IONIZING RADIATION:
SOURCES AND BIOLOGICALEFFECTS
United Nations Scientific Committee
on the Effects of Atomic Radiation
1982 Report to the General Assembly, with annexes

UNITED NATIONSNew York, 1982

NOTE
The report of the Committee without its annexes appears as Official Records of the General Assembly, Thirtyseventh Session, Supplement No. 45 (A/37/45).
The designations employed and the presentation of material in this publication do not imply the expression of
any opinion whatsoever on the part oft he Secretariat of the United Nations concerning the legal status of any country,
territory. city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries.

UNITED NATIONS PUBLICATION
Sales No. E.82.IX.806300PANNEX K
Radiation-induced life shortening

CONTENTSParagraphs

INTRODUCTION .............•.•........
A.

B.
C.
D.

Historical background ............ .
Methodology .................... .
Theoretical foundations ........... ,Life shortening and aging .......... .
I.
Specific and non-specific life
shortening ................. .
2.
The phenomenon of aging .... .
3.
Mechanisms or aging and life
shortening ................. .
4.
Conclusions ................ .

I. THE
EFFECTSOF
PHYSICALVARIABLES ........................ .
A. The effects of acute single doses .... .
I.
Mouse ...................•.•
2.
Other species ............... .
Data analysis ............... .
3.
4.
Conclusions .....•...........
B. The effect of continuous life-time irradiation .............•••..........
I.
Mouse ..................... .
2.
Other species ............... .
Data analysis ....•...........
3.
4.
Conclusions ................ .
5.
Internal irradiation .......... .
6.
Uncommon findings ......... .
C. Dose rate, dose fractionation, protracted exposures ................ .
1.
Dose rate .................. .
2.
Dose fractionation .......... .
3.
Protracted exposures ........ .
4.
Conclusions ................ .
D. Radiation of different types and energies ............................ .
I.
Data ..................... ..
2.
Conclusions ................ .
E. Specificity of life shortening ....... .
II. THE EFFECTS OF BIOLOGICALVARIABLES ........................ .
A.

Genetic background .............. .
1.
Inter-species differences ...... .
2.
Intra-species differences ...... .

1-63

Paragraphs

B.

Sex and body weight .............. .
1.
Sex ....................... .
2.
Body weight ................ .
Age at irradiation ................ .
1.
Irradiation in utero .......... .
2.
Irradiation during extra-uterine
life ........................ .
Conclusions ..................... .

241-250242-249250
251-272251-255

48-61
62-63

III. MODIFYING FACTORS ......•......

281-31264-216...................

5-11
12-21
22-39
40-63
40-43
44-47

66-100
67-85
86-93
94-96
97-100101-153
107-118
119-121122-129130-133
134-146147-153

c.
D.

A.
B.

c.
D.
E.

Physical treatments ................
Physico-chemical and pharmacological treatment
1.
Anaesthesia, oxygen and hypothermia .....................
Chemical radioprotective drugs
2.
Biological treatments ..............
Bone marrow transplantation ..
1.
Other treatments ..•..........
2.
Partial-body irradiation ............
Mouse .....•................
1.
2.
Rat and hamster.....
Conclusions ......................

········

IV. THE HUMAN DATA ........•........

281-284285-294285-286287-294295-297295-296297
298-308298-303304-308309-312313-375

Introduction ..................... .
Data from occupationally exposed
people .......................... .
Data from radiotherapy patients .... .
Data from A-bomb survivors ....... .
Conclusions ..................... .

313-317

V. GENERAL CONCLUSIONS ......... .

376-392

217-280

VI. RESEARCH NEEDS ................ .

393-398

218-240219-232
233-240

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

154-188155-159
160-173
174-181182-188
189-204
189-201202-204205-216A.
B.

256-272273-280C.
D.
E.

318-344345-352353-362363-375

Page

717

655

Introduction
1. Since the 1958 and the 1962 reports of UNSCEAR!Ul, U2] the Committee has not presented a review of
the cumulative evidence in the lield of non-neoplastic
long-term effects of whole-body irradiation. 1l1e scopeof this Annex is to consider the data available in order
to ascertain:

The existence and extent of life-span shortening in
irradiated animals and man and the relationshipsof life shortening to the physical and biologicalvariables which may influence this effect ofradiation;(b) The extent and ranges of the physical andbiological components of this effect which might
be attributed by careful pathological analysis toeither real non-tumorous conditions or to specilic
neoplastic diseases;(c) The range of doses within which a non-specificradiation effect may be identified and measured;(d} Whether such a non-specific shortening of life may
be similar to the normal biological aging process.
Although answers to some of the above questions may
be difficult in the light of the present biological andradiobiological knowledge, the Committee believes thata review of the field may be of value as a selective
collation of the existing information. All data in thehuman species have been grouped for convenience inchapter IV. Causes of death due to non-stochastic
effects are dealt with in Annex J.
(a)

2. Due to its coherence and wide acceptance, theinternational system (SI) of units of measurements has
been employed wherever possible. The use of SI has
resulted in the replacement of the former unit ofabsorbed dose, the rad, by joule/kilogram and in a
special name of the unit, the gray (Gy), with one Gy
being equal to 1 J/kg and to 100 rad. Similarly, the unitof exposure, the roentgen (R), has been replaced by
C/kg, where one C/kg is equal to about 3876 R.
Furthermore, the unit of activity, the curie (Ci), hasbeen replaced by the reciprocal second and its special
name, the becquerel (Bq), where 1 Bq is (1/3.7 1010) Ci.
3. The use of the SI units poses problems in thepresentation of results, except those obtained in the
recent past. Due to the simple relation between the radand the gray and that between the curie and thebecquerel it is possible to easily perform these conversions. This has been done throughout this Annex. For
the quantity exposure, however, it has been decided to
employ the units provided by the authors.
4. The relation between exposure and absorbed dose
and the recent tendency to use the latter in quantifying
irradiations presents another difficulty. As an example,
for soft tissues exposure to I R of low-LET radiation
results in an absorbed dose of about 0.009 ± 0.0005
Gy, when the quantum energy is more than about 25
keV and electron equilibrium exists. However, thevariation in absorbed dose can be far greater for othertissues (e.g., bone). Other uncertainties arise when
animals larger than the mouse are irradiated. In thesecases the conversion depends on whether the exposure
quoted is that in free air or the mean exposure in the
animal. In the more usual case of free air exposure,there is a complex relation between exposure andabsorbed dose, depending on the size of the animal,
irradiation geometry and radiation energy. For thesereasons no attempt has been made to replace quoted
exposures by corresponding absorbed doses.
656

A.

HISTORICAL BACKGROUND

5. Radiation-induced
life-span shortening was
described first in the rat by Russ and Scott IR l] and in
the mouse by Henshaw [HI]. They reported that
irradiated animals had a shorter life span and appeared
to age more rapidly than their non-irradiated controls.
These and other observations led quite naturally to theestablishment of a conceptual link between the lifeshortening action of radiation and natural senescence.
In 1952 !hues and Sacher [BI] discussed the problem ofradiation-induced long-term radiation lethality. Theseauthors recognized that single acute exposures toradiation tended to displace the Gompertz agemortality function upward, while chronic exposure
throughout life increased the slope of this function.
Other techniques of analysis by the cumulative or theimpulse lethality functions were also proposed as quasiempiricalactuarialandkinematic descriptive
approaches. A comparative review of radiation lethality
in various mammalian species, particularly underconditions of chronic treatment for the entire durationof life was presented by Sacher in 1955 [Sl].
6. Although the treatment of this subject hadproceeded quite far by 1958, there was little coverage of
it in the 1958 report of the Committee [Ul]. At that time
the analysis of the biological end-point was not very
sophisticated. It had been established that the pathogenesis of early death was due to the failure of selfrenewing systems in the body, but that the precocious
extinction of an animal population as revealed byactuarial analysis, was due to different mechanisms.
However, there seemed to have been poor discrimination of the two mechanisms. In particular, noattention was given to the actuarial approach which
had already been advocated by Sacher [S2] and Brues
and Sacher [B1].
7. Although the review presented by Mole at the FirstInternational Congress of Radiation Research [Ml]criticized the idea that radiation-induced life shortening
might be equivalent to natural aging, this notion gained
acceptance as a result of some observations on animals
surviving doses in the lethal range made by Henshaw[H1] and later by Alexander [Al]. The "equivalence"idea was first based on actuarial observations of anincrease in mortality rate from all causes of death, with
an apparent shift of diseases characteristic of older age
to younger age groups. The occurrence of phenomena
typical of the old age in survivors (greying of the fur,cataracts, loss of reproductive capacity, etc.) tended tosupport the hypothesis of "equivalence". However,Upton in his 1957 [U3] and 1960 [U4] reviews warned
against the attempt to establish a close relationshipbetween certain effects of irradiation and aging,
because not all age-dependent changes were affectedsimilarly by radiation and the incidence and severity ofthe various diseases differed in control and irradiatedanimals.
8. Comfort [Cl] discussed similarities and differences
between natural aging and radiation-induced life shortening. His review is an important effort to define basic
concepts and to differentiate between the various
biological effects observed but his analysis of dataaccording to dose and time is less elaborate thanelsewhere. Storer and Grahn [S3] presented an accurate
review of information available. This paper is still ofinterest for reference purposes. Neary [Nl. N2]
regarded theories of aging as belonging to one of two
main groups: those interpreting aging as due to random

events in a population of supposedly uniform
individuals; and those examining the individual and its
component cells. Neary proposed his own theory,
based on the analysis of original data on irradiatedmice. According to his formulation aging proceeds in
two successive stages, induction and development, eachcharacterized by appropriate parameters. Although noattempt was made at the time to identify these stages,
experiments reported later from the Soviet Union [Y8,Y9, Vl 1, Y12] tend to show that induction consists ofthe spontaneous occurr_£nCe of lesions in cellular DNA
and development (promotion) in the activation ofendogenous viral genomes by chemical carcinogens orradiation.
9. Another interesting contribution was provided by
Casarett [C2]. By a critical comparison of natural aging
and of late radiation effects, he proposed that radiological aging can be ascribed to the damage ofendothelial cells of the fine vasculature, leading tofibrotic changes of the arterioles and of the interstitialcollagenous substance. These mechanisms would be
followed by loss of parenchymal cells, replacement
fibrosis of the organs, loss of the functional reserve
capacity and, eventually, by an increased susceptibility
to trauma, stress and disease.
10. In recent years research tended to be more experimental than theoretical, except perhaps for the work of
Sacher and Grahn [S4], Grahn and Sacher [Gl] andSacher [SS] who further elaborated previous ideas in an
attempt to derive, from a refined analysis of the data, abasis for a comprehensive theory of a natural andradiation-induced aging. Attempts towards a bettersystematization of the experimental data were also
carried out in contributions from scientists of the Soviet
Union [All, K26).
11. A recent report of Walburg [Wl] was essentially acritique of the concept of non-specific life shortening,
especially at the low doses of practical interest.
Walburg came to the conclusion that life-shortening
effects after irradiation may principally be explained by
the induction or acceleration of neoplastic diseases.
This conclusion was supported by Storer [S6]. Theseand other [K26] authors recognized that at higher doses
other mechanisms of death prevailed.
B.

METHODOLOGY

12. Life shortening can only be assessed on the basisof death, an end-point that can be defined rather
precisely in time. However, it is usually more informative to know also the reasons why an animal dies. To
ascertain the cause of death is often difficult and, insome cases, impossible as death is often the result of avariety of causes all acting jointly. This is particularly
true as animals grow older [Dl, A2, D2) because aging
animals of all species (but particularly of the long-livedones) die with multiple lesions, contrary to early death
where there is often a single pathological cause. In old
animals the number of possible causes of death
increases and the primary or precipitating cause isdifficult to diagnose. Most irradiated animals die of
diseases which are unrelated to radiation exposure andthis complicates the identification of the terminal
pathological syndromes. Thus, multiple disease conditions, and interactions between diseases in the same
animals should be correlated with parameters such as
age and dose to provide a meaningful interpretation of
the pathology at death.

