broerse, J.J., L.A. Hennen, MJ. van Zwieten et al.
Dose-effcct relations for mammary caramgenesis indifferent rat strains after irradiation with x-rays andmonoenergetic neutrons. p. 507-519 in: Biological
Effects of Low-Level Radiation. STl/PUB/646. IAEA,
Vienna, 1983.
0 2 4 Buul, P.P.W. van, J.F. Richardson and J.H. Goudzwaard. 'Zhe induction of reciprocal translocation in
Rhesus monkey stem-cell spermatogonia: effects oflow doses and low dose rates. Radiat. Res. 105: 1-7(19 86).
B25 Burch, P.R.J. Calculations of energy dissipation
characteristics in water for various radiations. Radiat.
Res. 6: 289-301 (1957).
B26 Boche, R.D. Effects of chronicexposure to x-radiation
on growth and survival. p. 222-252 in: Biological
Effects of External Radiation. (N.A. Blair, ed.)
McGraw-Hill, New York, 1954.
B27 Bmwn, J.M. The shape of the dose-response curve forradiation cardnogenesis. Extrapolation to low doses.
Radiat. Res. 71: 34-50 (1977).
8 2 8 Brues, A.M. and G.A. Sacher. Analysis of mammalianradiation injury and lethality. p. 441-465 in:
Symposium on Radiobiology. (JJ. Nickson, ed.) John
Wiley and Sons, New York, 1952.
B29 Bustad, L.K., N.M. Gates, A. Ross et al. Effects ofprolonged low-level irradiation of mice. Radiat. Res.
25: 318-330 (1965).
B30 Brenner, D.J. and E J . I-iall. The inverse dose-rate
effect for onmgenic transformation by neutrons andcharged particles: a plausible interpretation consistent
with published data. Int. J. Radiat. Biol. 58: 745-758(1990).
B31 Barendsen, G.W. Influence of radiation quality on theeffectiveness of small doses for induction of reproductive death and chromosome aberrations in mammalian cells. Int. J. Radiat. Biol. 36: 46-63 (1979).
B32 Batchelor, A.L., RJ.S. Phillips and A.G. Searle. A
comparison of the mutagenic effectiveness of chronic
neutron- and gamma-irradiation of mouse spermatogonia. Mutat. Res. 3: 218-229 (1966).
B33 Bond, V.P. and M.N. Varma. A stochastic, weighted
hit size theory of cellular radiobiological action. p.
423-437 in: Radiation Protection. Proceedings of theEighth Symposium on Microdosimetry. (J. Booz and
H.G.Ebert, eds.) EUR-8395 (1983).
B34 Brewen, J.G., RJ. Preston and H.E. Luippold. Radiation-induced translocations in spermatogonia. 111.
Effect of long-term chronic exposures to gamma-rays.
Mutat. Res. 61: 405-409 (1979).

nurch, P.RJ. Radiation carcinogenesis: a new hypo-thesis. Naturc 185: 135-142 (1960).
Burch, P.1t.J. and M.S. Cheslers. Mammalian cell survival and r;idiiltion quality: analysis with allowancefor delta tracks. Phys. Med. Biol. 26: 997-1018(1981).
Burch, P.R.J. and M.S. Chesters. Neoplastic transiormation of cells in vitro at low and high dose rates offission neutrons: an interpretation. Int. J. Radiat. Biol.
49: 495-500 (1986).
Barendsen, G.W. RBE-LET relations for induction of
reproductive death and chromosome aberrations inmammalian cells. p. 55-68 in: Proceedings of the
Sixth Symposium on Microdosimetry, Brussels, May
1978. (J. Booz and H.G. Ebert, eds.) Harwood
Academic Publication, London, 1978.
Balcer-Kubiaek, E.K., G.H. Harrison and T.K. liei.
Neutron dose-rate experiments at the AFRRI nuclear
reactor. Radiat. Res. 128: S65-S70 (1991).
Bums, F J . and M. Vanderlaan. Split-dose recovery
for radiation-induced tumours in rat skin. Int. J.
Radiat. Biol. 32: 135-144 (1977).
Billen, D. Spontaneous DNA damage and its significance lor the "negligible dose" controversy inradiation protection. Radiat. Res. 124: 242-245 (1990).
Booz, J. Microdosimetric spectra and parameters of
low-LET radiations. p. 311-344 in: Proceedings of theFifth Symposium on Microdosimetry. (J. Booz, N.G.
Ebert and B.G.R. Smith, eds.) EUR-5452 (1976).
Bettege, D., P. Calzolari, G. Noris Chiorda et al.
Transformation of QI-IlOTH cells with 4.3 MeV
a particles at low doses: effects of single andfractionated doses. Radiat. Res. 131: 66-71 (1992).
Boice, J.D. Jr., D. Preston. G. Faith et al. Frequent
chest X-ray fluoroscopy and breast cancer incidence
among tuberculosis patients in Massachusetts. Radiat.
Res. 125: 214-222 (1990).
Brenner, DJ. and EJ. Hall. Reply to letter by Harrison and Balcer-Kubizek. Int. J. Radiat. Biol. 61: 142(1992).
Committee on Biological Effects of Ionizing Radiation(BEIR V). Health Effects of Exposure to Low Levelsof lonizing Radiation. United States National Academy of Sciences, National Research Council. National Academy Press, Washington, 1990.
Cross, F.T. A review of experimental animal radon
health effects data. p. 476-481 in: Radiation Research:
A Twentieth Century Perspective. (J.D. Chapman etal., eds.) Academic Press, San Diego, 1991.
Cross, F.T. Experimental studies on lung caranogenesis and their relationship to future research onradiation-induced lung cancer in humans. p. 27-35 in:
The Futurc of Radiation Research. BIR Report 22.
(G.B. Gerber et al., eds.) British Institute o iRadiology, London, 1991.
Committee on Biological Effects of Ionizing Radiation(BEIR 111). n l e Effects on Populations of Exposure to
Low Levels of Ionizing Radiation: 1980. United States
National Academy of Sciences. National ResearchCouncil. National Academy Press, Washington, 1980.
Chadwick, K.H. and H.P. Leenhouts. The Molecular
Theory of Radiation Biology. Springer-Verlag, Berlin,
1981.

ANNE3 F: INFLUENCE OF DOSE AND DOSE M ,TEON STOCIIASTIC E F E m OF RADIATION

Chadwick, K.II., C. Seymour and B. Barnhart (eds.).
Cell Transformation and Radiation Induced CAnccr.
Adam Hilger, Bristol, 1989.
C7 Clifton, K H . Radiation biology in cancer research. p.
501-513 in: 32nd M.D. Anderson Symposium on Fundamental Canccr Research. (R.E. Meyn and I1.R.
Withers, eds.) Raven Press, New York. 1980.
C8 Clifton, KH. Thyroid cancer: re-evaluation of anexperimental model for radiogenic endocrine cardnogenesis. p. 181-198 in: Radiation Carcinogenesis.
(A.C. Upton et al., cds.) Elsevier Press, New York,1986.
C9 Cornforth, M.N. and J.S. Bedford. A quantitative
comparison of potentially lethal damage rcpair and therejoining of interphase chromosome breaks in low
passage normal human fibroblasts. Radiat. Res. 111:385-405 (1987).
C10 Cornforth, M.N. and J.S. Bedford. X-ray-induced
breakage and rejoining of human interphase
chromosomes. Science 222: 1141-1143 (1983).
C11 Cox, R., J. Thacker, D.T. Goodhead et al. Mutationand inactivation of mammalian cells by various
ionizing radiations. Nature 267: 425-427 (1977).
C12 Cox, R. A cellular desaiption of the repair defect inataxia-telangieaasia. p. 141-153 in: Ataxia-Telangieo
tasia: A Cellular and Molecular Link Between Cancer,
Neuropathology and Immune Deficiency. (B.A.
Bridges and D.G. Harnden, eds.) Wiley and Sons,
Chichester, 1982.
C13 Cox, R., P.G. Debenham, W.K. Masson et al. Ataxiatclangiectasia: a human mutation giving highfrequency misrepair of DNA double strand scissions.
Mol. Biol. Med. 3: 229-244 (1986).
C14 Cronkite, E.P., CJ. Shellabarger, V.P. Bond et al.
Studies on radiation-induced mammary gland neoplasia in the rat. 1. 'Ihe role of the ovary in the neoplastic
response of the breast tissue to total- or partial-body
x-irradiation. Radiat. Res. 12: 81-93 (1960).

C6

C15 Cole, LJ., P.C. Nowell and J.S. h o l d . Late effectsof X-radiation. The influence of dose fractionation onlife span, leukacmia and nephrosclerosis incidence inmice. Radiat. Res. 12: 173-185 (1960).
C16 Comfort, A. Natural aging and the effects of radiation.
Radiat. Res. (Suppl.) 1: 216-234 (1959).
C17 Crompton, N.E.A., F. Zoelser, E. Schneidcr et al.
Increased mutant induction by very low dose-rate
gamma irradiation. Naturwissenschaften 72: S439
(1985).
C18 Carnes, BA., D. Grahn and J.F. Thomson. Doseresponse modelling of life shortening in a retrospective analysis of the combined data for the JANUS
programme at Argonne National Laboratory. Radiat.
Res. 119: 39-56 (1989).
C19 Conard, R.A. Late effects in Marshall Islanders
exposed to fallout 28 years ago. p. 57-71 in: Radiation
Carcinogenesis: Epidemiology and Biological Significanoe. (J.D. Boice Jr. and J.F. Fraumeni Jr.. eds.)
Raven Press. New York, 1984.
C2O Cai, L. and S.-Z. Liu. Induction of qtogenetic
adaptive response of somatic and germ cells in vivo
and in vitro by lowdosc X-irradiation. Int. J. Radiat.
Biol. 58: 187-194 (1990).