13. The first difficulty with much of the work
reviewed, particularly with the earlier contributions, isthe lack of careful pathological observations on the
animals at death, or a refined multifactorial analysis.
Many experimental series are therefore difficult tointerpret, as the representation of the life-span shortening, which may be accurate with respect to time,masks the complexity of the biological end-points.
Another difficulty is that even when good pathology isavailable, information is usually collected at death.
Under these conditions it is impossible to assess thecontribution of each specific cause to life shortening,since there is no reason to presume that all causes areequally accelerated by radiation. Serial sacrifice experiments could. in principle, provide such information,
but these require considerable time and effort and suchreports are therefore not common in the literature [K 1,
C3, A3].
14. Apart from the difficulties in defining anddescribing a complex effect such as life shortening,quantification can create problems by giving implicit
support to one or another possible interpretation. Interesting comments have been made by Mole in thisrespect [M2, M3]. He points out that it is not immaterial
to think of the effect as a differential between the life
span of the control population (to) and the life span of
the irradiated animals. If it is postulated that survival
after a given dose (to) is a function of that dose, it is
implicitly ignored that animals may die of someunrelated pathology, and there is no implication thatthe effect of radiation may persist up to the end of life.
If, on the other hand. the postulate is that the differential life time (to - to) is a function of the dose, thenthe implication is that the effect of radiation may beequivalent to natural aging. No problems arise forsingle acute exposures given at young ages or for
duration-of-life experiments, because under these
conditions the two postulates are compatible. However,when experiments with various to are involved, that is,when groups of animals are started on a course ofirradiation at variable ages, one could come to quite
different conclusions from the same experimental data
simply by accepting one or the other postulate.
15. By definition, life shortening is an effect that mustbe estimated statistically by comparing irradiated andnon-irradiated animal populations. The different waysof describing and expressing the effect quantitatively
include the mean or median life span, the per centcumulative mortality or the age-specific mortality rate.
All these may be regarded as compounded expressionsof specific and non-specific causes, acting within eachindividual to decrease fitness and ultimately to cause
death.
16. Life shortening is expressed in days of life lost andsince the time to death has a statistical variability, life
shortening may be represented by one of the following
statistics: shortening of mean or median age at death,shortening of mean or median survival time. In thesecases the effect is given in units of time. Alternatively,
the effect can be given as a percentage of control values
and in such cases the per cent shortening of the mean ormedian age at death or the per cent shortening of themean or median survival time would be the relevant
parameters. It should be noted that the percentage
effect as measured by the shortening of the mean ormedian age at death is not equivalent in most cases tothat measured as per cent shortening of the mean ormedian survival. Although it would have been desirable
to use the same method of expressing the effect657

throughout this Annex, it was impossible to do so dueto the Jack or suitable data in the documents reviewed.
17. Mean and median lire span are the average
duration or life experienced by the animal populationand the time required for 50 per cent or the animals todie, respectively. These statistics do not offer any
indication or the variability of the phenomenon withtime: they are therefore, as such, unsatisfactory
parameters for any statistical analysis. The curve
describing the extinction of the population in time ismore informative as it shows the time when this process
begins and ends and whether it has taken place
regularly. Irregularities of the curve may sometimes be
attributed to specific causes or set or causes. Both themean and the median life span can be easily calculated
and the per cent cumulative mortality as a function oftime can be readily plotted.
18. The age-specific mortality rate is a more elaborateparameter. It expresses the instantaneous rate ofmortality of the animals at risk as a [unction of age. Thechange over time is the main disadvantage in using thisparameter. The main advantage lies in its sensitivity inmeasuring the changes in the distribution of times atdeath. It should be recalled that the displacement of theage-specific mortality rate curve for irradiated animals
above the curve for non-irradiated controls does notmeasure days of life Jost, but the increased rate of dying
at a given age. The trend of this parameter in time andany irregularity in it are extremely useful to identify
possible specific causes of death.
19. In estimating mortality rates it is desirable thatassessments be independent of the proportion ofanimals that have died by any given time, i.e., that theestimate should be truly non-parametric with respect tosurvival. To this end, different formulas for its calculation have been proposed and may be utilized inradiation experiments [U5]. Upton, Kastenbaum andConklin [U6], in an analysis of the age-specific death
rates in irradiated LAFl and RF mice pointed out thatbeyond a certain age this parameter tends to assume an
exponential trend and that death rate curves specific for
certain diseases vary in shape and slope. These observations emphasize the complexity of the relationships
between dose and disease incidence. Therefore, thegeneralized notion that irradiation may advance theonset of old-age diseases is an oversimplification in thelight of the variability observed with respect to specificinjuries.
20. Other refinements in the analysis of life-shortening data may be introduced in order to account for
the effect or competing diseases. It has long been
known that the estimates of final incidence of diseases
occurring late in life may be affected by the rate ofmortality at times preceding the onset of these diseases[M4, F9]. Hoel and Walburg [H2] have comparedvarious interval techniques of analysis with a noninterval technique by Kaplan and Meyer and havecome to the conclusion that the latter may be used withadvantage when the age at death of the animals isknown. This technique has been employed foranalysing the significance of the difference between
treatment groups with respect to their cumulative
mortality. There are also techniques to adjust thecomparisons of mean ages at death, according to thepresence of competing, lethal and non-lethal, diseases.
Using these techniques Walburg [WI] has analysedsome existing data on life-span shortening in experimental animals and has convincingly shown the658

use[ulness of such methods in discriminating between
specific, i.e.. neoplastic, and non-specific lire shortening.
21. Risk estimates for long-term somatic effects orradiation exposure have mainly been based on theincidence or fatal tumours. In principle, an
improvement in these estimates could come fromconsideration, in addition to cancer incidence, or themean ages at death. Sato et al. [S52) proposed an index
which takes into account the contribution of each causeof death to life shortening. This index is the sum or
three terms. The first reflects the tumour incidence, thesecond the changes in mean age at death from eachcause of death and the third is an interaction factor forthe preceding two terms. If radiation exposure increases
the incidence of a given death cause and shortens therespective mean age at death, the index gives a large
positive value. On the other hand. an increase inincidence or a late occurring cause or death gives asmall positive or even a negative value for the index.
The paper has a numerical example based on animal
data.
C.

THEORETICAL FOUNDATIONS

22. Although it is the primary object of this Annex toreview and discuss experimental data on lire-span
shortening, it is impossible to do so without somebackground information on the hypotheses or aging.
Such information is given in the next fow paragraphs ina very simple form and is limited to those hypotheses
that were proposed in the field of radiation research.
More comprehensive discussions of the various theories
of aging are, for example, in Strehler [S7], Walburg[WI], Vilenchik [V8], Nikitin [N13].
23. Gompertz in 1825 found that the age-specificmortality rate in man as a function of age increased
exponentially over a considerable portion of lire andassumed that this phenomenon reflected an exponential
decline with age of some vital system. In the field orradiation research Brues and Sacher [BI] first introduced a mathematical approach to long-term mortality
based on the observation of Gompertz and this wasfollowed later as a basis for the analysis or experimental data and for many theoretical formulations.
According to this approach, the survival characteristics
of a group or individuals may be described by actuarial
functions. One of the most widely used is the Gompertz
function.
24. The Gompertz function In Q(t) is the logarithm of
the age-specific rate of mortality which is defined as[SI6]
Q(t) =

I dN
N dt

(I)

where Q(t) is the age-specific mortality and N is thenumber or animals surviving up to the time t. Linearityor the Gompertz function with time implies that(2)

where Po and P1 are positive constants. Experience
shows that a single acute dose of radiation is followed(after a period or latency) by an upward displacementof the Gompertz function without change in slope andthat the amount or displacement with respect to thecontrol is a function or dose. In other words, acuteirradiation changes the constant Po in equation (2),without affecting P1• If single exposures would affectmedian survival, tmed, linearly with dose D, thentmcd (D) = a - bD

(3)

where a is the median survival time of the control groupand b a dose-dependent constant. Chronic irradiation,on the other hand, characteristically increases the slopeof the Gompertz function proportionally to intensity ofirradiation, so that(4)tmed (I) = a e-cl

where tmcd (I) is the survival time following durationof-life exposure at dose rate I and c is a dose ratedependent constant. These basic trends of the rate ofmortality in irradiated mammalian populations areshown in Figure I.
,o•~-~----·r----.GREENHOUSE ~

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36

TIME AFTER TREATMENT, MONTHS

A.
Gompertz plots for LAFl mice (fer.iaZes)
after single acute exposures to gamma radiation.
Data from Furth et aZ. [F2] plotted by Sacher [S2]
e.e,

I

'U

.;. io-l

-

t-

...J

<
t-

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TIME, DAYS

B.

Gomperta pfots for LAF1 mice (uoth se::i:es)
wuier dai7,y exposui•e to ga,r."Tla radiation.
Data from Lorena et aZ. [161 pZotted by Sac11er fS2).
Figure I. Basic trends of actuarial parameters In Irradiatedmammalian populations. In the mouse exposure to 1 R wlll
result In an absorbed dose or approximately 0.009 Gy

25. The assumptions underlying such interpretations
are that the Gompertz function is a measure of theamount of aging injury present at any given time. Acuteexposure increases this amount of injury initially andfor the rest of life. However, if a new induced injury
adds to the residual present injury at any given time orto the underlying aging injury, one should expect achange in slope produced by chronic irradiation, with adivergence from the control slope proportional to theamount of daily dose administered. It should be clearthat such characteristics of the actuarial functions are
not necessarily related to the form of the dose-effectrelationships, which may themselves be linear or not, as
discussed in the next chapter.
26. In 1952 [82, 83] and again later in a more
complete form [84, 85] Blair formulated a model of therelationships between radiation dose and life shortening. This model postulates that total injury is linearly
proportional to dose and that such injury is only in part
reparable. Recovery from reparable injury proceeds
exponentially at a rate proportional to its magnitude:
while, on the contrary. the irreparable portion of injury
would accumulate linearly with dose. Finally, reparable
and irreparable injuries add and death occurs when theeffect of their sum is proportional to the remaining life
expectancy. Starting from these premises, Blairdeveloped simple equations relating dose and injury
under different conditions of exposure and showed thatsome of them conformed to the then available data .
Blair's formulation stimulated much research toascertain the amount of reparable injury and the
kinetics of repair under a variety of experimental conditions but was recognized later as an oversimplification
leading to incorrect estimates and as such inadequate toaccount for the form of the dose-injury functions.
27. Mewissen et al. [MS] developed a complex
equation relating life shortening to chronic whole-body
irradiation and applied this formula to the irradiationof the burro. The formula is based on an analysis of the
injury, which is also assumed to consist of a reparable
and an irreparable fraction. Wasted radiation is
accounted for by the transformation of a latent into an
actual injury at a given measurable rate. The numericalparameters of the equation may be computed fromexperimental results in cases of chronic and acuteirradiation. Weekly exposure to gamma radiation of
burros, between 175 and 2800 R, with corresponding
mean survival times of 9 weeks to 1 week, were thetime-dose conditions in which the above formula wasfound to apply. They are clearly of little value to thepresent discussion referring to low dose rates and toextended survival times. Storer [SS, S9] in a review ofdata on recovery rates and their possible relationships
to life shortening showed that the mean rate at whichmice recovered from radiation exposures, which if
acute would result in acute death, could be related to
the number of fractions delivered daily, rather than tothe size of the exposure. This and other observations
suggested modifications of the original formulation of
Blair.
28. Krebs, Brauer and Kalbach [K3] measured the
kinetics of non-recoverable injury by exposing C3H
female mice to conditioning irradiations (600 to 1500
R) and then estimating at different times (4 to 20 weeks)
the injury remaining. This estimate was obtained
indirectly by taking the LDso/30 values on the preirradiated mice. A proportionality between conditioning
dose and reduction in tolerance to x rays, as measured
by a reduction of LDso130, was found; however, the659

injury parameter did not account for the observedmortality when animals were chronically irradiated.
Further work [K4, KS] suggested that different recovery
components with different half-times could be shown toapply to acute and chronic radiation exposure conditions:
29. Complete disappearance of residual damage wasseen by Alexander and Connell [A4] three weeks after
conditioning exposures of 600 to 1100 R prior toLD50130 determinations. Spalding et al. [SlO] gave
conditioning fractionated doses of gamma rays (2.4 to
12 Gy) or of fission neutrons (0.9 to 4.5 Gy) to RF
female mice and, after a repair period of 3 months,
exposed them for the rest of their lives to a dose rate of
0.5 Gy d-1. They found that radiation-induced damage
had a permanent and irreversible component, that atleast a part of this damage was proportional to the doseand measurable in terms of reduction of survival time,
and that fission neutrons produced about five times asmuch irreversible injury as gamma rays. Always withthe same animals, an investigation of the twocomponent theory of Blair [84, 85] under theassumption that the half-time of the reparable
component was 7 days and that the irreparable injury
would be equivalent to 5% of any given dose, showedthat such a formulation was only useful under a limited
range of exposure conditions.
30. The above limited discussion of the results of avast amount of literature shows that short-, mediumand long-term mortality are produced from different
pathogenetic mechanisms. There is probably more than
one single formula to account for the variety ofmechanisms. Further, no single recovery time orresidual injury value can define all of the conditions ofprotracted exposure. The constants applicable to acuteinjury may to some extent predict the results of
exposures to within about 100 days and 15 Gy in themouse, but for longer times and low doses a new set of
relations between injury and recovery must be
established [Gl].
31. Neary [NI, N2] also proposed a model, based on
the observation that the great majority of animals in a
population die during the last part of the life span. The
preceding period of life, in which deaths are relatively
few, is called "induction" by Neary, who defines it as astate of intracellular changes and intercellular reactions
proceeding insidiously and without marked functional
impairment. When a certain level of this type of change
is reached, the second stage sets in quite abruptly. This
stage, called "development" involves a different level oforganization and is sustained by physiological interactions proceeding autonomously and autocatalyticallyand culminating in death. The most interesting featureof this model is that once development sets in further
inductive change is superfluous and therefore irradiation during development has comparatively little
effect. This point was emphasized conceptually byMole [M6] and by Mole and Thomas [M7] in the notionof "wasted radiation". Neary suggested that small
radiation doses would essentially act by shortening
induction without affecting development, and also
showed that there was a good correlation between the
results of experiments on mice [N3) and the formal
requirements of the model. Kohn and Guttman [K6]pointed out, however, that the model, derived fromresults of duration-of-life exposure was difficult toapply to results derived from acute irradiation experiments. Experimental evidence has more recently beenreported [V8, V12] in support of a two-stage model of
aging.
660

32. Jn a paper published in 1956 Sacher [S2] proposeda model in which all individuals in a population wereassumed to be initially identical. However, with time,
due to nuctuations in the physiological state of theanimals and to external stresses, there was a progressivechange and a dispersion in the physiological state of the
population. In this model, when a nuctuation of large
amplitude in the homeostasis of an animal takes place,death ensues. By a mathematical description of aphysiologic fluctuation process, it is possible to derive
an approximate relationship between the rate ofmortality and the mean physiologic state of the
population. The relationship has the form of a linear
function of the logarithm of the mortality rate withrespect to the mean physiologic state of the population
at any given age.
33. A more analytical presentation of this theory andof the derived functions can also be found in otherpapers [S4, SI2]. In a later contribution [S13] attempts
were made to interpret lethality in terms of very simple
cell population kinetics, without building into themodels known parameters of cell kinetics such as
maturation time or feed-back control of self-renewing
systetns. Other features of cell kinetics, with special
regard to lengthening of the generation cycle upon
continuous irradiation, were discussed in another paper[SS] as possible causes for a cumulative lesion related to
the life-shortening effect. Cytogenetic injury due torearrangements of chromosomes has also been
considered to account for radiation-induced life-span
shortening [S14].
34. A critical comparison between the model of Blairand that of Sacher is contained in Sacher and Grahn[S4]. The latter model assumes linearity and additivity
functions formally equivalent to those contained in theformer, although Blair postulated the existence of only
one component of recovery from injury, which
operated soon after exposure and caused the injury tofade away exponentially. When the equations derived
by Blair were fitted to the cumulant lethality functionof Sacher the fit failed, owing to significant systematicdeviations. In addition, the mean recovery time
estimated from Sacher's data was 4 to 10 times longer
than the recovery value of 5 days accepted by Blair on
the basis of fractionation experiments. For thesereasons Sacher and Grahn [S4] rejected the central
assumption of Blair referring to the single linear
component of recoverable injury. All the remaining
assumptions of Blair are included in the moregeneralized formulations of Sacher. The assumptions
are that radiation injury is proportional to dose and todose rate; the recovery rate from this injury is proportional to the amount of injury present and isindependent of age; death occurs when the sum of all
injuries reaches a given value, called the lethal bound;radiation injury is additive to the injury accumulating
due to age; and that age-cumulative injury is linear withage.
35. Stover and Eyring [S15] and Eyring and Stover[El] developed a steady-state theory of mutation rates
and applied it to the survival data of beagle dogs
injected with 239Pu and 226Ra. The fits of the experimental data obtained by the use of this model weregood and allowed the identification of various
mechanisms of death caused by the two nuclides. The
formalisms developed in this series of papers
adequately describe the experimental data and may beof use in further interpretations.

36. Sato, Nakamura and Eto [Sl 6] performed calculations of the life-shortening effects of radiation as afunction of dose and dose rate under the assumption of
linearity of the Gompertz function for both acute andcontinuous exposure. They showed that within therange of doses usually employed with mice the valuesof percentage life shortening are not appreciably
changed if the survival time is measured as mean,
median or mode.

issue. It should first be recognized that speculations
about specificity often conceal the lack of good pathological analysis. Life shortening must be due, if
properly assessed, to some specific cause. However, theword specific has been taken to mean that theirradiated animals die earlier than their controls with acharacteristic spectrum of diseases or causes of death
different from the spectrum seen in the non-irradiatedcontrols.

37. Iberall [13) examined the various models ofradiation lethality in great detail and attempted aunitary description of the various modes of death, fromthose due to very high acute doses to those due to low
chronic treatments, through an analysis of much experimental data. In so doing he illustrated the level ofcomplexity required for a careful mathematicaldescription of the actuarial properties of a population.
This description pointed towards the isolation of five or
six possible conditions affecting lethality as a result of
the various irradiation regimes. The paper supplemented the studies of Sacher and Grahn [S4] with awidespread examination of the entire problem from amathematical point of view.

41. Since it is well known that not all diseases arereadily induced by radiation, to expect that radiationacts non-specifically in shortening the average life of ananimal population would be to reject all radiobiologicalexperience. Recently the discussion has been morereasonably centered on whether or not radiation may
produce life shortening by induction of tumours andhow much of the observed shortening can be accounted
for by neoplastic diseases. Though never defined
clearly, the words specific and non-specific havetherefore been taken to indicate neoplastic and nonneoplastic contributions to life shortening. Under these
conditions, the question of specificity of the life-shortening action is legitimate and of great practical significance.

38. Another model for life shortening by late effectsof ionizing radiation was developed by Scott and
Ainsworth [S47J. It applies to data in the mouse and it isspecific for doses much below the LDso130. It focuses on
the number of individuals with life-shortening injury
and variations due to dose, dose rate and quality ofradiation. For these individuals the survival time
distribution differs and shows earlier times to death ascompared to other members of the population without
life-shortening injury. The results of the model'sanalysis are consistent with available data at comparatively low doses, including the convex upward lifeshortening responses. The model predicts enhancementof effects after fractionated exposure to 60Co gamma
rays and an approximately linear response in mostcases of acute exposure to low-LET radiation. The
model also provides a means of extrapolating between
mouse strains or age groups, an extrapolation which
can be achieved by changing a single parameter [S48].

42. In discussing the problem of specificity, ICRP
publication 14 [Ill and Mole [M2, M3] point out that inorder to detect a general non-specific deleterious effectof radiation, Jong-term survival data should first be
corrected for diseases known to be specifically inducedby radiation. The concept of life shortening is
ambiguous as it may be regarded either as an overallmeasure of deleterious effects or as a measure of theeffects remaining after allowance for the induction oftumours and other defined diseases. Non-specific life
shortening, if it exists, must have some basis in damage
to biological structures and functions. Actually, somedamage, anatomical or functional. may be shown forsome tissues [C4, D3. C5], but not for all. Under these
conditions an increase of causes of death related todamage in those particular tissues may be expected.
The resulting effect should be a change in the spectrumof diseases induced in irradiated animals. On the other
hand, one could envisage that damage to body components such as the blood vessels or the connective tissue,
which are uniformly distributed in the body, could be
the cause of non-specific life shortening at high doses.
However, it appears unlikely that damage to bloodvessels in skin, muscle and fat tissue results in changes
ultimately affecting the vital capacity of an individual,
whereas damage to blood vessels of the kidney, thebrain. the heart can be expected to result in importantchanges affecting the capacity for survival. Thus, if thedetermining factor is the anatomical location of thedamaged blood vessels, again a change in the spectrumof diseases compared to the spectrum of diseases of
unexposed animals would be expected in irradiatedanimals.

39. Finally, other publications should be cited forcompleteness, where the problem of long-term chronic
exposure to carcinogenic agents in general (or specifically to radiation) was addressed. in an attempt toaccount for both the increased incidence and the early
displacement of the tumours induced which, in turn,cause shortening of life span. In this context the papers
of Blum [827], Druckerei [Dl 1], Albert and Altschuler[A15], Hug [H20] and Mayneord and Clarke [M32]should be recalled as valuable contributions. However,these papers refer to tumour induction and not to life
shortening in general and have therefore a narrower
approach to the problem under discussion here thanmany of the papers cited previously. They should be
kept in mind mainly in view of the general conclusions
to be arrived at in this Annex.
D.

LIFE SHORTENING AND AGING

1.

Specific and non-specific life shortening

40. There is considerable discussion in many of thepapers reviewed about the specificity or non-specificityof the life shortening observed in a variety of experimental situations. Semantic considerations as well as
important reasons of substance have complicated this

43. In conclusion. the notion of non-specific life
shortening is compatible with that of aging (advancedor accelerated) induced by radiation. The two concepts
are inevitably linked with the demonstration of theprinciple that radiation, although advancing the instantof death, does not modify the spectrum of normallyoccurring diseases. This demonstration is difficult inpractice and probably impossible to visualize as themechanisms that may be hypothesized for non-specificeffects will also change the spectrum of diseases
appearing in irradiated animals. Such change is incompatible with the notion of aging or of non-specific life
shortening.
661

2.

The phenomenon of aging

44. Attempts to show that irradiation may non-specifically age animals were begun with observations thatradiation did produce life shortening and that
irradiated animals showed phenomena similar to thoseobserved in old age (greying of the fur, appearance of
cataract, loss of fertility). Although it should have beenclear that the resemblance was only superficial [M3), thehypothesis of radiation-induced
aging gained
momentum and stimulated much work. The interested
reader may refer to the following reviews - which aresome of the many available - for more detailed evaluations of data obtained in experimental animals [Al,A 11, U4, C2, C32, H3, C6, C7] and in man [A4, A6, Fl,86).
45. Difficulties in experimental work on aging are
related to its definition, to the lack of any direct
measure of senescence other than in terms of life span,
and to the impossibility of deciding whether pathological processes in old animals are the causes of aging,
the effects of aging or indeed aging itself. The only
acceptable generalization is that in mammals the agespecific death rate increases as a function of time in aroughly exponential manner by a constant factor foreach year of the adult life. That is, that the probabilityof death per unit time increases with age (see control
curves in Figure I). However, to accept this generalization as a measure of aging requires the assumptionthat aging of each individual is paralleled by theaverage changes of the population to which theindividual belongs. In addition, there are uncertainties
in sorting out, both for the individual and for the
population, intrinsic and environmental factors,
primary and secondary effects, specific and nonspecific phenomena.
46. Radiation is by no means the only agent
producing life shortening. Other treatments have often
been reported to produce similar effects in conjunction
with radiation experiments. These life-shortening
agents include various types of toxins and non-specifictoxic substances [C8, C9] or cytotoxic drugs [ClO, A4,
U6, Cl 1, D4] in various combinations and dosages. It
appears from all the data that the effect of these agentsis in general less readily induced than the effect fromradiation and that the diseases leading to precocious
death are specific for each drug.
47. In the context of the hypothesis of radiationinduced aging, the concept o'f differences between
advanced or precocious aging on the one hand, andaccelerated aging, on the other has been discussed
repeatedly (see, for example. [C2] and [C7)). The two
notions can be formally visualized in terms of thetheory of radiation injury of Blair [82. B3, 84, 85]. If
one assumes that aging in an individual is determinedby the sum of deleterious irreparable injuries accumulating in time; that radiation causes irreparable injuries
which may add to the aging injuries: that beyond agiven level of injury death of the animals occurs: thatsuch processses within each animal may also bereflected by the Gompertz curve: then a displacement
upward of this curve without change of its slope would
be interpreted as precocious aging, whereas an increaseof the slope would be formally equivalent to accelerated aging (Figure I). However, such definitions may
hold formally but are difficult to verify experimentally.
662

3.