717

C21 Cardis. E.M. Modelling the Eflect of Exposure to
Environmentel Carcinogens on Incidence of Cancer~:in Populations. Ph.D. Dissertation, University ofWashington, 1985.
C22 Carnes, B.A. and D. Grahn. Neutron issues in the
JANUS mouse program, International Colloquium on
Ncutron Radiation Biology, Maryland. 1990.
C23 Chadwick, K.11. and 1I.P. Leenhouts. A moleculartheory of cell survival. Phys. Med. Biol. 18: 78-87(1973).
C24 Caswell. R.S. and J J . Coync. Microdosimetric spectra
and paramcters of fast neutrons. p. 97-123 in:Proceedings of the Fifth Symposium on
Miaodosimctry. (J. Booz, H.G. Ebert and B.G.R.
Smith, eds.) EUR-5452 (1976).
C25 Charles, M., R. Cox, D. Goodhead et al. CEIR forumon the effects of high-LET radiation at low doses/dose
rates. Int. J. Radiat. Biol. 58: 859-885 (1990).
C26 Charlton, D.E., H. Nikjoo and J.L. Humm. Calculationof initial yields of single and double strand breaks inoell nuclei from electrons, protons and alpha particles.
Int. J. Radiat. Biol. 56: 1-19 (1989).
C27 Comings. D.E. A general theory of carcinogenesis.
Proc. Natl. Acad. Sd. (USA) 70: 3324-3328 (1973).
C28 Curtis. S.B. Lethal and potentially-lethal lesions
induced by radiation a unified repair model. Radiat.
Res. 106: 252-270 (1986).
C29 Covelli, U., V. Di Majo. M. Coppola et al. Neutron
cardnogenesis in mice: a study of the dose-response
curves. Radiat. Res. 128: S114S116 (1991).
QO Carnes, R.A. and T.E. Fria. Responses of the Beagle
to protracted irradiation. I. Effeds of total dose anddose rate. Radiat. Res. 128: 125-132 (1991).
D l Debenham. P.G., N.J. Jones and M.B.T. Webb.
Vector-mediated DNA double strand break rcpair
analysis in normal and radiation-sensitive Chinese
hamster V79 cells. Mutat. Res. 199: 1-9 (1988).
D2 Di Majo. V., M. Coppola. S. Rebessi et al.
Dose-response relationships of radiation-induced
Harderian gland tumours and myeloid leukaemia of
the CBA/Cne mouse. J. Natl. Cancer Inst. 76: 955-963(1986).
D3 Di Majo. V., M. Coppola. S. Rebessi et al. Agerelated susceptibility of mouse liver to induction oftumours by neutrons. Radiat. Res. 124: 227-234(1990).
D4 Doniach, I. Cflects including carcinogencsis of 1-131
and X-rays on the thyroid of experimental animals: a
review. Health Phys. 9: 1357-1362 (1963).
D5 Darby, S.C. and R. Doll. Radiation and exposure rate.
Nature 344: 824 (1990).
El
Edwards. A.A., D.C. Lloyd and J.S. Prosscr.
Chromosome aberrations in human lymphocytes - aradiobiological review. p. 423-432 in: Low Dose.
Radiation: Biological Bases of R i s k k c s s m e n ~(K.F.
Bavcrstock and J.W. Stathcr, eds.) Taylor and Francis,
London, 1989.
E2 Elkind, M.M. Kaplan lecture: target theory. linearity
and repairlmisrepair in radiobiology. p. 2%-305 in:Proceeding of the 8th International Congress ofRadiation Research, Edinburgh, 1987 (Volume 2).
(E.M. Fieldcn et al., eds.) Taylor and Francis. London,
1987.

-

71 8

UNSCEAR 1993 REPORTElkind, M.M.. 17.Q.11. Ngo. C.K. llill ct al. Letter to
Ihc editor: Do Icthal mulations influence radiation
Iransformalion frcqucndcs? 1111. J. Radiat. Biol. 53:
849-859 (1988).
Eguchi-Kasai, K., T. Kosaka. K. Sato ct al. Rcparabilily of DNA doublc-strand breaks and radiation scnsitivity in fivc mamrniilia~lall lincs. Int. J. Radiat.
Kol. 59: 97-104 (1991).
Evans, 11.11.. MA:. Ilorng, J. Mcncl ct al. I h c influcnce of dosc ratc on the lclhal and mutagenic effectsof x-rays on proliferating L5178Y cclls differing inradiation sensitivity. Inl. J. Radiat. Biol. 47: 553-562(1985).
Elkind. M.M. Physical, biophysical and cell-biologicalfactors that can mntributc to neoplastic transformation
by fission-spedrum neutrons. Radiat. Res. 128: S47S52 (1991).
Evans, H.E., M. Niclsen, M. Jaroslav et al. The effectof dose rate on x-radiation-induced mubnt frequency
and the nature of DNA lesions in mousc lymphoma
L5178Y cells. Radiat. Res. 122: 316-325 (1990).
Edwards, A.A. Low dose and low dose rate efleds inlaboratory animals. NRPB-TM/l-92 (1992).
Fertil. B., P.J. Guculcttc, J. Wambersie et al. Dependence of the quadratic model parameters on dosc rate(y rays) and 5 0 MeV ncutrons: an analysis based on
the in vitro survival curves of 6 human cell lines.
Radiat. Environ. Biophys. 17: 315 (1980).
Furuno-Fukushi, I., K. Aoki and H. Matsudaira. Mutation induction by different dose ratcs of y rays innear-diploid mousc cells in plateau and log phaseculture. Radiat. Rcs. (in press, 1993).
Friedberg. E.C. and P.C. I lanawalt (eds.). Mechanisms
and Consequcnccs of DNA Damagc Processing. A.R.
Liss, New York, 1988.
Fry, R.J.M. Radiation protection guidelines for theskin. Int. J. Kadiat. Biol. 57: 829-839 (1990).
Freedman. V.H. and S. Shin. Cellular tumorigenicity
in malc mice: correlation with cell growth in semisolid medium. Cell 3: 355-359 (1974).
Furuno-Fukushi. 1. and H. Matsudaira. Mutationinduction by tritiated water and effeds of deuterium
oxide in cultured mouse lcukacmia e l l s . Radiat. Res.
103: 466-470 (1985).
Furuno-Fukushi, I., A.M. Ueno and H. Matsudaira.
Mutation induction by vcry low dose ratc gamma-rays
in cultured mouse leukacmia cells LS178Y. Radiat.
Rcs. 15: 273-280 (1988).
Furuno-Fukushi. I. and 11. Matsudaira. Mutationinduction by diffcrcnt dose rates of x-rays inradiation-sensitive mutants of mousc lcukaemia.
Radiat. Res. 120: 370-374 (1989).
Fry. RJ.M. The rolc of animal species in low dose
extrapolation. p. 109-1 18 in: I'roceedings of the 10th
Annual Meeting of the National Counal on Radiation
Protection a n d Mcasuremcnt on Critical Issues in
Setting Itadialion Dosc 1-imits. NCRP (1982).
Fry, RJ.M. lime-dose relationship and high-LET
irradiation. Int. J. Radiat. Biol. 58: 866-870 (1990).
Fabrikant, J.I., T.11. Ilsu, D.11. Knuclson et al. Effectof LET on radiation cardnogenesis: m m arison of
'~m.
3 2 ~
single and fractionated doses ofand X-rays on the production of ostcosarcomas in rals.

i'p. 322-346 in: Itadionuclidc Carcinogenesis. (C.L.
Saundcrs ct al., cds.) CON1:-720505 (1973).
Fcincndcgcn, 1-.I:., J. Ijooz, V.P. 13ond ct al.
Miaodosimctric npproacll to the analysis of all
rcsponscs at IOW dose and low dosc rate. Kadi;~t.Pmt.
Dosim. 13: 299-306 (1985).
Fritz, T.C., T.M. Secd, 1l.V. Tollc ct al. Late cflccts
of prolmcted wholc-lmdy irradiation of bcaglcs bycobalt-60 gnmrna rays, in: Lifcspan Radiation Effccts
Studics in Animals: What Can Thcy Tcll Us? (R.C.
Thompson and J.A. Mahaffcy, cds.) CONF-830951.
NTIS, Springfield VA, 1986.
Glickman, B.W., E.A. Drobctsky, J. Boer et a!.
Ionizing radiation induced p i n t 'mutations inmammalian oclls. p. 562 in: Proceedings of the 8th
Inlcrnational Congress of Radiation Research.
Edinburgh. 1987. Volumc 2. (E.M. Ficlden et al.,eds.) Taylor and Francis, London, 1987.
Goodhead. D.T. Deductions from cellular studies ofinactivation, mutagcncsis and transformation. p.
369-385 in: Radiation Cardnogenesis: Epidemiology
and Biological Significance. (J.D. Boicc Jr. and J.F.
Fraumcni Jr., cds.) Ravcn Press. New York, 1984.
Goodhcad, D.T.
Biophysical models ofradiation-action - introductory review. p. 306-311 in:Proceeding of the 8th International Congress ofRadiation Rcscarch (Abstract), Edinburgh, 1987.
Volume 2. (E.M. Fielden et al., cds.) Taylor andFrancis, London, 1987.
Goodhead, D.T. Relatiorlship of microdosimetrictcchniqucs to applications in biological systcms. p.
1-89 in: 'lhc Dosimetry of Ionizing Radiations.
Volume 2. (K.R. Kasc et al., eds.) Academic Press,
Orlando, 1987.
Goodhead, D.T. Spatial and temporal distribu~ionof
energy. I-leallh Phys. 55: 231-240 (1988).
Goodhead, D.T. and 1.1. Nikjoo. Track structure
analysis of ultrasoft x-rays compared to high- andlow-LET radiations. Int. J. Radiat. Biol. 55(4):513-529 (1989).
Gragtmans, NJ., D.K. Myers, J.R. Johnson et al.
Occurrence of mammary tumours in rals after
exposure to tritium beta rays and 200-kVp x rays.
Radiat. Res. 99: 636-650 (1984).
Grahn, D. and G.A. Sacher. Fractionation and~ ~radiation in
protraction factors and thc late e f f c ofsmall mammals. p. 2.1-2.27 in: Proceedings of a
Symposium on Dose Rate in Mammalian Radiation
Biology. (D.G. Drown ct al., 4 s . ) CONF-680410.
USAEC. Oak R i d p , 1968.
Griihn, D. Biological cffccls of protraclcd low doseradiation cxposurc of man and animals. p. 101 in:
Late Effcc~sof Radiation. (R.J.M. Fry et al., cds.) Van
Nostrand Rcinhold Co., New York, 1970.
Griffith, W.C., U.13. 13occkcr, K.G. Cuddihy C I al.
Preliminary radiation risk cstimalcs of carcinoma
incidence in thc lung as ;I lunclion of cumulative
radiation dosc using proportional tumour incidence
ratcs. p. 196-204 in: Inhalation Toxicology ResearchInstitute Annual Report 1986-1987. LMF-120. ITRI,
Albuquerque (1987).

ANNIX F: INFI,IJI'.NCE OF IIOSE AND DOSE RA'I1 ON STOCI IASTIC EFECTS OF W l A ' I l O N

G I 1 Grosovsky. A.J. and J.13. Little. Evidcncc for lincar
response for the induction of mutations in human cclls
by x-ray exposures below 10 rad. I'mc. Natl. Acad.
Sci. (USA) 82: 2092-2095 (1985).
G12 Grahn, D. and B.A. Carncs. Quotcd in [FlO].
G I 3 Goldman, M. Expcrimcntal carcinogcncsis in thc
skeleton. p. 214-231 in: Radiation Carcinogcncsis.
(A.C. Upton et al., cds.) Elsevier, Ncw York. 1986.
G14 Gilbert. E.S., S.A. Fry, L.D. W i g g et al. Analyxs ofcombincd mortality data on workcrs at the Ilanford
site, Oak Ridge National Laboratory, and Rocky 1:laki
nuclear weapons plant. Hadiat. Hcs. 120: 19-35(1989).
G15 Goodhead, D.T., R J . Munson, J. Thacker et al. Mutation and inactivation of cultured mammalian cclls
exposed to beams of accelerated hcavy ions. IV. Biophysical interpretation. Int. J. Radiat. Biol. 37:
135-167 (1980).
GI6 Goodhcad, D.T. and D.J. Brcnncr. Estimation of asingle property of low LET radiations which correlates with biological effectiveness. Phys. Med. Biol.
28: 485-492 (1983).
G17 Goodhead, D.T. Saturable repair models of radiation
action in mammalian cells. Radiat. Res. 104: S58-S67(1985).
GI8 Goodhead, D.T.. D.E. Charlton, W.E. Wilson ct al.
Current biophysical approaches to understanding of
biological elleas in terms of local energy deposition.
p. 57-68 in: Radiation Protection. Proceeding of theFifth Symposium on Neutron Dosimetry. (H. Schraube
et al., eds.) EUR 9762 (1985).
GI9 Goodhead, D.T. Physical basis for biological effcct. p.
37-53 in: Nuclear and Atomic Data for Radiothcrapy
and Related Radiobiology. STI/PURP41. IAEA,
Vienna, 1987.
G20 Goodhead, D.T. The initial physical damage producedby ionizing radiations. Int. J. Radiat. Biol. 56: 623634 (1989).
G21 Goodhead, D.T. Biophysical features of radiations at
low doses and low dose rates. p. 4-11 in: New Developments in Fundamental and Applied Radiobiology.
(C. Seymour and C. Mothenill, cds.) Taylor andFrancis, London, 1991.
G22 Gunther, K. and W. Schulz. Biophysical Theory ofRadiation Action - A Treatise on Relative Biological
Effectiveness. Akademie Verlag, Berlin. 1983.
G23 Grahn, D.. RJ.M. Fry and R.A. Lea. Analysis ofsurvival and cause of death statistics for mice undersingle and durationsf-life gamma irradiation. p. 175186 in: Life Sciences and Space Research. Akadamic
Verlag, Berlin, 1972.
G24 Gray, R.G.. J. Lafuma and S.E. Paris. Lung tumors
and radon inhalation in over 2000 rats: approximate
lineariety across a wide range of doses and potentiation by tobacco smoke. p. 592-607 in: Lifespan
Radiation Effects Studies in Animals: What Can They
Tell Us? (R.C. Thompson and J.A. Mahalfey, cds.)
CONF-830951. NTIS, Springfield VA, 1986.
H1 Hall, E.J. and R.C. Miller. The how and why o i invitro onmgcnic transformalion. Radiat. Res. 87:
208-223 (1981).
H2 Hall, E.J. Radiobiology for the Radiologist.
Lippincolt, I'hiladelphia, 1988.

113

719

Ilall. EJ. Finding a smoothcr pcbble: a workshop
summary. p. 401-412 in: Cell 'I'ransformation andRadiiition Induced Cancer. (K.11. Chadwidc ct al.,cds.) Adam Ililgcr, Bristol. 1989.
114 Ilan, A. and M.M. Elkind. Transformation of mouse
QIIlOT!h cells by single and fractionated doscs of
x-rays and Cission-spcctrum neutrons. Cancer Hcs. 39:
123-130 (1979).
11.5 Ilan, A., C.K. Hill and M.M. Elkind. Repair of ocll
killing and neoplastic transformation at rcduccd dose
ratcs of Co-60 y-rays. Cancer Rcs. 40: 3328-3332(1980).
116 Iian, A.. C.K. liill and M.M. Elkind. Repair processes
and radiation quality in neoplastic transformation of
mammalian cclls. Radiat. Rcs. 99: 249-261 (1984).
H7 Hiebcr. L., G. Ponsel, H. Roos el al. Absence of adose rate effed in the transformation of UHlOT!4
cells by a particles. 11-11.J. Radiat. Biol. 52: 859-869(1987).
t18 Hill, C.K., F.M. Buonaguro, C.P. Myers et al. Fission
spectrum neutrons at reduced dose rates enhanceneoplastic transformation. Nature 298: 67-69 (1982).
149 llill, C.K., A. Ilan, F.M. Buonaguro et al.
Multifraction of&-60 gamma rays reduces neoplastictransformation in vitro. Caranogenesis 5: 193-197(1984).
1110 Hill, C.K., A. Han and M.M. Elkind. Fission speclrum
neutrons at low dose rate cnhance neoplastictransformation in the linear low dose region (0-10cGy). Int. J. Radiat. Biol. 46: 11-15 (1984).
I411 Ilill, C.K., B.A. Carncs. A. Han et al. Neoplastictransformation is enhanced by multiple low doses offission spectrum neutrons. Radiat. Res. 102: 404-410(1985).
HI2 Hahn, F.F., B.A. Muggenburg, B.B. Boecker et al.
Insights into radionuclide-induoed lung cancer inpeople from life-span studies in Beagle dogs. p. 521534 in: Lifcspan Radiation Effects Studies in Animals:
What Can They Tell Us? (R.C. Thompson and J.A.
Mahaffey, eds.) CONF-830951. NTIS, Springfield
VA, 1986.
H13 Holm. L.-E., G. Lundcll and G. Walinder. Incidencz
of malignant thyroid tumoun in humans after
exposurc to diagnostic doses of iodine-131. I.
Retrospective mhort study. J. Natl. Cancer Inst. 64:
105.5-1059 (1980).
1114 Ilolm, L.-E., G. Eklund and G. Lundell. Incidcnce ofmalignant thyroid tumours in humans aftcr cxposure
to diagnostic d o s a of iodine-131. 11. Estimation of
actual thyroid size, thyroidal radiation dose andpredicted vcrsus observed number of malignant
thyroid tumours. J. Natl. Cancer Inst. 65: 121 (1981).
1115 Holm, L.-E., K.E. Wiklund, G.E. Lundcll et al.
Thyroid cancer aftcr diagnostic doses of iodinc-131:
a retrospective cohort study. J. Natl. Cancer Inst. 80:
1132-1138 (1988).
1116 Howe, G.R. Epidemiology of radiogcnic breasl cancer.
p. 119-130 in: Radiation Carcinogcnesis: Epidemiology and Biological Significance. (J.D. Boice Jr. and
J.F. Fraumeni Jr.. cds.) Raven Press, New York, 1984.
I117 flumphreys, E.R. Medical Research Council Ri~diobiology Unit. United Kingdom. Communication to the
UNSCEAR Secretariat (1989).

720

UNSCEAR 1993 KEPOI1T

1318 Ilenshaw, P.S. Experimental roentgen injury. IV.
Effects of repeated small doses of x-rays on the blood
picture, tissue morphology and life span in mice. J.
Natl. Cancer Inst. 4: 513-522 (1944).
1119 Hursh, J.B., T.R. Noonan, G. Casarett et al. Reductionof lifespan of rats by roentgen irradiation. Am. J.
Roentgenol., Radium rher. Nucl. 74: 130-134 (1955).
1320 Ifill, C.K. Is the induction of neoplastic transformation
by radiation dependent upon the quality and doserate? Inst. Phys. Chem. lies. 83: 31-35 (1989).
H21 Hahn. G.M. and J.B. Little. Plateau-phase culture of
mammalian cells in an in vitro model for humancancer. Can. Topics Radiat. Rcs. Quost. 8: 39-83(1972).
H22 Holm, L.-E., K.E. Wiklund, G.E. Lundell el al.
Cancer risk in population examined with diagnostic
doses of l3'l. J. Natl. Cancer Inst. 81: 302-306(1989).
H23 Harder, D. The painvise lesion interaction model. p.
159-170 in: Quantitative Mathematical Models in
Radiation Biology. (J. Kiefer, ed.) Springer Verlag,
I leidelbcrg, 1988.
H24 Hethcote, H.W. and A.M. Knudsen. Model for theincidence of embryonal cancers: application toretinoblastoma. Proc. Natl. Acad. Sci. (USA) 75:
2453-2457 (1978).
H25 Hofman, W. and I;. Daschil. Biological effects ofalpha particles in lung tissue. Radiat. Prot. Dosim. 13:
229-232 (1985).
H26 Hutchinson, F. Chemical changes induced in DNA by
ionizing radiation. Prog. Nucleic Acid Res. Mol. Biol.
32: 115-154 (1985).
I127 Hsiao, W.L., C.A. Lopez, T. Wu et al. A factor
present in fetal calf serum enhanocs oncogene-induced
transformation of rodent fibroblasts. Mol. Cell. Biol.
7: 3380-3385 (1987).
I128 Huiskamp, R. Acute myeloid leukaemia induction in
C B M I mice by irradiation with fission neutrons as afunction of exposure rate. Radiat. Environ. Biophys.
30: 213-215 (1991).
H29 Huiskamp, R., J.A.G. Davids and R.H. Mole. Acutemyeloid leukaemia induction in C B M 1 mice byirradiation with fission neutrons as a function of
exposure rate. p. 258 in: Radiation Research: A
Twentieth Century Perspective. Volume 1. (J.D.
Chapman, W.C. Dewey and G.F. Whitmore, eds.)
Academic Press, San Diego. 1991.
H30 Hulse, F.V. and R.H. Mole. Skin tumour incidence in
CBA mice given fractionated exposures to low energy
beta particles. Br. J. Cancer 23: 452-463 (1969).
1131 Hall, EJ., R.C. Miller and D J . Brenner. Neoplastictransformation and the inverse dose rate effect forneutrons. Radiat. Res. 128: S75-S80 (1991).
1132 Holm, L.-E. Malignant disease following iodine-131
therapy in Sweden. p. 263-271 in: Radiation
Carcinogenesis: Epidemiology and BiologicalSignificance. (J.D. Boice Jr. and J.F. Fraumeni Jr.,eds.) Raven Press. New York, 1984.
1133 liendry, J.11. 'Ihe slower cellular recovery after highLET irradiations, including neutrons, focuses on thequality of DNA breaks. Radiat. Res. 128: S111-S113(1991).

Harrison, G.11. and E.K. Ualcer-Kubiaek. Ambiguity
o i the Rrcnncr-Ilall model. Int. J. Radiat. Biol. 61:
139-142 (1992).
tlol~n, L.-ti., K.E. Wiklund, G.E. Lundell et al.
Cancer risk in population examined with diagnostic
doses of 1311. J. Natl. Canccr Inst. 81: 302-306(1989).
lnlernational Commission on Radiological Protection.
Recommendations of the International Commission on
Radiological Protection. lCRP Publication 26. Annalsof the ICRP l(3). Pergamon Press, Oxford, 1977.
International Commission on Radiological Protection.
Recommendations of the International Commission on
Radiological Protection. ICRP Publication 60.
Pergamon Press, Oxford. 1991.
International Commission on Radiological Protection.
Limits for Intakes of Radionuclides by Workers. ICRP
Publication 30.Annals of the ICRP 2(3/4). Pergamon
Press, Oxford, 1979.
International Commission on Radiation Units andMeasurcmcnts. "Microdosimetry". ICRU Report 36(1983).
Iliakis, G. The influence of conditions affecting repair
and fixation of potentially lethal damage on the
induction of 6-thioguanine resistance after exposure of
mammalian cells to x-rays. Mutat. Rs. 126: 215-225(1984).
International Commission on Radiation Units andMeasurements. The Quality Factor in Radiation
Protection. ICRU Report 40 (1986).
International Commission on Radiological Protection.
RBE for Deterministic Effects. ICRP Publication 58.
Annals of the ICRP 20(4). Pergamon Press. Oxford.
1989.
Ikushima, T. Chromosomal responses lo ionizing
radiation reminiscent of an adaptive response incultured Chinese hamster cells. Mutat. Res. 180: 215221 (1987).
Johnson, J.R. and D.K. Myers. Is L 3 1 less~efficientthan external irradiation at producing thyroid cancers?
p. 289-301 in: Biological Effects of Low-Level
Radiation. STI/PUB/646. M A , Vienna, 1983.
Jones, C.A., B.A. Sedita, C.K. Hill et al. Influence ofdose rate on the transformation of Syrian hamster
embryo cells by fission spectrum neutrons. p. 539-546
in: Low Dose Radiation: Biological Bases of Risk
Assessment. (K.F. Baverstock and J.W. Stather, eds.)
Taylor and Francis, London, 1989.
Kemp, L.M., S.G. Sedgwick and P.A. Jeggo. X-ray
sensitive mutants o l CI10 cells defective in double
strand break rejoining. Mutat. Res. 132: 189-196(1984).
Kohn, 11.1. and P. Guttman. Ageat exposure and thelate effects of X-rays. Survival and tumor incidence in
CAFl mice irradiated at 1 to 2 years of age. Radiat.
Res. 18: 348-373 (1963).
ffiplan, I1.S. and M.B. Brown. A quantitative doseresponse study of lymphoid-tumour development in
irradiated C57 black mice. J. Natl. Cancer Inst. 13:
185-208 (1952).
Koenig. F. and J. Kiefer. Level of dose-rate effect for
mulation induction by gamma-rays in human TK6cells. Int. J. Radiat. Biol. 54: 891-897 (1988).