Mechanisms of aging and life shortening

48. In spite of the above important considerations ofprinciple, attempts were often made to identify apossible effect of life shortening with some nonspecific, diffuse, subclinical deterioration of tissues thatmight advance the onset of all old-age diseases toroughly the same degree. There are a great variety ofnon-tumorous degenerative changes in irradiated tissue[U4, C7]. Some of these superficially resemble senescentchanges, although on closer inspection there arc
profound dissimilarities between radiation-accelerated
and senescent lesions [Wl, M3]. Among the least
equivocal mentioned by van Cleave are [V7) the
following: involution of the cartilage discs, involutionof the thymus and all lymphatic tissues, lymphocytopenia, marrow hypoplasia, atrophy of the iris, atrophyand dysplasia of skin and degeneration of the skincollagen, degeneration of the elastic walls of thearteries, nephrosclerosis with glomerulosclerosis,
dysplasia of the lens epithelium, vacuolization anddegranulation of endocrine glands, involution of testisand ovary. generalized progressive fibrosis of thearteriocapillaries and generalized increase in tibrillar
density of the interstitial connective tissue.
49. Casarett [C7] proposed a "histopathologicaltheory" of natural and radiation-induced prematureaging. It rests on the notion that the most generalized
deleterious change in aging mammals is an increase of
the histohematic barrier, the layer of connective tissue
between blood and parenchymal cells, with an increaseof arteriocapillary fibrosis. Functionally, a loss of selectivity of the barrier to. nutrients and to wastes and adecreased efficiency of circulation are the consequencesof such changes. Under these conditions a decrease ofparenchymal cells and functions follows with more
fibrosis and loss of vasculature becoming progessively
more serious with time and leading to increased susceptibility to infection, stress, degenerative and neoplastic
conditions and eventually to death.
50. Irradiation advances such an increase of thehistohematic barrier and ensuing consequences, tovarious degrees in various tissues, depending on thesensitivity of the constituent parenchymal cells. Nonspecific damage to the endothelium of the tine vasculature directly or indirectly caused by radiation would
be the primary cause. The consequent morphological(interstitial oedema, increased fibrillar density) andfunctional changes (loss of reserve capacity of single
organs reflecting gradually and progressively on otherparts or on dependent organs) would tend to perpetuate
and to increase themselves by circular reactions where
the natural and radiation-induced aging would not be
separable any longer.
51. The basic notions of Casarett's model [C7] appear
to be well founded, as it is known that radiation may
cause an interstitial fibrillar density and capillary
fibrosis. The mechanisms of these phenomena haverecently been discussed by Streltsova [S58], by Gerber[Gl] who has examined the possible pathways responsible for fibrosis and by Hopewell [Hl6] who has particularly addressed vascular changes. But whether the
initial endothelial and connective changes operating in
natural and in radiation-induced aging may be thesame, remains to be demonstrated as do the further
steps of Casarett's hypothesis, which should be set on
firmer ground [Wl]. In addition, more recent information on the radiosensitivity of the endothelial cells[R 11 I ,eem, to cast considerable doubt on the applica-bility of the hypothesis to very low doses and dose rates
and to confine its applicability to the region of theintermediate to high doses.
52. The hypothesis that late effects of radiation on the
duration of life may be brought about via alterations of
the immune system can also be entertained. In thisrespect two possible mechanisms of action can beenvisaged. The lirst implies that auto-immune diseases
are possible causes of a diffuse deleterious action.
Alternatively, life shortening can be viewed as the resultof an earlier appearance and a higher incidence oftumours, elicited in turn by radiation-induced immune
disturbances. In no case does the effect of life shortening have a truly non-specific character, because an
acceleration or an advancement in time of old-age
diseases without changes in their spectrum could hardly
be expected as a result of such mechanisms.
53. In 1972 the Committee extensively reviewed theeffects of radiation on the immune response andconsidered the general question of radiation as it may
relate to auto-immunity and possibly to aging [U15]. At
the time there were few results on irradiated animals
consistent with the hypothesis of a breakdown in thebalance of self-tolerance leading to auto-immune
conditions. On the whole the data were thought to beinconclusive as far as positively showing any such
effect.
54. Studies of the late effects of radiation on the
immune system are relatively· few and their results vary
according to the test system and radiation doses [S46].
In general, intact animals examined individually many
months after exposure to moderate doses (1.5 to 6 Gy)of x or gamma rays showed little if any changes of theirimmunologic competence [S45, S46]. On the other
hand, lymphoid cells derived from these animals andexaminedfor various immunologic functions
frequently show significant delayed effects [see S46 fora review]. However, this reduced immunologic competence could be due to an artifact resulting from adilution of the lymphocytes or from suppression oflymphocyte functions by an excess of non-lymphoidelements in the test cell preparations. Reduced immunologic competence may or may not be compensated bya change in the total number of lymphoid cells in thewhole animal. The radiation dose, the age at exposure,genetic and environmental factors (particularly the
microbiological flora) could affect the expression oflate immunological affects and, hence, the life span ofthe exposed animals, if radiation-induced shortening oflife is indeed related to a dysfunction of the immune
system.

The first one suggests that radiation can alter tissue
constituents to create new auto-antigens or to releasepreviously inaccessible components. The second possibility is action via somatic mutations thus leading to theemergence of auto-reactive clones. The third is action
through the imbalance of natural mechanisms ofregulation controlling the potential auto-immune
expression. Several studies are in favour of the third
mechanism but at the present time few definitive statements are warranted. The first statement is that theinterplay of regulatory mechanisms in the immune
system is so complex and variable that radiation effects
are hardly predictable and at present cannot be extrapolated with any confidence from one experimental
situation to another. Secondly, although immunologicalmechanisms may actually operate at high radiation
exposures and cause extensive tissue damage, their
possible relevance at the low doses of interest forradiation protection can only be viewed with great
reservations given the present state of knowledge.
57. The Committee has reviewed in its 1977 report[Ul4] the role of the immune system in the pathogenesisof radiation-induced tumours. The conclusions pointed
to a secondary role of immune reactions in the development of neoplastic conditions, particularly at low
doses and dose rates. No new information has
appeared since then that might change this general
proposition. A most recent review of the subject [S46]confirms the above conclusion and therefore indirectly
supports the view that, whatever the role of tumours inradiation-induced life-span shortening, there is as yet
no clear evidence that the role is mediated throughimmunological mechanisms.
58. There are other hypotheses of aging that havebeen considered either alone or in conjunction withradiation and for which some experimental evidence
has been claimed. The older theories were discussed by
Walburg [W1] and their applicability to a possible effectof premature aging was criticized as mortality data andcauses of death in irradiated animals indicate a lifeshortening action essentially related to tumour
induction. Acc·ording to that analysis, exposure of
mammals to life-shortening doses of radiation almost
uniformly fails to accelerate lesions characteristic ofsenescence.

55. A life span study performed with Biozzi mice
specifically selected for a high or a low antibody
response has some relevance to the present discussion.
It was shown in that study [C30) that mice with a low
antibody response had a higher incidence of
spontaneous malignancies and a shorter life span thanothers of the same genetic background having a highantibody response. On the other hand, it is known that
total lymphoid irradiation performed on NZB/NZW
mice with a high incidence of an auto-immune disease
reversed the expression of this condition and thus
produced a prolongation of survival [K22].

59. Recently other hypotheses related to molecularchanges have been considered. Cutler [C31] reviewed
the concept of primary aging processes. This term
covers causes which can underlie many different
specific disease processes at the organismic level andmany age-related losses of function resulting in a
progressive decline of general health. At the molecularlevel, cross-linkage between biologically important
molecules effected by various agents (free radicals andtheir derivatives, aldehydes) may be postulated to be at
the origin of natural senescence and of possible
radiation-induced changes. This hypothesis hasreceived little experimental support when applied tocellular and extra-cellular constituents such as collagen,age pigments, etc. It can, however, be more attractive
when applied to information transfer molecules such as
DNA or to structures such as chromatine. For thesecellular constituents a more systematic approach might
be envisaged.

56. In a comprehensive review of the immunologicalaction of radiation Anderson and Warner [AlO]
discussed three general hypotheses for the possible
induction or acceleration of auto-immune processes.

60. Work by Vilenchik [V8, V9, VlO] and others [L20]
was directed to illustrate the similarities between thechanges in the DNA induced by aging and byradiation, showing that spontaneous DNA lesions663

result from thermal degradation of DNA at normal
body temperatures and lesions may also be induced byfree radicals such as Off, which are known to be
responsible. for radiation-induced damage. Accumulation in this molecule of various lesions (alkali-labilesites, DNA-protein bonds, changes in the circulardichroism spectra) as a function of age has been taken
as valid confirmatory evidence of a hypothesis of agerelated multistage DNA damage advanced in the past[V8]. For a review of the free-radical theory of the aging
process see [H21].
61. DNA damage is, however, only the initial step inreactions of this kind, as it is well known that thisdamage can be repaired. Hart [H17] discussed the mostrecent data concerning another complementary
working hypothesis. This envisages the aging process asa sequence of events involving the induction of the
DNA damage and its subsequent manifestation at thephysiological level. The ability of the system to repair
DNA damage and the redundancy of the genetic information for vital functions within the system are thefactors controlling the manifestation of such damage.
Alterations in one or both of these mechanisms are
expected to modify life expectancy. Since it is known
that DNA damage and repair is also involved inradiation carcinogenesis, the hypothesis has been entertained [V8, VIO] that physiological aging and carcinogenesis (both spontaneous [V8, Vto] and induced [V9])may be inhibited by error-free repair systems. Althoughinteresting and often supported by some indirect
evidence, all the above hypotheses have not yet been
sufficiently formalized and their general applicability
has not been extensively tested to warrant more thanthe present mention.
4.

Conclusions

62. In summary, although at some stage research on
aging was advocated on the ground that radiation
might represent a unique tool for the study of senescence [C7] resulting efforts have been rather unproductive. Data in animals and man lend no support tothe view that radiation may cause premature aging orthat the carcinogenic effect observed is only part of amore general effect of acceleration of aging [86].
Attempts to identify a possible life-shortening action
with non-specific diffuse changes in tissues, particularlyof the connective and vascular structures have beendifficult and are probably inapplicable at low doses
and dose rates. Information about a possible role of theimmune system via an increased incidence of autoimmune conditions or a favouring influence on tumour
acceleration or induction are few and contradictory. In
any case, such mechanisms are not expected to yieldnon-specific life shortening without changes in the
spectrum of old-age diseases.
63. Therefore, in view of the difficulties of defining
aging, of the lack of reliable parameters of senescence,of the impossibility of distinguishing between specificand non-specific causes of aging and between genetic
and ambient factors, of the generally negative conclusions to be drawn from the available data, theCommittee decided to limit the present analysis to the
only effect of radiation that has been shown convincingly, namely the shortening of life span. It would infact be unreasonable under the extremely undefinedconditions discussed above, to carry out an analysis of
the physical and biological variables affecting such an
ill-defined effect as aging. Pending clarification of the664

points reviewed previously, the relationships between
radiation-induced life shortening and aging (if indeed
the latter effect exists to justify such relationships) will
not be taken up again for discussion in the rest of thisAnnex.

I.

THE EFFECTS OF PHYSICALVARIABLES

64. Establishing a relationship between the degree oflife shortening and the characteristics of the acute or
chronic exposure to radiation is important in determining criteria and levels for human exposure. Such a
relationship may also be useful in order to indirectly
validate hypotheses and models of the nature of aging
and on the similarity between natural and radiationinduced senescence, Experiments on single acutelydelivered doses are the simplest of all possible models.
Single-dose irradiations are not interesting for radiation
protection purposes, but represent the most efficientmeans of exposure, as under these conditions the actionof any repair system is minimal. On the other hand.
there are experimental treatments such as the duration~of-life exposure which may more closely resemble thesituations of interest in practice. These yield, dose for
dose, less effect than the acute exposures. Between these
two extremes there is a whole range of exposures where
any given amount of effect can be obtained by infinite
combinations of many interrelated variables. These
include the number and size of the dose fractions, theradiation-free time intervfll between fractions, the timeover which a given radiation treatment extends, thetotal accumulated dose, the instantaneous dose rate, etc.
All these variables interact for any given radiation
treatment to produce the final effect on survival and it
is in practice extremely difficult to design experimentsallowing their separate analysis. It should also be addedthat each experimental system has its own biological,
physiological and pathological characteristics (to be
examined in chapter II) and that an end-point such as
life shortening may be the result of an infinite number
and type of underlying biological effects.
65. Having thus recalled the complexity of the
problem at hand, the following irradiation conditions
will be considered in turn; single acutely-delivered
exposures; continuous life-time irradiation; the effectof dose rate; the effect of fractionation; protracted
exposures; and the effects of different types ofradiation. The various effects will be examined in thesections thought to be most relevant. However, acertain amount of overlapping and repetition is
unavoidable in comparing the various conditions ofirradiation. The problem of partial-body exposure will
be dealt with in chapter III.
A.

THE EFFECTS OF ACUTE SINGLE DOSES

66. ln the following section the effect on long-term
survival of acutely-delivered single doses of radiation is
examined. The data are reviewed with the criterion of
considering together all information pertaining to agiven species. The data are arranged according to thetime of publication to give some historical perspective.
As it was often found that data on low- or high-LET
radiation were included in the same paper, the review
will consider the information pertaining to different
types of radiation together. A summary of thenumerical values to be derived from the documents
reviewed is given in Tables 1 and 2, where low- andhigh-LET data are tabulated separately.

67. The earliest data of Gowen and Stadler [G2],
Grahn and Sacher [G3]. Furth et al. [F2], Kallman and
Kohn [K7], Storer and Sanders [Sl7], Storer et al. [S18],
Boone [B8, B9] and Nowell and Cole [N4] will only bementioned in this context. The essential information inthese reports may be derived from Tables 1 and 2.

parameter (0.28 d of life lost/R or 19% life lost forirradiation at the LD50130) applying to all strains andsexes. Other factors, specific for life shortening due toleukaemia and ovarian tumours, could be superimposed on this basic parameter to give predictableamounts of effect at any dose and for any strain andsex. Other data by Vogel. Frigerio and Jordan [Vl] aresummarized in Table 2.

68. In 1960 Upton et al. [US] reported on a very
extensive series of data (the Greenhouse experiment) onlate effects including life shortening in LAFl mice (6 to
12 weeks old) exposed at a nuclear test site. Nineteengroups of 220 mice each were exposed to gamma raysfrom 1.79 to 7.82 Gy. Neutron doses in eight groups
ranged from 0.28 to 2.5 Gy. Mean survival times wereobtained for each exposure group and tested forlinearity versus dose. In both sexes, for the gamma as
well as for the neutron data, significant departures fromlinearity were observed and the best interpolation tothese data was a curvilinear quadratic relationshipfitted empirically. The authors felt that the shape of thecurve should be taken with some reservation, particularly since later tests with more refined dosimetricmethods (which in this particular instance leftsomething to be desired) gave more nearly linear doseeffect relationships.

72. Lindop and Rotblat [Ll, L2} reported on experiments with SAS/4 inbred mice exposed to single
whole-body irradiation (50-780 R, 15 MeV x rays).
When the percentage of survivors was plotted against
age for each dose group, the life-shortening effect forthe pooled sexes had a good fit to a linear relationshipwith dose without apparent threshold. The datasuggested that life shortening was the result of a loss ofearly life and not of a contraction of the time scale.
Lindop and Rotblat [L2] established the cause of deathof these animals and came to the conclusion that life
shortening was not due to induction of specific diseases
but to the forward displacement in time of all causes ofdeath. In this respect radiation could thus beconsidered as a cause of aging, although not identical tonatural aging, as the relative ages of onset of the various
diseases were different in irradiated and control
animals.

69. In the Greenhouse series [US] the Gompertz plotof irradiated mice showed a displacement upwards andto the left of the control curves for both sexes. Life-span
shortening was reported to be due to premature onsetof all diseases observed in normal aging mice. The
onset of old-age diseases was advanced to essentiallythe same extent by any one dose, an exception was
thymic lymphoma whose incidence was greatly
increased in both sexes. There was no consistent
relationship between frequency of neoplasia and dose,
because the incidence of some tumours (thymic
lymphoma, granulocytic leukaemia, tumours of theovary) increased but that of others (reticulum cellsarcoma, mammary sarcoma) decreased with increasing
doses within the dose range studied. Thus, no overall
clear-cut relationship could be established between
life-span shortening and tumour incidence. It should bepointed out that the classification of lymphoreticulartumours in the mouse is a controversial issue and thatthese diseases are different in many respects withregard to similar conditions seen in man.

73. Starer's [S19] data on RF/J mice were limited to asingle exposure of 400 R of 250 kVp x rays administered at the age of 90 days. They are summarized inTable 1. Storer also performed other experiments [S20]on DBFl/J female mice treated at three months of age
with graded exposures (100, 300, 500 R) of 250 kVp x
rays. Under these conditions shortening of mediansurvival followed a linear non-threshold function ofdose. Autopsies performed on large samples of theanimals showed that tumour incidence was notincreased by radiation exposure, although tumours
tended to occur earlier. The time interval between
irradiation and the occurrence of a significantly
increased death rate was inversely related to the size of
dose, as though low doses required longer times for the
injury to become manifest. On this basis Storer postulated that in experiments where animals are sufficiently
long-lived (or the latent period is sufficiently short) sothat the elevation of the death rate may show over thetime interval in which essentially the whole population
is dying out, life shortening will be proportional toradiation dose. But with low doses or short-lived
animals a curvilinear relationship may apply.

I.

Mouse

70. Some of the data from the Greenhouse experiment(male and female animals receiving up to 2.67 Gy) wereanalysed again by Walburg [Wl] on the basis of theoriginal pathology data and with appropriate corrections for competing probabilities of death [H2, H4]. A
significant life-shortening effect was observed when all
causes of death were considered together; but when
only non-neoplastic deaths were taken into accountthere was no advancement in time of mortality due tothese diseases. Walburg therefore concluded that
evidence of life shortening due to non-neoplastic causes
was lacking, although these experiments are often citedas an example of non-specific life shortening.
71. Using data from work on six mouse strains
irradiated with single doses of x rays around theLD50130, Grahn [G4] reported a curvilinear type of
relationship with dose. By appropriate correction foranimals dying of leukaemia and ovarian tumours, he
was able to eliminate much of the variability between
strains and sexes and to analyse the whole process
culminating in life shortening to produce a basic injury

74. Upton and collaborators [U7, U9] performed an
exhaustive series of experiments on RF/Un mice
irradiated with various doses and dose rates of 1 and 5
MeV neutrons, 250 kVp x rays and 60Co gamma rays.
At high dose rate (about 0.1 Gy/min or higher) bothwith x rays and with 1 MeV fast neutrons, the shape ofthe curves appeared distinctly non-linear (convex
upwards). With x rays within the 3 to 30% range of life
shortening the days lost per Gy at the various doses
varied between 56 and 2 at progressively higher doses,with differences between male and female animals.
With fast neutrons between about 20 and 50% of life
shortening, the days lost per Gy were between 21 and 3,
again with differences between the two sexes. In theseanimals death was characteristically associated withneoplastic and degenerative diseases common to thenatural aging, except for animals treated with highdoses in which death was attributed to necrosis andaplasia of the lymphatic and haemopoietic tissues. The
shape of the dose-survival curve (for both neutrons and665

x rays) may conceivably be explained by differences inthe effects responsible for life shortening, as not alleffects which may contribute to earlier death are
identical in dose-response relationships. Leukaemia
and other neoplasms could not entirely account for life
shortening in this series of experiments.
75. Data on induction of neoplasia in the experiments
described above were reported in a paper by Upton,
Randolph and Conklin et al. [U9). There is no specificdiscussion in this paper about the relationships withlife-span shortening but some of the data (60Co irradiation at high dose rates for single doses of 1 and 3 Gy)
were analysed again by Walburg [Wl). on the basis ofrather careful macroscopic examination of the animals
at death. There was no significant difference between
control and irradiated animals when all causes of deathother than neoplasia were considered. But when all
causes of death including tumours were analysed
together the difference between control and irradiatedmice became very significant. It may thus be concluded
that there was no significant residual life shortening
when only the non-neoplastic causes of death wereconsidered. This conclusion which is partly at variancewith the conclusions of the authors themselves is to be
attributed, in Walburg's view [WI], to the use of a morerefined analysis of the lethality data.
76. Darden et al. [DI] also reported data on RF/Un
female mice exposed to graded doses of 14 MeV
neutrons (dose rate 0.01-0.02 Gy/min). The mean age
at death of animals surviving beyond 30 days decreased
with increasing dose, with a maximum difference
between control and irradiated animals being observedin the 4 Gy group and amounting to 151 days or 27% of
the control life span. Life shortening per unit absorbed
dose was an approximately constant or slowly
decreasing function of dose up to about 2 Gy, but at
higher doses the efficiency/Gy tended to decrease, as in
the series by Upton [U7]. Tumour induction could notentirely explain the life shortening observed, althoughthymic and myeloid leukaemia could account for mostof the increase in mortality in irradiated groups.
77. By the use of a radioprotective agent (WR-2721 or
S-2(3-aminopropylamino) ethylphosphorothioic acid)
which protects against acute mortality more efficiently
than it does against the life-shortening effects ofradiation, Yuhas [Yl] expanded the range of doses
studied. The shapes of the dose-response relationships
were consistently different for the two strains studied.
In the A/J strain the curve was linear non-threshold at
low doses and came to a plateau in the high dose range.
In the C57BL/6J life shortening was curvilinear overthe entire range of doses. It is impossible to assess
whether the radioprotective treatment altered the actual
shape of the dose-response relationship in ways andamounts different for the two strains used. Actually, if
one considers the dose relations obtained at doses
below the LDso,30 without the use of the WR-2721, acertain amount of curvature can be seen in both sets ofdata, perhaps more pronounced in the C57BL/6J.
78. In a more recent experiment Grahn, Fry and Lea[GS] gave LAFl hybrid mice of both sexes single
exposures of 60Co gamma rays in the range of 390 to
900 R. Mean after-survival showed a curvilinear trendwith dose. The principal life-shortening effect was attributable to excess tumour mortality up to 390 R, while athigher exposures the loss of life expectancy was notparalleled by a further increase of tumour incidence.
Walburg [Wl] commented on these data and inter-

666

preted them to show that when the life-shortening effectis 15% or less of the control the increased mortality isentirely attributable to induction or acceleration oftumours.
79. Clapp et al. [Cl 2) reported on a large-scale experiment on life shortening and disease incidence in
RF/Un mice irradiated with 300 kVp x rays (0.5-4 Gy)
and with 60 MeY protons (0.47-3.72 Gy). The data
indicated a nattening of the dose-response curve atdoses in excess of 2 Gy and a reasonably straight trend
at the lower doses. When animals dying from thymic
lymphoma and myeloid leukaemia (which were
induced in up to about 40 and 25%, respectively, of themice) were removed from the calculations, the mean
survival time of the remaining animals still showed adecrease as a function of dose. Gompertz's analysis
confirmed that removing the leukaemic animals didbring the death rate curve nearer and more parallel tothe control line. The curves, however, did not superimpose except at doses below 1 Gy. Thus, not all of theobserved life shortening, particularly at doses above theLDso130, can be explained by the induction ofleukaemia, as in male RF animals. A possibility does
remain (but was not examined in a more recent publication, [Cl 51) that ovarian tumours occurring in 50% ormore of the animals might account for the extra life
shortening remaining after subtraction of leukaemia.
80. In his 1975 review Walburg [Wl] refers to data inthe male RFM mouse exposed when 5-6 weeks old to asingle acute treatment of 300 R of 300 kVp x rays.
Routine histopathology allowed the assessment ofcauses of death with reasonable accuracy and the data
were corrected for competing probabilities of death.
The cumulative mortality curves for all causes showedsignificant life shortening; when deaths attributable toleukaemia were excluded the cumulative mortality
curves of the control and of the irradiated mice became
superimposable. suggesting that radiation did not
significantly induce or accelerate under these conditions other non-specific causes of death.
81. Ainsworth et al. [A 7) irradiated male and female
B6CF1 mice with single doses of gamma rays (0.9 to
7.88 Gy) and found that life shortening had areasonably linear dose-response. In the case of fission
neutron irradiation, however, the shape of the doseresponse curve (0.2-2.4 Gy) appeared to be convex
upward. Possible explanations for this shape of therelationship were suggested. They will, however, remain
unclear until the causes of death will be completely
worked out. A paper updating these experiments
confirmed essentially the above conclusions [T4].
82. Data of life-span shortening induced by single
acute exposures of 250 kVp x rays (100 to 900 R) wereobtained by Maisin et al. [MS] in the course of experiments on the effects of chemical protectors. Data referto male BALB/c mice (4-12 weeks old) and to male
C5781 mice (1 to 3 months old, 350 and 650 R). In spiteof the dose-square form of the relationships for tumour
induction an essentially linear decrease of the life spanwith dose was found for the two sets of data: thenumerical values are given in Table 1. Pathologicalobservations in these experiments were evaluated by themethod of competing risks [M JO) with a classificationof the causes of death comprising various forms ofleukaemia and solid tumours, glomerulosclerosis, nonneoplastic lung lesions and others. In the nonirradiated BALB/c animals tumours were mainly
responsible for deaths, while in the normal C57Bl miceother non-neoplastic causes were observed in the
majority of cases. An increased and advanced
incidence of specific diseases, mainly thymic
lymphoma, was associated with radiation-induced life
shortening in the low-to-medium range of exposures.
For higher doses in excess of the LDso life shortening
was instead characteristically associated with glomerulosclerosis.
83. Very extensive data on RFM and I3ALB/c mice
were presented by Ullrich and Storer [A8] and Storer et
al. [S44]. The effects of dose, dose rate and radiation
quality on life shortening and carcinogenesis were
examined. Caesium-137 gamma rays at 0.~.45
Gy/min and 0.083 Gy/day (0.1 to 4 Gy total doses) andfission neutrons at 0.05-0.25 Gy/min or 0.01 Gy/day(0.05 to 1.88 Gy total doses) were used. Dose-effectrelationships for life shortening at high dose rates will
be examined here. In the RFM females a dose-squared
or linear-dose-squared model described the data
adequately between zero and 0.5 Gy. with the dosesquared component predominating after about 0.04 Gy.
The curve for RFM male animals was thought to belinear. High dose rate neutron curves in both RFM andBALB/c females were linear in the range of zero to 0.47
Gy, with an ensuing decrease of effectiveness whichgave rise to an upward convex trend up to 2 Gy. No
specific discussion was given of the contribution ofparticular diseases to life shortening.
84. Metalli et al. [M9] irradiated hybrid male mice ofthe (C57BLxC3H)F1 strain (100 d old, 250 kVp x rays, 1
to 7 Gy). A dose of 9 Gy with bone marrow infusionfrom isogeneic donors or with shielding of one leg inorder to overcome the early effects of radiation on
survival was also used. These procedures did notappear to appreciably alter the long-term survival of theanimals. The mean after-survival of the mice as afunction of dose could be reasonably fitted by a linear
function. These animals had a spontaneous incidenceof about 55 to 60% of reticulum cell sarcoma. The
incidence of this disease was still quite high at 4 Gy but
fell gradually at higher doses to about 5 % at 9 Gy. On
the contrary, the incidence of glomerulosclerosis (which
is very low in normal animals) increased to about 70%
after 9 Gy. Since life-span shortening versus dose could
be fitted by a linear regression. in spite of suchprofound changes in the spectrum of induced diseases,
linearity should probably be regarded as a fortuitous
event. The data are in no way reconcilable with theories
which postulate a non-specific aging effect.
85. Some data have also been reported about a very
extensive study designed by Spalding et al. [S22] toinvestigate in the same experimental series the effect ofdose, dose rate, age at exposure and genetic
background for a variety of late effects, including life
shortening. by 60Co gamma rays in mice. Preliminary
data on C578I/6J mice [S54] indicate that in this strain,
which has normally a very low incidence of neoplastic
diseases at death. radiation-induced life shortening is
not statistically significant at all combinations of doses,
dose rates and age tested.
2.