ANNFX F: INFLUENCE OF DOSE AND DOSE RATE ON STOCl M T l C E F E m OF W l A 1 1 0 N

KSKatz, 11.. B. Ackerson, M. Homayoonfar et al.
Inactivation of cells by heavy ion bombardment.
Itadiat. Res. 47: 402-425 (1971).
K6 Kellerer, A.M. and H.H. Rossi. A generalized
formulation of dual radiation action. Radiat. Res. 75:
471-488 (1978).
K7 Knudsen, A.G., H.W. I-iethcote and B.W. Brown.
Mutation and childhood cancer: a probabilistic modelfor the incidence of rctinoblastoma. Proc. Natl. Acad.
Sci. (USA) 72: 5116-5120 (1975).
K8 Kronenberg, A. and J.B. Little. Mutagenic propertiesof low doses of X-rays, fast neutrons and selectedheavy ions in human cells. p. 554-559 in: Low Dose
Radiation: Biological Bases of Risk Assesment. (K.F.
Baverstock and J.W. Stather, eds.) Taylor and Francis,
London, 1989.
K9 Kadhim, M.A., D.A. Macdonald, D.T. Gwdhead et al.
Transmission of chromosome instability after
plutonium a-particle irradiation. Nature 355: 738-740(1992).
K10 Kossenko, M.A. and M.O. Degteva. The follow-up of
the population exposed as a result of the release ofradioactive wastes into the Techa river. Part 3. Cancer
mortality and risk evaluation. Sci. Total Environ.
(1993, accepted for publication).
K11 Kendall, G.M., C.R. Muirhead, B.H. MacGibbon et al.
Mortality and occupational exposure to radiation: first
analysis of the National Registry for Radiation
Workers. Br. Med. J. 304: 220-225 (1992).
K12 Koshumikova, N.A., L.A. Buldakov, G.D. Bysogolov
et al. Mortality from malignancies of the hematopoietic and lymphatic tissues among personnel of thefirst nuclear plant in the USSR. Sci. Total Environ.
(1993, accepted for publication).
L1 Lefrancois, D., W. Al Achkar, A. Aurias et al.
Chromosome aberrations induced by low-dose
gamma-irradiation. Study of R-banded chromosomesof human lymphocytes. Mutat. Res. 212: 167-172(1989).
L2 Liu, Z.H.,C.S. Fu, C.M. Li et al. 131-1 and 132-1
carcinogenic effects in rat thyroid glands. Chin. Med.
J. 95: 641648 (1982).
U Lea, D.E. Actions of Radiations on Living Cells.
Second edition. Cambridge University Press, London,
1955.
LA Lee, W., R.P. Chiacchierini, B. Shleien et al. Thyroid
tumours following 1-131 or localized x-irradiation lo
the thyroid and pituitary glands in rats. Radiat. Res.
92: 307-319 (1982).
L5 Lehmann, A.R. ?he cellular and molecular responsesof ataxia-telangiectasia cells to DNA damage. p.
83-101 in: Ataxia-Telangiectasia: A Cellular andMolecular Link Between Cancer, Neuropathology and
Immune Deliciency. (B.A. Bridges and D.G. Hamden.
eds.) Wiley and Sons, Chichester. 1982.
L6 Liber. H.L.. V.H. Olaki and J.B. Little. Toxicity andmutagenecity of low dose rates of ionizing radiationfrom tritiated water in human lymphoblastoid cells.
Muiat. Res. 157: 77-86 (1985).
L7 Little, J.B. Origins of human cancer. p. 923-939 in:
Cold Spring Harbour Conferences on Cell
Proliferation. Volume IV. (H.H. Iliatt et al., eds.)
Cold Spring I.Iarbour, New York, 1977.

72 1

Little. J.B. Quantitative studies of radiationtransformalion with the ,431-11 mouse BALBnT3
a l l line. Cancer Res. 39: 1474-1480 (1979).
1.9 Little, J.B. Characteristics of radiation induced
neoplastic transformation in vilro. Leuk. Res. 10:
719-725 (1986).
L10 Little, J.B. Induction of neoplastic transformation by
low dose-rate exposure to tritiated water. Radiat. Res.
107: 225-233 (1986).
L11 Little, J.B. The relevance of cell transformation tocarcinogenesis in vivo. p. 396-413 in: Low Dose
Radiation: Biological Bases of Risk Assessment. (K.F.
Baverstock and J.W. Slather, eds.) Taylor and Francis,
London, 1989.
L12 Lloyd, D.C. and A.A. Edwards. Chromosome
aberrations in human lymphocytes: effect of radiation
quality, dose and dose rate. p. 23-49 in: Radiationinduced Chromosome Damage in Man. (T. Ishihara
and M.S. Sasaki, eds.) A.R. Liss, New York, 1983.
1.13 Lloyd, D.C., A.A. Edwards, A. Leonard et al.
Frequencies of chromosomal aberrations induced inhuman blood lymphocytes by low doses of x-rays. Int.
J. Radiat. Biol. 53: 49-55 (1988).
L14 Lloyd, D.C., A.A. Edwards, A. Leonard et al.
~h*rnosomal aberrations in human lymphocytes
induced in virro by very low doses of X-rays. Int. J.
Rad. Biol. 61: 335-343 (1992).
L15 Liicke-Huhle, C., M. Pech and P. Herrlich. Selective
gene amplification in mammalian cells after exposure
to Co-60 y rays, Am-241 a particles, or UV light.
Radiat. Res. 106: 345-355 (1986).
L16 Lamson, B.G., M.S. Billings, J J . Gambino et al.
Effect of single and divided doses of X-irradiation on
longevity in rats. Radiat. Res. 18: 255-264 (1963).
L17 Lyon, M.F., R.J.S. Phillips and H J . Bailey. Mutagenic
effect of repeated small radiation doses to mouse
spermatogonia. I. Specificlocus mutation rates. Mutat.
Res. 15: 185-190 (1972).
L18 Little, J.B., A.R. Kennedy and R.B. McGandy. Effectof dose rate on the induction of experimental lungcancer in hamsters by a radiation. Health Phys. 103:
293-299 (1985).
L19 Lundgren, D.L., A. Gillett and F.F. Hahn. Effects ofprotraction of the a dose to the lungs of mice byrepeated inhalation exposure to aerosols of 2 3 9 ~ u 0 2 .
Radiat. Res. 111: 201-224 (1987).
L20 Leenhouts, H.P. and K.H. Chadwick. The influence ofdose rate on the dose-effect relationship. J. Radiol.
Prot. 10: 95-102 (1990).
L21 Lamson, B.G., M.S. Billing, R.A. Meek et al. Lateeffects of total-body roentgen irradiation. 111. Early
appearance of neoplasms and life-shortening in female
Wistar rats surviving IOOOR hypoxic total-body
irradiation. Arch. Pathol. 66: 311-321 (1958).
L22 Lamson, B.G., M.S. Billings. L.M.Ewell et al. Lateeffects of total-body irradiation. IV. Hypertension andnephrosclerosis in female Wistar rats surviving lOOOR
hypoxic total-body irradiation. Arch. Pathol. 66: 322329 (1958).
L23 Lindahl, T. and B. Nyberg. Rate of depurination ofnative deoxyribonucleic acid. Biochem. 11: 3610-3621(1972).

L8

722

UNSCEAK 1993 REPORT

L24 Lecnhouts, 1l.P. and K.11. Chadwick. Analysis ofradiation-induced caranogencsis using a two-stage
cardnogenesis model: implications for dose-cffcct
relationships. Radiat. Prot. Dosim. (1993, in prcss).
MI McClcllan, R.O., B.B. Uocckcr, F.F. Ilahn ct al.
Lovclacc ITRI. Studics or1 the toxicity of inhaledradionuclides in beagle dogs. p. 74-96 in: Lifcspan
IZadiation Effects Studies in Animals: What Can They
Tell Us? (R.C. Thompson and J.A. Mahaffey, c&.)CONF-830951. NTIS, Springfield VA, 1986.
M2 McCormick, J J . and V.M. Mahcr. Mammalian cellmutagcncsis as a biological consequence of DNA
damage. p. 739-749 in: DNA Repair Mechanisms.
(P.C. Ilanawalt ct al., eds.) Academic Prcss, Ncw
York, 1978.
M3 McCormick, J.J. and V.M. Maher. Towards an
undcrstanding of the malignant transformation of
diploid human fibroblasts. Mutat. Res. 199: 273-291(1988).
M4 McWilliams, R.S., W.G. Cross, J.G. Kaplan ct al.
Rapid rejoining of DNA slrand breaks in resting
human lymphocytes after irradiation by low doses of
Co-60 y rays or 14.6-MeV neutrons. Radiat. Res. 94:
499-507 (1983).
M5 Maisin, J.R.. A. Wambersie, G.B. Gerber et al. The
effects of a fractionated gamma irradiation on life
shortening and disease incidence in BALBIc mice.
Radiat. Res. 94: 359-373 (1983).
Moolgavkar, S.Il., F.T. Cross, G. Luebeck et al. A
Two-mutation model for radon-induced lung tumoursin rats. Radiat. Res. 121: 28-37 (1990).
M7 Mendonca, M.S., W. Kurohara, R. Antoniono et al.
Plating cfticicncy as a function of timepost-irradiation: evidence for the dclayed expressionof lethal mutations. Radiat. Res. 119: 387-393 (1989).
M8 Miller, R.C. and E.J. I-lall. X-ray dose fractionationand oncogenic transformations in cultured mouseembryo cells. Nature 272: 58-60 (1978).
M9 Miller, R.C., E.J. Hall and H.H. Rossi. Oncogenictransformation of mammalian cclls in vitm with split
doses of x-rays. Proc. Natl. Acad. Sci. (USA) 76:
5755-5758 (1979).
MI0 Miller, R.W. Highlights in clinical discoveries relating
to ataxia-telangiectasia. p. 13-21 in: AtaxiaTclangiectasia: A Cellular and Molecular Link
Between Cancer, Ncuropathology and Immune
Deficiency. (B.A. Bridges and D.C. Ilarnden, eds.)
Wilcy and Sons, Chichester, 1982.
MI1 Miller, R.C.. DJ. Brenner, C.R. Geard et al.
Onmgcnic transformation by fractionated doses ofneutrons. Radiat. Rcs. 114: 589-598 (1988).
M12 Miller, R.C., C.R. Geard, D.J. Brcnner et al. The
cffccts of temporal distribution of dosc on
neutron-induced transformation. p. 357-362 in: Cell
Transformation and Kadiation Induced Cancer. (K.11.
Chadwick ct al., eds.) Adam Ililger, Bristol, 1989.
M13 Mole, R.11. and I.R. Major. Mycloid leukaemia
frequency aftcr protracted exposure to ionizing
radiation: experimental mnfirmation of the flat doscresponse found in ankylosing spondylitis after a single
treatment course with X rays. Leuk. R a . 7: 295(1983).