Other species

86. There are a few data of single-dose irradiation ofrats. Hursh et al. [H5] irradiated Wistar male andfemale animals with 250 kVp x rays in the range of 150
to 600 R. A decrease of the survival time roughly
proportional to exposure was found. The per centreduction of life span/100 R was between 4.2 and 4.9
for male and between 2.8 and 4.0 for female animals.
Inspection of the data shows an approximate linearityof the experimental points. although the error is fairly
large, as the various dose groups included a maximumof 24 animals each.
87. Wistar females surviving an acute whole-body
exposure to hypoxic irradiation (250 kVp x rays, 1000R) showed some life shortening compared to controls.
Tumours appeared sooner in the irradiated animals but
their final incidence was not increased. This early onsetof neoplasia was best explained as one aspect of theaccelerated aging process. although other diseases
prevalent in old rats (cataract, acute inflammations,epilation. skin ulcerations) were also accelerated to acomparable degree [L3]. Nephrosclerosis in 46% of
these animals and increased blood pressure (the two
conditions being rather unrelated) were reported as
pathological findings in another paper by the samegroup [LS]. Also in the rat (female Long-Evans-Wistar
hybrid) life-span shortening was observed after acute
whole-body x ray exposures (250 kVp at 55 R/min) of120. 240 and 480 R. Under these conditions theefficiency of the treatment per unit dose was found tovary from 0.60 to 0.76 to 0.52, respectively, at theabove-mentioned exposures [L4].
88. Jn experiments by Kimeldorf. Phillips and Jones[K8, K9] young adult male guinea-pigs from an SPF
Hartley colony were exposed to a simulated fission
spectrum of fast neutrons. The median life span of thecontrols was 828 days: of the 1 Gy-exposed animals,
730 days (12% reduction): of the survivors in the lethal
dose range (1.2-1.6 Gy), 698 days (16% reduction). Bothvalues of the median life span were significantly lower
than control survival. In a related study [K9] young
adult male rats (94 to 110 d of age) were treated with
2.15 to 2.3 Gy from the same neutron source. Although
this dose was sublethal to the animals at 30 d, themedian life span was reduced by about 22%. It was
concluded that the dose range producing acutemortality in the guinea-pig is less effective in reducing
life span than a sublethal dose in the rat. The reduction
in median life span per unit dose is, however,comparable for the two species.
89. There are a few data obtained by Kohn andGuttman [K 11] on the Chinese hamster. Although thisanimal is more resistant to the acute effects of irradiation than other rodents under similar conditions, thelate effects tend to be more severe, at least judging fromthe life-span shortening. In fact, 5.5 Gy of x-ray
whole-body exposure caused a loss of 32 weeks (corresponding to about 30%) of the life span remaining at
the age of 230 days. At higher doses, for each incrementof 1 Gy above 5.5 Gy and up to 9.5 Gy there is anadditional approximately linear loss of life span of 20
weeks up to a per cent life-span reduction of 93%.
90. Hulse [H18] reported recently some data on
rabbits exposed acutely to 4.4-14.1 Gy of gamma rays
or to 1.8-5.5 Gy of fission neutrons. Although theirradiated animals died earlier than the non-irradiatedcontrols, the difference was statistically significant only
after the highest neutron doses. The earlier deaths could
be accounted for by an increased incidence of tumours,of which a large spectrum was observed, while otherphenomena associated with natural aging (particularly
nephrosclerosis and teeth degeneration) were notchanged or were even decreased after irradiation.
667

91. An experiment on the life span of 360 normal andirradiated female beagle dogs has been reported byAndersen and Rosenblatt [A2]. At 10-12 months of age
the dogs were given single or fractionated 250 kVp
x-ray treatments to a total of 100 or 300 R. All
irradiated beagles had a shorter life span than controls.
For single-dose treatments the life-span shortening
relative to controls amounted to 9.5% and 20.7% in the
100 and 300 R groups, respectively. The average
life-span shortening per 100 R amounted to 6.7%.
Mortality rates were calculated for the last 6 years oflife and the Gompertz slopes were found to be similar
for all control and treated groups, except that theirradiated dogs attained higher rates of mortality earlier
in life than controls. Major causes of death were
tumours and chronic diseases (nephrosclerosis, heart
failure, pancreatitis) with no obvious qualitative differences between control and irradiated animals.
However, malignant neoplasms developed at an earlier
age in irradiated dogs, thus accounting in large part for
the life-span shortening.

irradiated dogs with respect to normal animals.
However, this increase disappeared when the neoplastic
deaths were excluded from the comparison. Thus, in
Walburg's opinion, the data are in accordance with theview that all the radiation-induced shortening of life
seen at relatively low doses can be explained byinduction or acceleration of neoplasia.
93. Experiments on life-span shortening in large
animals were also carried out. In the burro irradiations
with single and fractionated doses of gamma rays andwith single doses of neutron-gamma radiation from thedetonation of a nuclear weapon have been performed[810]. Results on this series are not sufficiently
advanced for any definite conclusion. Jn the cow, single
and fractionated doses of gamma rays were also administered in April 1960 for a life-span study [N5] but theexperiment was terminated in 1973. The relevant data
are of no use for life-span shortening since more thanhalf of the animals were still alive when the experiment
was ended.

92. The above data were reanalysed by Walburg [Wl]by the method of Kaplan-Meier [K.2] for competing
causes of death, the analysis being limited to controls
and to dogs exposed to 100 R, where sufficient numbers
were available. For ages at death beyond 3000 days (anepidemic of canine distemper or a vitamin-E deficiency
altered the pattern of early deaths to some extent) there
was a significantly increased rate of mortality in the
A =
B :

C =
D :
E =
F =

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[S19]
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[S21)

3.

94. Most of the data pertaining to the effects of single
acute doses of x and gamma rays in the mouse aresummarized in Table 1 and are plotted together inFigure I I which shows the percentage of life-span short-

[U 7)

l "

H C

rY 1)
[C12)
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(A 7)
Q = [C1L)R :[M 9]
s = fM 8)
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u = fM 8]
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0 =
p =

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40

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y

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w

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Data analysisr'r N II

4
DOSE (Gy)"!lr,:
et!

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r

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r r "

p

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8

10

Figure II. Dose-effect relationship for life shortening In the male and female
mouse following single acute exposure to x and gamma rays. Various experiments

ening as a function of dose. The data in the Figure refer
to about 35 experimental series performed on about 20
strains of inbred, outbred of hybrid mice of both sexes
and various ages, performed in various laboratories
around the world since 1956. A large scatter of theexperimental points would not be unexpected undersuch conditions and in fact the agreement among suchvery heterogeneous data appears rather surprising. The
variability about each experimental point (which isavailable in many of the experiments, although not inall) has not been plotted as it would be expected to beaccounted for in the variability between series andcould not in any case be used to weigh the points in theanalysis to follow. In order to avoid including animals
dying from early radiation effects, mice surviving lessthan 60 days were excluded. The analysis was limited todoses of up to 900 rad and to corresponding maximum
effects of about 60%. In order to standardize theabscissa dose scale a conversion factor of 1 R - 0.0095

668

Gy was used. The ordinate scale is the percentage oflife-span shortening (calculated from mean or medianvalues as they were available) by comparison with thelife span of non-irradiated mice, irrespective of theduration of life of the normal animals or of thepathology at death.
95. The nature of the plot in Figure II is such that forvery high doses a saturation of the effect must become
manifest, although it may reasonably be assumed thatwithin 50-oOo/o no saturation might distort the plot. In
the absence of any information as to the possible formof the dose-effect relationship a non-weighted linear
regression was first interpolated to the data, according
to the formula
y=a+bD(5)

where y is the percentage of life shortening, D is thedose and a and b are the coefficients of the regression.

The calculated least-square solution to the above
equation wasy = (1.524 ± 1.873) + (4.806 ± 0.264) D(6)

and it gave an R2 value of 0.747 implying a moderately
good correlation. Although at inspection of the data ahigher-order component was not clearly apparent, its
existence could not be excluded and therefore thefollowing relationship was also fitted

y = a + b D + c D2

y = (1.289 ± 3.022) + (17.140 ± 0.204) yi5(R 2 = 0.694)(12)

The square-root relationship seems to fit the data fairly
well as it adequately describes the increase of effectseen at very low doses of neutrons and the ensuinglevelling-off of the data for doses up to 5 Gy, along aslope roughly parallel to the slope of the low-LET
radiation dose relationship.

(7)
4.

Conclusions

which yielded the following solutiony = (0.853 ± 1.989) + (5.639 ± 0.120) D -- (0.115 ± 0.020) D 2(8)

The R2 of this fit was 0.749.
96. The data obtained in the mouse by neutron irradiation (see Table 2) were similarly plotted on a common
graph as in Figure III which includes doses up to about~ 60

F - fU51
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w = [519)
X = rmJy = [US]z = [!17]

L

Vy L

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;f..

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u.l
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V •
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p - [A7]

Ly

M

M M

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0

4

2

6

8

DOSE (Gy)Figure Ill. Dose-effect relationship for life shortening In themale and female mouse following single acute exposure to
fast neutrons. Various experiments

5 Gy and life-span-shortening effects up lo about 50%
of normal. Only the results with monoenergetic-,
fission- and weapon-neutrons delivered acutely were
included, for a total of 14 series and 4 different strainsof mice. Inspection of the data makes it immediately
apparent that the nature of the dose-relationship is in
this case quite different from that observed with x andgamma rays. This impression is confirmed when thefollowing equations are fitted to the data with thefollowing results
y =a+ bD

97. In conclusion. data are not available in the mousefor x or gamma rays below 0.1 Gy and the scatter of theexperimental points is such that for doses below about
1 Gy apparent life lengthening (rather than life shortening) may be found, depending on the variability of
the control and irradiated groups of animals. Althougherrors affecting the above numerical constants must be
fairly large under the conditions of the analysis
performed, the life-shortening data for the mouse may
follow a linear non-threshold relationship as a functionof the x- and gamma-ray acute dose. indicating a lifeshortening efficiency of about 5% per Gy down to thesmallest doses. The data may, however, also be fitted bya linear-quadratic function, where the quadratic term is
negligible and thus does not give rise to an appreciably
different relationship within the errors of such ananalysis or give rise to substantially different quantitative conclusions.

y = (6.896 ± 3.082) + (8.107 ± 0.200) D(R 2 = 0.565)
y = a + bD + cD 2

(9)y = (3.044 ± 2.799) ++ (17.885 ± 0.521) D - (2.731 ± 0.202) D2(R 2 = 0.683)(JO)

Clearly, none of these two relationships provides asatisfactory interpolation to the neutron data, because
the first fails to show the initial steep rise and thesecond shows a maximum of effect between 3 and 4 Gyand bends down rapidly towards lower values. Thiseffect is difficult to interpret. The following relationshipwas also fitted [KlO]
y=a+byi)and it yielded the following solution(11)

98. Analysis of the data in the various experimental
series and an inspection of Table 1 makes it quite
obvious that in any given instance the dose-effectrelationship for life shortening may be linear or curvilinear (with upper concavity or convexity). The actual
shape of any such curve depends on the interplay of thebiological variables (strain, sex, age) with dose, which
results in a different spectrum of life-shortening
diseases or pathological conditions at the various doses.
The observation that the combination of a variety ofexperiments produces a linear relationship cannot
therefore be considered to depend on any particularbiophysical Jaw, at this stage of the analysis. It may
simply reflect the fact that when all experimental conditions and all the resulting life-shortening effects areaveraged over a number of different series. they
combine by chance to produce an approximate linear
relationship with dose. Therefore, taken as such, thisobsen'ation may have no special meaning in the interpretation of the life-shortening action, but may be
regarded as a very interesting observation in practice. Itshows, in fact, that in a highly non-homogeneous
mammalian population where all ages, sexes andstrains are represented, the use of a linear function todescribe the dose-effect relationship for acuteexposures to x and gamma rays is not unreasonable.
99. Under the conditions of the present analysis, theneutron data at the energies available are best describedby a relationship having a convex upward trend with
dose, such that the efficiency of low neutron doses ishigher than that of higher doses. The numerical value of
this higher efficiency will be discussed in section Il.D.
It should be again stressed that there is no fundamental
biophysical reason why the shape of the neutron curve
is of the form roughly described by the above
equations, as the same observations pointed out before
for the x- and gamma-ray data can be expected to apply
to the neutrons as well. However, the form of theneutron relationship is curvilinear (convex upward)
669

within a range of effects where a linear function applies
to low-LET relationships. As saturation phenomena
with respect to the expression of the biological damage
may not be expected under such conditions. the only
way to interpret the neutron data is to assume that theshape of the relationship rcnccts some primary biophy-sical difference in the mode of action of low- andhigh-LET radiation, particularly at the low doses.
100. The effects of single acute exposures of low-LET
radiation on animals other than the mouse arcsummarized in Figure IV, in comparison with all the

80

"'
;z:
z
,u

R = RAT[ H~ lC = HAMSTER f;:11]
0 = DOG
[t.21

0-

~ 60
:r

.

"'z
Q.

VI

~ 40

II

:;

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II

2

4

6

8

10

DOSE (Gy)Figure IV. Dose-effect data for Ille shortening In various
mammalian species following acute single exposure to x andgamma rays, compared with the response ol the mouse. The
dotted llne is the best flt to the data for the mouse In Figure II, as
In equation (6). Various experiments

mouse data. On inspection, no large differences may be
traced from the small series reported in the literature.
This is particularly true for the data for the rat, that are
well superimposable up to 5 Gy with the mouse
response. The effect on the dog has only been examinedat relatively low doses and the data are perhaps on thehigh side of the data for the mouse. The Chinese
hamster, on the contrary, has only been examined atdoses in excess of 5 Gy and the data are suggestive of aconcave upward trend. Among the species tested,
however, the variability of the response is apparently
rather small.

B.

THE EFFECTOFCONTINUOUS LIFE-TIME
IRRADIATION

101. The "duration-of-life" exposure condition has
been used since the very beginning and is documented
in the early papers of Henshaw [Hl), Evans [E2),
Lorenz et al. [L6) and Boche [811). It has been widely
utilized in the experimental series of Sacher and Grahn[S4] who have largely contributed to the interpretationof this type of data and is still in use [N6, N7]. In caseof internal irradiation from radionuclides of long
half-life it is the only possible irradiation condition.
Exposure for the entire life represents a base-line
condition of irradiation useful for comparison withother exposure types such as the acute single-dose. In
this respect it has the advantage of mimicking an
exposure pattern which is of most practical interest.
Research workers [Gl, G6] have pointed out otheradvantages, such as the linearity of the relationshipbetween the log mean after-survival of the animals andthe daily exposure level. That property may facilitate
the description of the effect and justify comparisons
between various animal species or various types ofradiation.
102. On the contrary, others believe that the terminated exposure technique, rather than the exposure to
death may be more apt to give unbiased answers. Basedon evidence from irradiated OBA mice, Mole [M6]examined the concept of what he called "wasted
radiation" for exposure to death, that is, the amount of670

radiation administered in excess of that strictly required
to kill the animals. Mole showed that under someconditions of exposure the wasted radiation amounted
to over one-half of the mean accumulated dose. Thisimplied that the duration-of-life exposure condition
was unsuitable to establish precise dose-time relationships for life shortening. Actually, the mean accumulated dose would have been overestimated on accountof the wasted radiation and the mean survival time
would have been put in doubt by the fact that eachspecific biological response to radiation might havetaken a different and characteristic time to develop.
According to Mole [M6], for these reasons it ispreferable to use terminated exposure conditions.
103. The concept of wasted radiation was used bymany research workers, although often without much
experimental basis, to account for data that could nototherwise be explained. The concept stems from thenotion that each specific disease or pathologic
condition has a latency time between induction andclinical manifestation; there is also more time intervening between the appearance of the disease and its
development to a lethal condition. The biologicalarguments underlying the concept of wasted radiation
are well founded but there are different views as to thepractical importance of this concept as the amount ofwasted radiation appears to be either negligible [L7] orvery substantial [M6] under different experimental
conditions. Sacher and Grahn [S4], Grahn and Sacher[Gl] and Sacher [S23] have repeatedly criticized theconcept of wasted radiation pointing out that it does
not lend itself to any easily testable implications. In
their opinion, there are changes in the effectiveness of agiven dose with an increase of the protraction time (seesection J.C.) and under appropriate circumstances thesechanges may at least in part be interpreted as being due
to an effect of wasted radiation. According to Grahn
and Sacher [G 1J this concept is contradicted for rather
high doses and short survival times (the concept was
actually derived from experiments al 200 to 25 R per
day and on the LDsotJo end-point); but for longprotraction periods the idea would be unjustified as no
amount of radiation ma·y be considered as truly wasted.

104. In continuous exposure until death, time anddose cannot be experimentally separated from eachother. Thus. it becomes difficult to isolate the dose thatwould have been given in excess of the minimum
required to kill the animal within a given time from an
end-point such as the life-span shortening, which ismeasured in units of time. An additional difficulty liesin the nature of the biological event of death which is a
final end-point in survival experiments. whereas inexperiments on tumour induction, for example. it ispossible to account in part for the wasted radiation bycomputing the dose absorbed at the tissue of interest up
to the time of the first appearance of the tumour or tosome such extrapolated time [F3, M11, M12].
105. It is natural therefore that, in spite of its wide
acceptance, specific work to experimentally test theconcept of wasted radiation has not been very
extensive. In fact, this concept has a shortcoming in the
difficulty of its experimental analysis and in the precise
evaluation of its importance under each specified
experimental condition. There appears to be little hopethat these problems will be settled in the near future.
Any conclusion concerning the relevance of this notionin the interpretation of radiobiological experiments inanimals or, more so, in human radiation biology mustremain open for the time being.
106. The available evidence of the biological effects ofchronic radiation exposure for the whole life of theanimals is reviewed in the following. This field has beenreassessed at various times, among others, by
UNSCEAR [U1], by Sacher and Grahn [S4], Grahn and
Sacher [G1], Grahn [G6]. Sacher [S14]. The reader isreferred to those contributions for more extensive
coverage of the subject. The life-shortening effects ofincorporated radioisotopes are considered in a separate
subsection.
1.

Mouse

107. All known experiments on irradiation for theduration of life [Hl, H6, H7, E2, B1 L L6, LS, S2, N3]
were reviewed by Mole in 1957 [MB] and his paper was
made a part of the 1958 report of the Committee [Ul).
Only 5 of 11 known reports (see [MB) for a complete
list of references) contained sufficient details for thereconstruction of a curve showing the decrease of themean survival time versus the dose per week. Fastneutron as well as gamma-ray data were plotted
together with the dose scales in the ratio of 1 to 13 (seeFigure XIV). The agreement of the experimental series
was, at least for the mouse, surprisingly good andexposure levels of 10 R per week or higher of gamma
rays shortened the mouse life in a reproducible manner.
There were eight experimental estimates at weekly
exposures of less than 10 R (or its neutron equivalent)and in none of them the duration of life was significantly different from the respective control value.
Taken at face value, these data suggested therefore anapparent threshold at dose rates below 10 R per weekor its neutron equivalents.
108. Moos et al. [M14) and Yusken et al. [Y2) carriedout experiments on CFW mice of both sexes, individually caged and irradiated with 400 k Vp x rays at daily
exposures of 2 to 512 R. The survival time of the micedecreased as the daily dose increased but the decline
was not very rapid up to 8 R per day. Exposure of up to
4 R per day allowed the animals to accumulate 600 to
1400 R before one-half of the mice died. About 2900 R
of accumulated radia~on was given at 16 or 32 R per

day. In a subsequent paper Moos [M15] tested thepossible existence of a threshold in the same mice. He
showed that variability of the control population and of
the animals receiving 2 R per day was the same or
could not be resolved statistically and concluded for acontinuous effect of life-span reduction down to thesmallest dose rates tested.
I 09. Of particular interest to the problem of life-time
irradiation are the data by Sacher and Grahn [S4] on
more than 5000 LAFI male and female mice given 60Co
gamma-ray exposure starting from the age of 100 days.
These data represent up to the present the mostcomplete and exhaustive experimental series on thissubject. The exposure levels used were 36, ranging from
5 to 200 OOO R per day and corresponding mean
survival times from about 500 days to 6 hours. The
daily exposures between 5 and 2500 R (giving mean
after survival times of 5 or more days) were delivered
during 12 or 15 hours per day; higher daily doses were
given almost continuously. Dosimetry was particularly
accurate and fully discussed.
110. Survival data were analysed by an empiricalfunction of survival time and dose rate, the cumulant
lethality function, CL, defined ast*)Cdt*) = I1 ( I - ~(13)

where l is the daily exposure in R, t* is the mean aftersurvival at dose rate I and 10 the mean after-survival ofcontrols. The first derivative of this function, called theimpulse lethality function, SL, allowed the identification of four distinct phases of injury with peaks at
0.5, 5, 13 and 40 days and these times could be related
to different modes of injury to the nervous system, theintestinal epithelium, the leukopoietic and the erythropoietic marrow, respectively (see Figure V). A plot of
the log mean after-survival versus the daily dose wasfound to be very nearly linear for mean after-survivals
in excess of 60 days. This procedure allowed theassessment of life-shortening coefficients with small
uncertainties. The paper by Sacher and Grahn [S4]contains a full discussion of the mathematicalformalism
underlying the cumulative lethality
functions. This represents an advancement in the identification of the phenomenology of radiation injury andlethality.
111. Lesher et al. [L9] reported on the pathology ofthese animals, in an attempt to establish the cause ofdeath. The daily exposures of 5 and 12 R per day wereconsiderably more carcinogenic than higher exposure
rates, and the lower carcinogenic efficiency of thehigher dose rates was tentatively attributed either to theearlier death of the more heavily irradiated animals or
perhaps to a "therapeutic" effect on the potentiallytransformed cells as the dose rate increased. It was
found, in general, that the duration-of-life exposureyielded fewer tumours per R of accumulated exposure
than single or terminated irradiation regimes. Tumoursof the genital tract and a higher incidence of lymphoma
were responsible for the much higher tumour incidence
in female mice. Furthermore, some diseases were accelerated in the irradiated mice and some were not.
112. Sacher and Trucco [S13] analysed a model for
mammalian radiation lethality and recovery, which wasessentially based on the kinetic characteristics of selfrenewing cell populations. The model assumes that
671

1200

i'
::! 1000
";"

e;
>-

=
...

800

......,_~

600

...B:
i?

400

~

200

3

6

10

20

:00

60

100

200

600

TIME FROM BEGINNING OF EXPOSURE (DAYS)

Figure V. A plot of the Impulse lethality function versus time fromthe beginning of exposure In duration-of-Ille experiments. The
data are for LAF1 male (solid line) and female (broken line) mice
exposed to cobalt-60 gamma radiation at exposures from 5 to
200 OOO A d-1. Data from Sacher end Grahn [S4]population growth proceeds at a rate proportional tocell number but that growth is constrained, so that eachcell population attains a given stationary size. The rateof growth is therefore the product of two terms, one ofwhich is a monotonic function of the size of the
population and the other is a function of the difference
between actual size and limiting size at any given time.
Based on these simple assumptions Sacher and Trucco
produced a complex phenomenological theory which
was applied to radiation data on survival after split
doses, multiple fractionation and protracted continuous
exposure and showed some qualitative agreement
between the curves obtained experimentally and thosepredicted by the model. However, the formulation ofthis theory is not sufficiently developed and may be
regarded as a first attempt towards a more comprehensive treatment.
113. In another paper Sacher, Grahn, Fry et al. [SS]examined the late consequences of gamma-radiation
with respect to two major categories of effects: theincidence of tumours of the reticular tissue and the life
shortening induced by all causes other than thereticular tumours. The data were obtained from maleand female mice of four different genotypes exposed in
duration-of-life experiments (60Co gamma rays, 0.3 to
56 R per day). In agreement with that observed on the
LAFl mouse [S4] the data showed that the log mean
after-survival plotted as a function of the daily dose
followed a very nearly straight line.
114. The Gompertz transforms of these data (seeFigure VI) for all causes of death were slightly convex
upward and formed a fan of lines of increasing slopewith increasing dose rate with small differences
between genotypes. When the cumulative incidence offour tumour types (reticular, pulmonary, hepatomas,
ovarian), summed over the four genotypes was plotted
as a function of daily dose, three tumours showed amodest increase in incidence with a peak at 6 R per day
or less followed by a sharp decline. Reticular tumours,on the contrary, rose to a peak between 24 and 32 R per
day and then showed a sharp decline at higher daily
dosages. This phenomenon was explained in terms of
the hypothesis put forward by Gray [G7] which postulates two phenomena (induction and cell killing) acting
together but with different dose dependencies in therelevant target cell populations.
115. In the experiments under discussion [S5] the log
mortality rate data for all causes except leukaemia
672

plotted as a function of age indicated in the BCFl
mouse a linear rise at all daily dose levels. The slopes ofthese lines increased with increasing dose levels to form
a fan of lines intersecting with the control slope at 100
days, at which time exposure began (see Figure VII A).
These slopes plotted on a semi-logarithmic scale as afunction of the exposure rate (R per day) gave linear
C578l/6

en
UJ
en

::>
c:(
u

........_. 43Ridc:y

...J
...J

0--0 24R/day'Q<---9 12 P. tc..,c:(~ 6Rl.!at-

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<

0

......

A/Jaa

0
0
0
0

.......
en

:i:

.....
c:(
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900

AGE (DAYS)
Figure VI. The logarithm of the age-specific mortality rates
for all causes of death (Gompertz transform) In mice of lour
different genotypes (BCF1, C57BL/6, BALB/c, A/Jax)
plotted as a function of age. Mice were Irradiated In
duration-of-Ille experiments at the exposure rates shown.
Data from Sacher, Grahn, Fry et al. [SS]relationships and thus justified the conclusion that theslope of the Gompertz lines increases exponentiallywith daily dose (see Figure VI I B). Finally, this paper[S5] has interesting aspects concerning the cellular·
mechanisms of life shortening because it provides somelink between phenomena at the whole-body level and at
the cell population level.

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we

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0 br~r-;);oo;--~4~oo~----;;6001'7."--"lit9.--~~---,1~00""""~AGE (DAYS)

The logaI'ithm of the age-specific mortality rate (Gompertz transfoI'm) for allcauses of death except leukaemia in BCF1 mice of both sexes irradiated in
cfuration-of-Zife experiments at the exposuz,e rates shoi.m. Straight Zines werefitted by least squares through the control incidence at 100 days of age whenthe exposure began.