M6

MI4 Mole, 1Z.11. Dose-response relationships. p. 403-420
in: Radialion Qrcinogcncsis: Epidemiology and
Uiological Significance. (J.D. Boice Jr. and J.F.
Fraunlcni Jr., cds.) Ravcn Press, New York, 1984.
MI5 Morgan, W.F., M.C. Djordjcvic, R.F. Jostcs ct al.
Ilclaycd rcpair o l DNA binglc strand brcaks docs notincrease cylngenclic damage. Int. J, liadiat. Biol. 4:
71 1-721 (1985).
M16 Morgan, C.R., C.J. 1~oixrLs and P.D. flolt. Thc
influence of dose-rate on the biological effect of low
doscs of radiation. p. 129 in: Promedings of the 8thInternational Congress or Radiation Research(Abstract), Edinburgh. 1987. Volume 1. (E.M. Fielden
ct al., eds.) 'I'aylor and Francis, London, 1987.
M17 Miller, R.C., G. Randers-Pchrson, L. Hiebcr et al. The
inverse dose-rate effect for oncogenic transformationby charged particles is dependent on linear energy
transfer. Radiat. Rcs. 133: 360-364 (1993).
MI8 Malsuda, Y., I. Tobari, J. Yamagiwa ct al.
Dose-response relationship of y-ray induced reciprocaltranslocations a1 low doses in spermatogonia of the
crab-eating monkey (Macaca fasdcularis). Mutat. Res.
151: 121-127 (1985).
M19 Maisin, J.R., G.B. Gerber, M. Lambeit-Collier et al.
Chemical protection against long-term effects ofwhole-body exposure of mice to ionizing radiation.
111. The effects of fractionated exposure to C57B1
mice. Radiat. Res. 82: 487-497 (1980).
M20 Maisin, J.R., A. Wambersie, G.B. Gerber et al. Lifcshortening and disease incidence in C57B1 mice after
single and fractiorlated y and highenergy neutron
exposure. Radiat. Res. 113: 300-317 (1988).
M21 Metalli, P., G. Silini, S. Casillo et al. Induction oftumours and lcukaemia by split doses of X-rays. p.
277-288 in: Radiation-Induced Cancer. STIIPUBn28.
IAEA, Vienna. 1969.
M22 Mole, R.11. Patterns of response to whole body
irradiation: thc cficcts of dosc intensity and exposure
lime on duration of life and tumour production. Br. J.
Radiol. 32: 497-501 (1959).
M23 Mole, R.N. and A.M. Thomas. Life-shortening infemale CBA mice exposed to daily irradiation for
limited periods of time. Int. J. Radiat. Biol. 3: 493508 (1961).
M24 Morlier, J.P., M. Morin, J. Chameaud et al.
Importance du r6le du debit de dose sur I'apparitiondcs cancers chez le rat apres inhalation de radon. C.R.
Acad. Sci., Ser. 3 (315): 436-466 (1992)
M25 Maisin, J.R., G.U. Gerber, A. Wambersie et al. Lifcspan shortening and disease incidence in male
HA.LB/c and C57BI mice after single, fraclionatedd(50)-Re neutron or gamma exposure. p. 172-183 in:Lifespan Radiation Effects Studies in Animals: What
Can They Tell Us? (R.C. Thompson and J.A.
Mahaffcy, eds.) CONF-830951. NTIS, Springfield
VA, 1986.
M26 Milo, G.E. and J.A. Di Paolo. Neoplastictransformation of human diploid cells in vitro after
chc~nicalcarcinogen trcxrtmcnt. Nature 275: 130-132(1978).
M27 Michalik. V. Particle track structure and its c~rrclation
with radiobiological endpoint. Phys. Med. Riol. 36:
1001-1012 (1991).

a

ANNM F: INFLUENCE OF DOSE AND DOSE HATE ON SMClMSIlC EI:r;llCE OF RADIATION

M28 Millcr. R.C., D J . Ijrcnncr, G. Kar~dcrs-l'ehrson ct al.
Thc cffccts of thc tcmporal distribution of dose on
oncogcnic transformation I)y neutrons and charged
particles of intcrmcdiatc 1,C'l'. Icadiat. Rcs. 124: S62S68 (1990).
M29 hlorin. M., R. Massc and 1. L3fuma. Icblc dc I'5gc au
moment dc I'irradiation sur I'induction dcs tumcurs.
C.R. Acad. Sci., Scr. 3 (312): 62963.1 (1991).
M30 Mitchcll, J.B., J.S. Ucdford and S.K. B;~iley.Dosc ratecifccls in mammalian cclls in culture. 111. Comparisonof ccll killing and ccll proliferation during continuous
irradiation for six dillcrcnt ccll lines. Radiat. Rcs. 79:
537-551 (1979).
M31 Mothersill. C., C.B. Scymour and M. Moriarty.
Development of radiation transformation systems forepithelial cclls - problcms and perspectives. p. 414422 in: Low Dose Radiation: Biological Bases of Risk
Asscssmcnt. (K.1:. Baverstock and J.W. Slalher, eds.)
Taylor and Francis, London. 1989.
M32 Miller, A.B., G.R. Ilowc, G J . Sherman ct al.
Mortality from breast cancer after irradiation during
fluoroscopic examinations in patients being treated fortuberculosis. N. Engl. J. Mcd. 321: 1285-1289 (1989).
M33 Marples, B. and M. Joiner. Cell survival at very low
radiation doses. p. 53-55 in: Gray Laboratory Annual
Report. Cancer Research Campaign, London, 1989.
M34 Marshall, J.H. and P.G. Groer. A theory of theinduction of bonc canccr by alpha radiation. Radiat.
RCS.71: 149-192 (1977).
M35 Marshall, J.11. and P.G. Groer. Thcory of theinduction of bonc cancer by radiation. 11. A possible
low-lying linear component in the induction of (bone)
cancer by alpha radiation. p. 110-144 in: Radiologicaland Environmental Research Division, Annual Rcport.
ANL-77-65 (1977).
M36 Muirhcad, C.R., R. Cox, J.W. Stather ct al. Estimatesof late radiation risks to the UK population.
Documents of the NRPB. Volume 4(4) (1993).
M37 Moolgavkar, S.H. and DJ. Venson. Two event models
for caranogcncsis: incidence curves Tor childhood andadult tumours. Math. Biosci. 47: 55-77 (1979).
M38 Moolgavkar, S.11. and A.G. Knudscn. Mutation andcanccr: a model for human carcinogcnesis. J. NaU.
Canccr Inst. 66: 1037-1052 (1981).
M39 Moolgavkar, S.H. Modcl for human carcinogcnesis:
action of environmental agents. Environ. Health
Persped. 50: 285-291 (1983).
M40 Mfiller, W.A., A. Luz, B. Murray et al. The effect ofdose protradion with a very low radium-224 activity
in micc. p. 32-36 in: Risks From Radium and?horolrast. BIR Report 21. (D.M. Taylor, C.W. Mays.
G.B. Gerber ct al., eds.) British Institute of Radiology,
London. 1989.
M41 Moolgavkar, S.1 I. 1 lormones and multistage
carcinogcnesis. Cancer Survcys 5: 635-648 (1986).
M42 Moolgavkar. S.11. A two-stage carcinogcncsis modcl
for risk asscssmcnt. Ccll Diol. Toxicol. 5: 445-460(1989).
M43 Morin, M.. 11. Massc and J. Lafunla. Effects decancdrogi?nes dc I'irradiation gamma B faible debit dedose. C.R. Acad. Sci., Ser. 3 (311): 459-466 (1990).
M44 Mole. 11.M. Some aspccts of mammalian radiobiology.
Kadiat. Res. (Suppl.) 1: 124-148 (1959).

723

M.15 Maisin, J.R., A. Dcclcvc. (3.13. Gcrlxr et al. Chcmical
protection against thc long-tcrm clfccts of a singlc
whole-body cxpnwrc of mice to ionizing radiation. 11.
Causcs of dcalh. Radiat. I1cs. 74: 415-435 (1978).
M46 Miller, C.E. and ILJ. llall. Oncogcnic transformationof C3IIlO'I'Sfr cclls by aculc and protracted cxposurcs
to monocncrgctic neutrons. Radiat. I1cs. 128: S60-S64(1991).
M47 Maisin, J.R., A. Wambersic, G.B. Ccrbcr ct al. Lifcshortening and disease incidence in mice ancr
exposure to gamma rays of high-cncrgy ncutrons.
Radiat. Kes. 128: S117-S123 (1991).
M48 Matsuda, Y. and I. Tobari. Rcpair capacity of fertilizcd mouse cggs for X-ray damage induccd in sperm
and mature oocytcs. Mutal. Res. 210: 35-47 (1989).
M49 Matsuda, Y., N. Scki, T. Utsugi-Takcuchi et at. X-rayand mitomycin C (MMC)-induced chromosome
aberrations in spermiogcnic germ cells and the repair
capacity of mouse eggs for the X-ray and MMC
damage. Mutat. Res. 211: 65-75 (1989).
hlSO Matsuda. Y., N. Seki, T. Utsugi-Takeuchi ct at.
Changes in X-ray sensitivity of mouse eggs fromfertilization to the early pronuclear stage and thcir
repair capacity. Int. J. Radiat. Biol. 55: 233-256(1989).
M51 Matsuda, Y., M. Maemori and 1. Tobari. Relationshipbetwccn cell cycle stage in the fertilized egg of miceand repair capacity for X-ray-induced damage in the
sperm. Int. J. Radiat. Biol. 56: 301-314 (1989).
N1 National Council on Radiation Protection andMeasurements. Influence of dose and ils distribution
in tirne on dose-response relationships lor low-LET
radiation. NCRP Rcport No. 64 (1980).
N2 National Council on Kadiation Protection andMeasurements. Induction of thyroid canccr by ionizing
radiation. NCRP Rcport No. 80 (1985).
N3 Neary, G J . Aging and radiation. Nature 187: 10-18(1960).
N4 Neary, G J . Aging and radiation. Am. Iicart .I.6 2
433-435 (1961).
N5 Namba, M., K. Nishitani, T. Kimoto et al. Multistep
ncoplastic transformation of nomal human fibroblasts
and its genetic aspects. p. 67-74 in: Cell
Transformation and Radiation Induced Cancer. (K.H.
Chadwick, et al., eds.) Adam tlilgcr, Bristol, 1989.
N6 Nakamura. N. and S. Okada. Dasc-rate effects of
gamma-ray-induced mutations in cultured mammaliancells. Radiat. Rcs. 83: 127-135 (1983).
N7 Nakamura, N. and S. Okada. Mutations induced bylow doses of gamma-rays with different dose rates incultured mouse lymphoma cells. papcr B-248 in:Proceeding of thc 7th International Congress of
Kadiation Rcsearch. Amstcrdam. 1983. Martinus
Nijhoff, Amsterdam. 1983.
N8 Ncyrnan. J. and E. Scott. Statistical aspects of thc
problcm of carcinogencsis. p. 745-776 in: Fill11
Bcrkclcy Symposium on Mathematical Statistics andI'rohability. University of California I'rcss. Derkelcy,
1967.
N9 National Council on Kadiation I'rotcction andMeasuremcnts. 'Ihc rclativc biological cllcctivcncss ofradiations of difrercnt quality. NCKI' R c p r t No. 104(1990).

724

U N S C M R 1993 KI3'OK'I'

Nikjoo, H. Track structure analysis illustrating theprominent role of low-energy electrons in radiobiological effecb of low-LET radiations. Phys. Med.
Biol. 36: 229-238 (1991).
Obu, ll., M. Yasukawa and T. Terasima. In vitro properties and tumorigenicity of radiation-transformed
clones of mouse 10T% cells. J. Radiat. Res. 24: 118130 (1983).
Oftedal, P. A theoretical study of mutant yield andcell killing after treatment of heterogeneous cell
populations. IIereditas 60: 177-210 (1968).
Oftedal, P. A holistic view of low-level radiation
effects in biological systems. Can. J. Phys. 68: 974978 (1990).
Olivieri, GJ. and S. Wolff. Adaptive response ofhuman lymphocytes to low concentrations of radioactive Ihymidine. Sacnce 223: 594-597 (1984).
Ootsuyama, A. and H. Tanooka. One hundred percent
tumor induction in mouse skin after repeated p irradiation in a limited dose range. Radiat. Res. 115: 488494 (1988).
Ootsuyama, A. and H. Tanooka. Induction of osteosarcomas in mouse lumbar vertebrae by repeatedp irradiation. Cancer Res. 49: 1562-1564 (1989).
Ootsuyama, A. and I-I. Tanooka. Threshold-like doseof local fiirradiation repeated throughout the life spanof mice for induction of skin and bone turnours.
Radiat. Res. 125: 98-101 (1991).
Paretzke, H.G. Physical aspccts of radiation quality. p.
514-522 in: Low Dose Radiation: Biological Bases of
Risk Assessment. (K.F. Baverstock and J.W. Slather,eds.) Taylor and Francis, London. 1989.
Pierce, D.A. and M. Vaeth. The shape of the cancer
mortality dose-response curve for atomic bomb survivors. RERF TRP-89 (1989).
Pierce, D.A. and M. Vaeth. Cancer risk estimationfrom the A-bomb survivors: extrapolation to low
doses, use of relative risk models and otheruncertainties. p. 54-69 in: Low Dose Radiation:
Biological Bases of Risk Assessment. (K.F. Bavcrstock and J.W. Stather, eds.) Taylor and Francis,
London, 1989.
Preston, D.L. and D.A. Pierce. The effect of changes
in dosimetry on cancer mortality risk estimates in theatomic bomb survivors. RERF TR19-87 (1987).
Purrott, R.J. and E. Reeder. Chromosome aberration
yields in human lymphocytes induced by fractionateddoses of x radiation. Mutat. Res. 34: 437-446 (1976).
Phillips, R.J.S. A comparison of mutation induced byacute x and chronic gamma irradiation in mice. Rr. J.
Radiol. 34: 261-264 (1961).
Pohlit, W. Interaction of energy depositions andprimary radiation lesions along a particle track andbetween different tracks. Radiat. Prot. Dosim. 13:
271 -273 (1985).
Pohl-Ruling, J. Chromosome aberrations in man inareas with elevated natural radioactivity. p. 103-111
in: Benelius Symposium XV. Umea. Sweden, 1989.
Paretzke, 11.G. Radiation track structure theory. p. 89170 in: Kinetics of Nonhomogeneous Processes. (G.R.
Freeman, ed.) Wiley and Sons, New York, 1987.
Paretzke, 1I.G. Biophysical models of radiation actiondevelopment of simulation codes. p. 17-32 in: The

Early Effects of Radiation on DNA. (E.M. Fielden
and 1'. O'Ncill, eds.) Springer-Verlag, fleidelberg,
1991.
I'olig, E.. W.S.S. Jec, R.R. Setterberg ct al. Local
dosimetry or 22%a in tlle trabecular skeleton of the
Rcaglc. Radiat. Rcs. 131: 24-34 (1992).
Itauth, A.M. Itadiation carcinogcnesis. p. 106 in: The
Basic Scicncc of Oncology. (I.F. Tannock and K.P.
I lall, cds.) I'crgamon I'rcss, Oxford, 1987.
Redpalh, J.C., C. Sun, M. Mendonca et al. The application of a human hybrid cell system to studies ofradiation-induced cell transformation: quantitative
cellular and lnolccular aspects. p. 85-90 in: Cell
Transformation and Radiation Induced Cancer. (K.H.
Chadwick et al., eds.) Adam Ililgcr, Bristol 1989.
Robinson, V.C. and A.C. Upton. Computing-risk
analysis of lcukaemia and non-leukaemia mortality in
x-irradiated male RF mice. J. Natl. Cancer Inst. 60:
995-1007 (1978).
Roesch, W.C. (ed.). US-Japan Joint Reassessment ofAtomic Bomb Radiation Dosimetry in Hiroshima andNagasaki, Final Report. RERF (1987).
Rossi, H.H. and A.M. Kellcrer. The dose ratedependence of oncogenic transformation by neutrons
may be due to variation of response during the cell
cycle. Int. J. Radiat. Biol. 50: 353-361 (1986).
Russcll, W.L., L.B. Russell and E.M. Kelly. Radiationdose rate and mutation frequency. Science 128:
1546-1550 (1958).
Russell. W.L. The effect of radiation dose rate andfractionation on mutation in mice. p. 205-217 in:Repair from Genetic Radiation Damage. (F.H. Sobcls,ed.) Pcrgamon Press, New York, 1963.
Russell, W.L. Studies in mammalian radiation
genetics. Nucleonics 23: 53 (1965).
Russ, S. and G.M. Scott. Biological effects of gammaradiation (11). Rr. J. Radiol. 12: 440-441 (1939).
Rossi, H.N. The effects of small doses of ionizing
radiation: fundamental biophysical characteristics.
Radiat. Res. 71: 1-8 (1977).
Russell, W.L. and E.M. Kelly. Mufation frequencies
in male mice and thc estimation of genetic hazards ofradiation in man. Proc. Natl. Acad. Sci. (USA) 79:
542-544 (1982).
Radford, I.R., G.S. Hodgson and J.P. Matthews. Critical DNA target size model of radiation-induced
rnamn~aliancell death. Int. J. Radiat. Biol. 54: 63-79(1988).
Redpath, J.L., C.K. Hill, C.A. Jones et al. Fissionneutron-induced expression of a tumour-associatedantigen in human cell hybrids (IleLa x skin fibroblasts): evidence for increased expression at low dose
rate. Int. J. Radiat. Biol. 58: 673-680 (1990).
Rossi, H.11. Microscopic energy distribution in
irradiated matter. p. 43 in: Radiation Dosimetry.
Volume 1. (I:.II. Atix and W.C. Roesch, eds.)
Academic Press, New York, 1968.
Rossi, 11.1-1. Microdosimetry and radiobiology. Radiat.
Prot. Dosim. 13: 259-265 (1985).
Redpath, J.L., C. Sun and W.F. Blakcy. Effect offission-neutron dose rate on the induction of atumour-associated antigen in human cell hybrids.
Icadiat. Res. 128: S71-S74 (1991).

ANNEX F: INFLUENCE OF DOSE AND DOSE RATE ON STOCllA!TllC EFK:CIS OF RADIATION

R17 Russell. W.L. and E.M. Kelly. Specific-locus mutation
frequcncics in mouse stemcell spermatogonia at vcry
low radintion dose ntcs. Proc. Natl. Auld. Sci. (USA)79: 539-541 (1982).
R18 Russell. W.L. and E.M. Kclly. Mutation frequcncics
in fcmalc mice and the estimation of genctic ha7"ardsor radiation in women. Pmc. Natl. Ac;ld. Sci. (USA)74: 3523-3527 (1977).
R19 Russcll, W.L. I h e genetic effects of radiation. p. 487500 in: I'caccful Uses of Atomic Encrgy. STI/PUI3/
300, Volume 13. IMA, Vicnna, 1972.
S1 Sachcr, G.A. and D. Grahn. Survival of mice undcr
duration-of-life exposure to gamma rays. I. ?hedosagc - survival rclation and thc lethality function. J.
Nad. Cancer Inst. 32: 277 (1964).
S2 Seymour, C.B.. C. Mothersill and T. Nper. Highyields of lethal mutations in somatic mammalian cclls
that survive ionizing radiation. Int. J. Radiat. Biol. 50:
167-179 (1986).
S 3 Shadley, J. and S. Wolff. Very low doses of x-rays
can cause human lymphocytes to become less susccptible to ionizing radiation. Mutagenesis 2:95-96 (1987).
S4 Shellabarger, C.J., V.P. Bond and E.P. Cronkite.
Studies on radiation-induced mammary gland neoplasia in the rat. VIII. The effcct of fractionation andprotraction of sublethal total-body irradiation. Radiat.
Res. 17: 101-109 (1962).
S5 Shellabarger, CJ., V.P. Bond, G.E. Aponte et al.
Results of fractionation and protraction of total-bodyradiation on rat mammary ncoplasia. Cancer Res. 26:
509-513 (1966).
S6 Shellabarger, CJ., V.P. Bond, E.P. Cronkite et al.
Relationship of dose of total-body WCo radiation toincidence of mammary neoplasia in female rats. p.
161-172 in: Radiation-Induced Cancer. STI/PUBL228.
M A , Vienna, 1969.
S7 Shellabarger, C.J. Modifying factors in rat mammary
gland carcinogencsis. p. 31 in: Biology of Radiation
Carcinogenesis. (J.M. Yuhas ct a]., c&.) Raven Prcss,
New York, 1976.
S8 Shellabarger, CJ., J.P. Stone and S. I-loltzman.
Experimental caranogenesis in thc breast. p. 169-180
in: Radiation Carcinogenesis. (A.C. Upton et al., cds.)
Elsevicr, New York, 1986.
S9 Shimizu, Y., I-I. Kato, WJ. Schull et al. Life Span
Study Report 11, Part I: Comparison of risk
coefficicn~sfor site-specific cancer mortality based on
the DS86 and T65DR shielded kerma and organ
doses. RERF TR/12-87 (1987).
S10 Shimizu, Y., H. Kato and W J . Schull. Lifc Span
Study Report 11, Part 11: Cancer mortality in the years
1950-1985 based on the recently revised doses(DS86). RERF TR/5-88 (1988).
S11 Shore, K.E., E. Woodard, N. Hildreth ct al. Thyroid
tumours following thymus irradiation. J. Natl. Cancer
Inst. 74: 1177-1184 (1985).
S12 Sinclair, W.K. Experirnenfal RBE's of high-LET
radiations at low doses and the implications for
quality factor assignment. Radiat. Prot. Dosim. 13:
319-326 (1985).
S13 Storer. J.B., LJ. Serrano, E.B. Dardcn et al. Life
shortening in RFM and BALR/c mice as a function ofradiation quality, dose and dose rate. Radiat. Res. 78:
122-161 (1979).

725

Slrnistc, G.F. and DJ. Chcn. Genotoxiaty of chronic.
low doses of low- or high-LET radiation in humancells. p. 39 in: Abstracts of Papers for Thirty-third
Annual Meeting of the Radiation Rcscarch Sodcty.
Radiation Research Sodety, Philadelphia. 1985.
S15 Shcllilbarger, C.J. and R.D. Brown. Rat mammary
neoplasia following a - 6 0 irradiation at 0.3R or 10R
per minute. Radiet. Res. 51: 493-494 (1972).
S16 Silini, G. and P. Metalli. Preliminary results from asplit dose expcrirnent on late ellects of ionizing
radiation in the mouse. Data on life span shortening.
p. 207-215 in: Radiation and Aging. (PJ. Lindop and
G.A. Sacher, cds.) Taylor and Francis, London. 1966.
S17 Spalding, J.F., J.R. Prine and G.L. Tietjen. Latebiological effects of ionizing radiation as influenced
by dose, dose rate, age at exposure and genetic
sensitivity to neoplastic transformation. p. 3-11 in:
Late Biological E k t s of Ionizing Radiation. Volume
11. Sll/PUB/489. IAEA, Vienna, 1978.
S18 Sachcr, G.A. A comparative analysis of radiation
lethality in mammals exposed at constant averageintensity lor the duration of life. J. Natl. Cancer Inst.
15: 1125-1144 (1955).
S19 Storcr, J.B. Radiation carcinogenesis. p. 453-483 in:
Canccr. Volume I. (F.F. Beckcr, ed.) Plcnum
Publishing Co.. Ncw York, 1975.
S20 Sanders, C.L., K.E. Lauhala and K.E. McDonald.
Life-span studies in rats exposed to U 9 ~ u 0 aerosol.
2Ill. Survival and lung tumors. Int. J. Kadiat. Biol.
(1993, in press).
S21 Stanbridge, EJ. An argument for using human cells inthe study of the molecular genetic basis of canccr.
p. 1-9 in: Cell Transformation and Radiation Induced
Cancer. (K.H. Chadwick ct al.. eds.) Adam Hilger,
Bristol, 1989.
S22 Shin. C., L.C. Padhy and R.A. Weinberg.
Transforming genes of carcinomas andneumblastomas introduced into mouse fibroblasts.
Nature 290: 261-264 (1981).
S23 Stevens, C., W.H. Brondyk, A. Burgess et al. Partiallytransformed anchorage-independent human diploidfibroblasts resulting from overexpression of the c-sis
oncogcnc: mitogenic activity of an apparent
mononcric platelet - derived growth factor 2 species.
Mol. Cell. Biol. 8: 2339-2096 (1988).
S24 Suzuki, M., M. Watanabe, K. Suzuki et al. Neoplastic
cell transformation by heavy ions. Radiat. Res. 120:468-476 (1989).
S25 Suzaki, N. and S. Okada. Gamma-ray mutagcnesis ofculturcd mammalian cells in vitro and in vivo. Mu~at.
Res. 43: 81-90 (1977).
S26 Searle, A.G. Mutation induction in mice. Adv. Radiat.
Biol. 4: 131-207 (1974).
S27 Storer, J.B. and R.L. Ullrich. Life shortening in
BALB/c mice following brief, protracted or
fractionated expsurcs to neutrons. Radiat. Res. 96:
335-347 (1983).
S28 Stathcr, J.W. Effects of a-particle irradiation on
carcinogenesis. Int. J. Radiat. Biol. 58: 871-874(19W).
S29 Sanders, C.L. and J.A. Mahaffey. Inhalation
carcinogenesis of high-fired 2 4 4 ~ m 0in2 rats. Radiat.
Res. 76: 384-401 (1978).

S14

UNSCEAR 1993 REPORT

Sandcrs, C.L. and J.A. Mahaffcy. Inhalation carcinogcncsis of rcpcatcd cxposures to high-fircd U 9 ~ u 0 2 .
llealth IJhys. 41: 629-644 (1981).
Stathcr, J.W.. C.R. Muirhcad, A.A. Edwards ct al.
I lealth crfccts modcls dcvclopcd from thc UNSCEAR
1988 Report. NRI'l3-R226 (1988).
Sandcrson, BJ.S. and A.A. Morlcy. Exposure ofhuman lymphocytes to ionizing radiation reduces
mulagncsis by subscqucnt ionizing radiation. Mufat.
RCS. 164: 347-351 (1986).
Storcr, J.B. Radiation rcsisfancc with age in normal
and irradiated populations of mice. Radiat. Res. 25:
435-459 (1965).
Scott, B.R. and Ell. Ainsworth. State-vector modcl forlife shortcning in mia: after brief exposure to low
doscs of ionizing radiation. Math. Biosci. 49: 185-205(1980).
Saran, A.. S. Pazzaglia. M. Coppola et al. Absence ofa dose-fractionation cffect on neoplastictransformation induced by fission-spectrum neutrons
in QHlOTH cells. Radiat. Res. 126: 343-348 (1991).
Sarahan, A., S. Panaglia, M. Coppola ct al.
Neoplastic transformation of C 3 H 1 0 m cells by
fractionated doscs of monoencrgetic neulrons. p. 437
in: Radiation Research: A Twentieth Century
Perspective. Volumc 1. (J.D. Chapman et al., eds.)
Academic Press, San Dicgo. 1991.
Sato. F., S. Sasaki, N. Kawashima ct al. Late effectsof whole or partial body X-irradiation on mice: life
shortcning. Int. J. Radial. Biol. 39: 607-615 (1981).
Selby. P.B., S.S. Lee, E.M. Kelly et al. Specific-locus
expcrimcn~rshow that fcmale mice exposed near thetimc of birth to low-LET ionizing radiation exhibit
both a low mutational rcsponse and a dosc rate effect.
Mutat. RCS.249: 351-367 (1991).
Shapiro. R. Damagc to DNA caused by hydrolysis. p.
3-18 in: Chromosome Damage and Repair. (E. Seeberg and K. Klecpc, eds.) Plenum Press, New York,
1981.
Sinchez-Reyes, A. A simple model of repair action
based on repair saturation mcchanism. Radiat. Res.
130: 139-147 (1992).
Sedgewick, S.G. Inducible DNA rcpair in microbes.
Miaobiol. Sd. 3: 76-83 (1986).
Savage, J.R.K. and M. Ilolloway. Induction of sister
chromatid exchanges in d(42 MeV)-Be neutrons inunstimulatcd human blood lymphocytes. Br. J. Radiol.
61: 231-234 (1988).
Sanders, C.L., K.E. McDonald and J.A. Mahaffey.
Lung tumour raponsc to inhaled Pu and its
implications for radiation prolcction. Health Phys. 55:
455-462 (19&8).
Sandcrs, C.L., G.E. Daglc, W.C. Cannon et al.
Inhalation carcinogcncsis of high-fircd U 9 ~ ~in 0 2
rats. Radiat. Res. 68: 349-360 (1976).
Shore, R.E., N. Ilildrcth, E. Woodard ct al. Hrcast
cancer among wnmcn given X-ray thcrapy lor acutepostpartum mastitis. J. Ni~tl.Cancer Inst. 77: 689-696(1986).
Terasima, T., M. Yasukawa and M. Kimura.
Neoplastic transformation of plateau-phase mouse
IOTU cclls following single and fractionated doses of
x rays. Radiat. Rcs. 102: 367-377 (1985).

Thackcr, J. and A. Strclch. Hccovcry from lethal andmutagcnic damagc during post-irridialion holding andlow-dosc-ratc irretliation of culturcd hamstcr cells.
Radiat. Rcs. 96: 380-392 (1983).
Ihi~ckcr,J. i~nd A. Strclch. Rcsponscs of 4 x-ray
sensitive CIIO all nlutanls to diflcrcnt radiations andto irradiation cnnditiorls promoting ccllular rccovcry.
Mutat. Rcs. 146: 99-108 (1985).
~
Bio.
Thackcr, J , lnhcrilcd sensitivity to x-rays i r man.
Essays 1 1: 58-62 (1989).
Thackcr, J. Thc mcasurcmcnt of radiation-induced
mulation in mammalian cclls at low doses and dose
ratcs. Adv. Radiat. Biol. 16: 77-124 (1992).
Thamcs, I1.D. and J.11. Ilcndry. Fractionation inRadiotherapy. Taylor and Francis, London, 1987.
Thomson, J.F., F.S. Williamson, D. Grahn et al. Life
shortcning in mice exposcd to fission neutrons andy-rays. 11. Duration-of-lifc and long-term fractionatedexposures. Radiat. Rcs. 86: 573-579 (1981).
Thomson. J.1:. and D. Grahn. Life shortcning in mice
exposed to lission ncutrons and y rays. Radiat. Res.
118: 151-160 (1989).
Tobari, I., Y. Matsuda, G. Xiaohung et al.
Dose-response relationship for translocation inductionin spcrmatogonia of thc crab-eating monkey (Macaca
lascicularis) by chronic y niy irradiation. Mutat. Res.
201: 81-87 (1988).
Thomson, J.F., F.S. Williamson, D. Grahn et al. Life
shortcning in mice exposed to fission neutrons and yrays. I. Singlc and short-tcrm fractionated exposures.
Radiat. Rcs. 86: 559-572 (1981).
Tanooka, I-I. and A. Ootsuyama. Threshold-like dosc
response of mouse skin cilncer induction lor repeatedbeta irradiation and its rclcvance to radiation-induced
human skin canccr. Recent Results Cancer Res. 128:231-241 (1993).
Thornson, J.F. and D. Grahn. Life shortening in mice
exposed to fission ncutmns and y rays. VII. EKcm of
60 oncc-wcckly exposurcs. Radiat. Res. 115: 347-360(1988).
Tcrasima, T., M. Yasukawa and M. Kirnura. Radiation-induced transformation of lOTL//, mouse mils in
the platcau phasc: post-irradiation changes and serum
dependence. GANN Monogr. Cancer Res. 72: 762-768(1981).
Tcniighi-llowe, M. Induction of prcneoplastic
alternations by x-rays and ncutrons in exposed rat
trachea and isolated trachcal epithelial cells. Radiat.
Res. 120: 352-363 (1989).
Thomson. J.F., F.S. Williamson and D. Grahn. Life
shortcning in micc cxposcd to fission ncutrons andy rays. V. 1:urthcr studics with single low doscs.
Radiat. Rcs. 104: 420-428 (1985).
Thackcr. J., R.E. Wilkinson and D.T. Goodhcad. Thc
induction of chrornosornc cxchangc aberrations bycarbon ultrasort x-rays in V79 hiinlstcr cclls. Int. J.
Radiat. Riol. 49: 645-656 (1986).
Thackcr, J. Thc involvcrncnt of repair proocsses inradiation-induced mutation of culturcd mammaliancells. p. 612-620 in: IJrocecding of the 6thInternational Congress of Radiation Research, Tokyo,
1979. (M. Okado ct al., cds.) Toppan, Tokyo, 1979.

Thomson, J.I:., P.S. Williamson and 11. G n h n . Life
shortcning in mia: exposed to fission ncutmns and Xrays. 111. Neutron cxpsurcs of 5 and 10 rad. Radiat.
Rs. 93: 205-209 (1983).
T19 Thompson, K.C. Life-span cffccts of ionizing radiationin the lraglc dog. 1'NL-6822 (1989).
T20 Teoulc, R. Radiation-induced DNA di~magcand its
repair. 11-11. J. Itadiat. Biol. 51: 573-589 (1987).
121 Tobias, C.A., E.A. Blakcly, F.Q.11. Ngo ct al. The
repair-misrepair model of cell survival. p. 195-230 in:
Radiation Biology in Cancer Kescarch. (K.E. Meynand H.R. Withen, eds.) Raven Prcss, NCW York,1980.
'122 Tatsumi, K. and 11. Takebe. y-irradiation induccs
mutation in ataxia-telangicctasia lymphoblastoid cclls.
GANN Monogr. Canccr Res. 75: 1040-1043 (1984).
U1 United Nations. Sources, Effects and Risks of Ionizing
Radiation. United Nations Scientific Committee on thc
ECTeck of Atomic Radiation. 1988 Report to theGeneral Assembly, with annexes. United Nations sales
publication E.88.IX.7. United Nations, New York,1988.
U2 United Nations. Genetic and Somatic Effects oflonizing Radiation. United Nations ScientificCommittee on the Effech of Atomic Radiation, 1986
Report to the General Assembly, with annexes. Unitcd
Nations sales publication E.86.IX.9. Unitcd Nations,
New York, 1986.
U3 Uniled Nations. lonizing Radiation: S o u r m andBiological Effects. United Nations ScientificCommittee on the Effects of Atomic Radiation, 1982
Report to the General Assembly, with anncxes. Unitcd
Nations sales publication E.82.IX.8. United Nations,
New York, 1982.
U4 United Nations. Sources and Effcck of Ionizing
Radiation. United Nations Scientific Committee on the
Effects of Atomic Radiation, 1977 report to thc
General Asscmbl y, with anncxes. Unitcd Nations salcs
publication E.77.IX.l. United Nations. Ncw Y o r k
1977.
U5 Unitcd Nations. Ionizing Radiation: Levels andEffects. Report of the United Nations ScientificCommittee on the Effec~sof Atomic Radiation. withannexes. Unitcd Nations sales publicalion E.72.1X.17
and 18. Unitcd Nations, New York, 1972.
U11 Ullrich, R.L.. M.C. Jernigan, G.E. Cosgrove et al. The
influence of d o x and dosc rate on the incidence ofneoplastic disease in RFM mice aftcr nculron
irradiation. Radiat. Kcs. 68: 115-131 (1976).
U12 Uilrich, R.L. and J.B. Storcr. lnfluencc of dosc, dose
rate and radiation quality on radiation carcinogcncsis
and life shortcning in RFM and BAI-B/c mice. p. 95113 in: Latc Biological Effects of lonizing Radiation.
Volume 11. STl/PUR/489. IAEA, Vienna, 1978.
U13 Ullrich, R.C. and J.U. Storcr. influence o f y irradiationon the development of neoplastic disease in micc. I.
Reticular tissue turnours. Radiat. Rcs. 80: 303-316(1979).
1114 Ullrich, R.L. and J.B. Storer. Influence of y irradiationon the devclopmcnt of neoplastic discasc in mice. 11.
Solid tumours. Radial. Kes. 80: 317-324 (1979).
U15 Ullrich, R.C. and J.R. Storer. lnflucncc of y irradiationon the development of neoplastic disease in mice. 111.
Dose-rate emects. Radiat. Res. 80: 325-342 (1979).

11116 Illlrich. R.1,. Tumaur induction in BALBlc mice alter
fri~ctionated or protracted exposures lo fission
spcctrum neutrons. Radial. Rcs. 97: 587-597 (1984).
U17 Ullrich, K.L. The n t c of progression of radiationtransformed mammary cpithclial cclls as enhanccd
i~flcrlow dosc rate nculron irradiation. Radiat. I h .
105: 68-75 (1986).
U18 Upton. A.C.. I:.F. Wolff, J. 1:urth el al. A comp~risonof the induction of myeloid leukacmias in x-irradiatedRF mioc. Cancer Res. 18: 842-848 (1958).
U19 Upton, A.C.. V.K. Jenkins and J.W. Conklin. Mycloid
lcukacrnia in the mouse. Ann. N.Y. Acad. Sci. 114:
189 (1964).
U20 Upton, A.C., V.K. Jenkins, 11.f5. Walburg ct al. Obscrviltion on viral, chemical and radiation-induced mycloid and lymphoid leukacmia in RF micc. N ~ I I .
C a n e r Inst. Monogr. 22: 229-347 (1966).
U21 Upton, A.C.. M.L. Randolph and J.W. Conklin. Latc
cffec~sof fast neutrons and gamma-rays in micc as
influenced by the dose rate of irradiation: induction of
ncoplasia. Radiat. Res. 41: 4 6 7 4 9 1 (1970).
U22 Upton. A.C. Radiobiological effects of low doscs.
Implications for radiological protection. Radiat. Ilcs.
71: 51-74 (1977).
U23 Upton, A.C., R.E. Albert, F.J. Burns et al. (cds.).
Radiation Carcinogencsis. Elsevier, New York. 1986.
U24 Ullrich, R.L. Tumor induction in BALBIc female
mice after fission neutron or y irradiation. Radiat. Res.
93: 506-515 (1983).
U25 Ullrich, R.L. Cellular and molecular changes inmamnlary epithelial cells following irradiation. Radiat.
RCS. 128: S136-S140 (1991).
U26 Ullrich, R.L., M.C. Jernigan. L.C. Satterficld ct al.
Radiation carcinogenesis: time-dose relationships.
Radiat. Kcs. 111: 179-184 (1987).
U27 Upton, A.C., A.W. Kimball, J. Furth et al. Somedelayed effects of atomic-bomb radiations in mice.
Cancer Res. 20: 1-62 (1960).
U28 Upton. A.C.. M.L. Randolph and J.W. Conklin. Latecffcc~sof fast neutrons and gamma rays in micc as
influenced by the dose rate of irradiation: lifcshortcning. Radiat. Rcs. 32: 493-509 (1967).
U29 Ucno. A.M.. I. Furuno-1:ukushi and H. Matcudaira. Induction of cell killing. micronuclci and mutation to 6thioguaninc resistance aftcr exposure to lowdosc-ratc
gamma-rays and tritiatcd watcr in cultured mammalian
cclls (L5178Y). Radiat. Res. 91: 447-456 (1982).
V1 van 13ckkurn. D.W. and P. Rcntvclzcn. The conccpt of
gcne transfer-misrcpair mechanism of radiation
carcinogenesis may challenge the linear cxtrdpolation
model of risk estimation for low radiation dosc.
Ilcalth I'hys. 43: 231-237 (1982).
V2 Vilcnchik. M.M. DNA damagc and repair in aging
and programmed dcath of cclls. Int. C o n g . Gcrontol.
Kiev 2: 40 (1972).
V3 Vilcnchik, M.M. Spontaneous DNA damngc andrepair. p. 266-267 in: Mcchanisnis of DNA Damagc
and Repair. Biologiwl Centre of the Academy of
Scicnccs, Puschino. 1971.
V4 Virsik, K.P.. R. Blohm, K.1'. tlerman ct al. Fas~.
short-ranged and slow, distant-ranged procase.
invcjlvcd in chmmosomc aberration formation. p. 943955 in: I'roceedings of thc Scvcnth Symposium on728

UNSCMR 1993 REPORT

Miaodosimetry. (J. Booz, H.G. Ebert and 1I.D.
Hartfiel, eds.) EUR-7147 (1981).
Vilenchik, M.M. Molecular Mechanisms of Aging.
Nuaka, Moscow, 1970. (in Russian)Vilenchik, M.M. Initial mechanisms of "natural" andradiation-induced aging. p. 87-97 in: Uspckhi Radiobiologii. Volume 7. (A.M. Kuzin and S.N. Alexandrov, eds.) Atomizdat, Moscow. 1978.
Vilenchik, M.M. Study of spontaneous DNA lesions
and DNA repair in human diploid fibroblasts aged invitro and in vivo. Stud. Biophys. 85: 53-54 (1981).
Vilenchik, M.M. DNA Instability and Late Radiation
Effect. Energoatomizdat, Moscow, 1987.
Walinder, G., CJ. Jonsson and A.M. SjMCn. Doserate dependence in the goilrogcn stimulated mousethyroid: a comparative investigation of the effects ofroentgen 131-1 and 132-1 irradiation. Acta Radiol.,
Ther., Phys., Biol. 11: 24-36 (1972).
Walinder, G. Late effects of irradiation on the thyroid
gland in mice. 1. Irradiation of adult mice. Acta
Radiol. Ther. Phys. Biol. 2: 433451 (1972).
Watanabe, M., M. IIorikawa and 0. Nikaido. Induction of oncogenic transformation by low doses of xrays and dose rate effect. Radiat. Res. 98: 274-283(1984).
Wolff, S. Is radiation all bad? The search for adaptation. Radiat. Res. 131: 117-123 (1992).
Wlodek, D. and W.N. Mittelman. The repair of double
strand breaks correlates with radiosensitivity of
L5178Y-S and LS178Y-R cells. Radiat. Kes. 112:
146-155 (1987).
Wollf. S., U. Alzal, J.K. Wiencke et al. Human lymphocytes exposed to low doses of ionizing radiations
become refractory to high doscs of radiation as well
as chemical mutagens that induce double-strand
breaks in DNA. Int. J. Radiat. Biol. 53: 39-48 (1988).
Wollf, S., J.K. Wiencke, U. Afial et al. The adaptive
response of human lymphocytes to very low doses ofionizing radiation: a case of induccd chromosomal
repair with the induction of specific proteins. p.

446-454 in: Low Dose Radiation: Biological Bases of
Risk Assessmerit. (K.F. Baventock and J.W. Stather,eds.) Tnylor and Francis, London. 1989.
W8 Walburg, 1I.E. Itadiation-induced life-shortening andpremature aging. Adv. Radial. Biol. 7: 145-179(1975).
W9 Ward, J.F. Response to commentary by D. Billen.
Radiat. Res. 126: 385-387 (1991).
W10 Wheeler, K.T. and G.B. Nelson. Saturation of a DNA
repair process in dividing and non-dividing mammalian cclls. Radiat. Res. 109: 109-117 (1987).
W11 Williams, A.C., S. f Iarpcr and C. Paraskeva. Neoplastic transformation of a human colonic epithelial cellline; experimental evidence for the adenoma to carcinoma sequence. Cancer Res. 50: 4724-4730 (1990).
Y1 Yang, T.C., L.M. Craise, M.T. Mei et al. Dose
protraction studies with low- and high-LET radiations
on neoplastic ccll transformation in vitro. Adv. SpaceRes. 6: 137-147 (1986).
Y2 Yates, J.M., R.W. Tennant and J.D. Regan. Biologyof Radiation Carcinogenesis, Proceedings of a
Symposium. Raven Press, New York, 1975.
Y3 Young, S. and R.C. Hallowes. Tumoors of the
mammary gland. p. 31-74 in: Pathology of Tumoun
in Laboratory Animals. Volume I. (V.S. Turosov, ed.)
IARC, Lyon, 1973.
Y4 Yuhas, J.M. Recovery from radiation-carcinogencsis
injury to the mouse ovary. Radiat. Res. 60: 321-332(1974).
Y5 Yasukawa, M., T. Terasima, T. Furuse et al. In vitro
neoplastic transformation by neutron beams - relative
biological effectiveness and dose fractionation. J.
Radiat. Res. 28: 268-273 (1987).
Z1 Zaidcr, M. and H.H. Rossi. Dual radiation action andthe initial slope of survival curves. Radiat. Res. 104:
S68-S76 (1985).
22 Ziegler, J.F. Ilelium: slopping powers and ranges inall elemental matter. The Stopping and Ranges of Ionsin Matter. Volume 4. Pergamon Press, New York,1977.