'"'
en
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<:
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<:

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008

56

1.3

DAY)

Plots of the Mean After Survival (MAS, open circles) and of the slope of theGompertz transfol'l11 (closed circles) versus exposure level. Data are for BCFl
mice of both sexes, as in panel A. The dashed line is that predicted by MAS
from the estimated Gompertz elopes in order to show the consistency of therelationships.
The lines were fitted by least squares analysis.
Figure VII. Changes of the Gompertz transform as a function of exposure rate In duretlon-of.llfe experiments [SS]116. Another paper by Grahn, Fry and Lea [GS]summarized a number of studies on various strains ofyoung adult mice exposed to various levels of 60Co
gamma radiation ranging from 0.3 to over 30 R per day
and discussed the problem of a "non-specific" lifeshortening effect as opposed to a "specific" effect, thatis the induction of neoplasia. Data from mouse strains
BALB/c, C57BL/6 and their F1 hybrid show a steadyincrement of mortality associated with neoplastic
disease upon irradiation as the age increases and thedaily exposure increases up to a few R per day. An
excess mortality from non-neoplastic conditions withrespect to controls was seen only at 6 R per day andabove. Thus, the risk of early or excess death fromradiation exposure at intensities of the order of 100 or
200 times the background is related entirely to the673increase in incidence and to the shift in the time of
appearance of the neoplastic diseases.
117. Sacher [S14] pointed out that when the slope of
the Gompertz curves obtained at various daily doses isplotted as a function of the daily dose on a double
logarithmic scale for two mouse strains, the LAFl [S4]and BCFl [S5], the resulting relationship can be
resolved into two straight lines (Figure VI 11). At
,'
(./)

w

(./)

::, (./)
~

u

a::

::,
0

01

...J ::E:...J ::,~

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120. The survival of goats was followed by Hupp et al.
[H8] and by Hupp [H9] for groups of 11-12 animals foreach sex submitted to chronic 60Co gamma-ray
exposure (3, 7, 15, 30 and 40 R/20 hour day). Great
individual variability was observed in the survival timeat all except the highest exposure level. The lethality
pattern observed was quite different from that of miceand rats. Females exhibited little exposure rate responsein the range of 7-40 R per d:1y, while males accumulated the maximum exposure at 7 R per day. Rats andmice, on the contrary, accumulate maximum exposures· at 30-50 R per day [G6].

I-w(./) a::N II- a..

a:: w
w u

a.. X

~w
0

I.!)

DAILY EXPOSURE, R PER DAY
Figure VIII. A plot of Ille shortening to dally exposure formice treated with Ille-time gamma-ray exposure. Life
shortening Is measured by the Increase of slope of theGompertz function In lrredleted as compared to control
populations. Open circles refer to BCF1 and closed
circles to LAF1 mice. The dashed line corresponds to theInferred relationship for single exposures with constanteffectiveness per roentgen of 0.003 R-1. Date from
Sacher [S14]exposure rates below 24 R per day the data lie close to afirst-power trend while above this value they conform
closely to a second-power trend. At about 24 R per day
the contribution of the two terms is equal.
118. New data were recently reported [T5] on the life
shortening in B6CF1 mice given weekly exposures to
60Co gamma rays (0.07, 0.174 or 0.319 Gy per weekly
fraction) or to 0.85 MeV fission neutrons (0.0067,
0.0167 or 0.0267 Gy per weekly fraction) either for 60
exposures or for the duration of life. The amount of life
shortening produced by the life-long or by the terminated exposure regimes was essentially identical, so thatthe two series were analysed as a single experiment. The
data are generally in good agreement with thosereported from other laboratories.

2.

Other species

119. One hundred day-old male and female
guinea-pigs were started on a fractionated course ofradiation (60Co gamma rays) for the entire duration oflife [R2]. Together with a number of control animals,
groups receiving 1.35 R, once or four times a week; 2.6
R, 5 times a week; 6.0 R, 4 times a week: 24 R, once a
week: 6 R. 6 times a week: were included for a total of
344 animals. The relationship of the log mean aftersurvival time against the weekly exposure in R was
674

approximately linear and the life-shortening coefficient
came to about 0.06 days/R, in close agreement with thedata of Lorenz et al. [L6]. At S.4 R per week a paradoxical early decrease of mortality was noted in males
for which no explanation could be given. Fatty degeneration of the liver, chronic kidney diseases, spleen
amyloidosis and various tumours were noted in theanimt1ls in no obvious correlation with life-span shortening.

121. Casarett [C16] reported briefly on the survival
data of dogs (1000 kVp x rays, 5 days per week at daily
exposures of 0.06, 0.12 and 0.6 R per day beginning at
21 months of age). The accumulated exposures at deathin these three groups varied between 122 and 257 R;
between 243 and 465 R; and between 1088 and 2198 R,
respectively. Average ages at death were 13.8, 13.2 and12.3 years, respectively, the control age being 13.0
years. Median death age was 13.1 years in the control
and 14.1, 13.8 and 12.7 years in the irradiation groups,
respectively. In addition to these groups, a similar
fractionation scheme was applied in other groups,
giving 3 R per day in 10 minutes for 5 days per week fora total of 25, 32 and 42 weeks. Two other groups
received 300 and 375 R whole-body at rates of 10 and
64 R per minute, respectively. For these latter groups
no survival data were reported. More recent data forthe dog are also to be found in [N7] (see subsection
II.A. I).
3.

Data analysis

122. The effect of life shortening induced bycontinuous exposure may be analysed as a function of
the dose rate of the treatment or against the total dose
received (at the various dose rates) from the beginningof exposure to death. There is enough data for themouse to examine both types of dependencies and toattempt some descriptive analysis.
123. Figure IX shows the percentage life shortening
induced at various dose rates. All data available forvarious strains and sexes have been grouped, separately
for the cases of neutron and of low-LET radiations. The
graph therefore includes all the variability expressed inthese experiments. The data by Moos et al. [M14. M15),
although qualitatively following a similar trend. havequite different quantitative relationships and cannot be
considered with the other series. The x- and gamma-ray
data include seven different series performed on fivestrains of male and female mice: the neutron data
include seven series on four strains and both sexes.
124. The nature of the plot in Figure IX is such thatthe low dose rate end of the abscissa is greatly
expanded. Sigmoid relationships of the typey = 100(1 -e-aA)

(14)

100

X_ANO_ GAMMA_ RAYSFAST _NEUTRONS~=!:

L = ;~,1

M = ri.:·n"';;s = [:,1,1

."'
z
w

75

0

= !G'.,Jy = '.1'51

G

~
z
,(
a..

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[Ji3]
[)17]
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ifi
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D

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a:

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YG

s

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y

©

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t

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0.001

1.0

0.1

0.01

~

DOSE RATE [Gy PER DAY)

Figure IX. The reletlonshlps between dose rate end the Ille-shortening
effect following duration-of-life exposures to lest neutrons end low-LET
radiation In the male end female mouse. Various experiments

where A is the dose rate in Gy per day, may reasonably
be fitted to the data. When a non-weighted curve wasfitted to the data by a least-square method, the solutions
were, in case of the low-LET radiationy = 100 {I - e- 3·89 A)

data to merge in the high dose region of the graph. The
relationshipy = 100 ( I - e-• lr,;; )(17)which fits the neutron data with the following values
y = 100 {I - e-s.o7s}'A)
(18)

(15)

and in the case of neutron irradiationy = I 00 ( I -seemed more adequate for that purpose.
125. Another analysis is one where the percentage life
shortening is plotted versus the dose accumulated at thevarious dose rates under duration-of-life exposure.
Data obtained in the experimental series shown in
Figure IX are plotted separately for the x and gamma
ray and for the neutron series in Figure X. For(16)e-44.14 A)

By inspection, the above relationships interpolate thelow-LET data quite adequately, but fail to properly
follow the fairly high effect seen at the very low dosesof neutrons and the tendency of the x-ray and neutron
X_AND. GAMMA_ RAYSFAST_ NEUTRONS

L = [I.ii)
M = [H7)I= [li7]= [E2]= (~3]= (M7]= (T5]S • [S4)
G = (G5)

Y = [T5]

100

"'z

®
®

!?

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5

5

z

~ 75

6

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w

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5

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w

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•
•

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y

II

l

•"

~·

.~

s

6

l
5

G

l y

--+------t-----t------11------t
15

45

30

60

75

DOSE (GylFigure X. Relationship between the total accumulated doses of lest
neutrons end low-LET radiation In the male and female mouse,
following exposure for the duration of Ille. Various experiments

increasing doses the life-shortening effect of low-LET
radiation also increases in an apparently linear fashion
at low doses and then with a progressively accentuatedupper concavity to doses of about 60 Gy administered
for the duration of life at dose rates of about 0.2 Gy perday.
126. At higher dose rates the life shortening continues
to increase but, owing to the progressive reduction oflife span, the accumulated dose decreases and the curve
bends backwards towards the origin. Such an effect waspreviously described by Lorenz et al. [L6] and may be

predicted by the theories of Blair [85) and Sacher [Sl].
Although this observation is not immediately apparent
from Figure X, all along the curve the data obtained at
approximately similar dose rates are reasonably wellclustered together. This immediately points to a
relationship between the three quantities under study inthe graph: dose, dose rate and life-shortening effect.
127. In order to describe the data with a maximum of
precision, an attempt was made to fit a curve where thethree quantities cited would all contribute to determine
the final shape of the relationship. The following
675equation was assumed to reasonably interpolate thedata
y = b D ecA

it follows that
(22)

(19)

A plot of total absorbed dose versus dose rate for data
belonging to the same experiments in Figure IX wasfound to agree reasonably well with an expression of
the above type. Therefore, the previous relationship was
fitted to the experimental data, yielding
D = 698.8 I A e- 3·687 A(R 2 = 0.97)(23)

where y is the percentage of life-span shortening; D thedose and A the <lose rate; b and c are proportionality
const,~nts. Such a relationship cannot be adequately
fitted m the absence of some function relating dose andd~se rate. In ?rder to find such a function the simplify111g assumption of an exponential decrease of the life
span with increasing dose rnte was made for any given
total absorbed dose

128. By the use of the above relationship a fit of theexperimental data was then attempted with optimization of the various parameters to achieve theminimum square deviations. The experimental points
from the lilted curve gave the following solution(20)
Since the total absorbed dose is the product of theduration of life and the dose ratey = 0.7253 D e 1469 A

D = ATin which the functional relationship between A and D isgiven by the above expression (equation 23). Figure XI

(21)

(24)

100

~ 75

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;;;

. ,.•21!

0

z
<

• 16

:J; 50

• 12

w

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;::

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• ID,

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•t

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.,

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w

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oL-----t------1-----------1-----115

~5

30

60

75

DOSE (Gy)Figure Xl. Best flt of the low-LET radiation data In Figure X. The
numbers In the body of the graph are the dose rates (1Q-2 Gy per day)at which the doses specified In the abscissa are cumulated during theentire life of the animals

represents the best fit to the experimental data in Figure
X and provides for each dose (in the abscissa) thepercentage of life shortening to be expected (on theordinate) at the dose rates (in Gy-2 per day) specified atthe various points along the fitted curve in the body ofthe graph.
129. The neutron data in Figure X deserve separate
mention because for them the very characteristic trendof the x- and gamma-ray data in duration-of-life experiments has not been verified. On the contrary, the data
available may point to a continuously increasing effectof life-span shortening without any inflection in thetrend. The data are too few and too scattered toestablish with certainty such a difference in shape. It
may be speculated that the effectiveness of the neutron
treatment in duration-of-life experiments is so highcompared with x and gamma ray that the bending of
the cun'e is not possible in view of the short life of theirradiated animals. But it should also be noted that theexperimental points in excess of about 60% of life shortening (where the curvature becomes apparent with the
low-LET radiation) are only two of the same series andtherefore insufficient to confirm a difference of shape.
In any case, the point is of little practical significancebecause the doses involved are extremely high.

4.

Conclusions

130. In duration-of-life experiments the variables"time" and "dose" are linked and difficult to resolve
676

experimentally. Data in the mouse were analysed by theCommittee as a function of the dose rate and showed
an increasing life-shortening effect following an exponential function of the dose rate, up to a maximum of 1
Gy per day. Neutrons appeared to be more effective incausing life shortening, particularly at dose rates of
0.001 Gy per day or less.
131. When analysed as a function of total cumulateddose, life shortening appeared to be induced according
to a linear trend up to doses of 30 Gy of x or gamma
rays. The percentage life shortening then followed acurve with a progressively accentuated upper concavity
up to 60 Gy administered for the whole life at dose
rates of about 0.2 Gy per day. At still higher dose rates
life shortening continues to increase. However, as theanimals have a shorter life, the dose accumulated
decreases and the dose-effect relationship bends
towards the origin. The same trend for the neutrons
cannot be precisely established for lack of data.
132. It is of great interest to examine the change ofeffectiveness observed in the mouse between the single
acute and the extremely low dose rate data. If the linear
term with dose of the single acute exposure (about 5%life lost for 1 Gy) is divided by the slope of the curve forduration-of-life exposure obtained at, for example, adose rate of 0.01 Gy per day (total dose about 7 Gy) the
efficiency is lower by a factor of about 7. In the case ofneutrons the experimental results show in some cases
increased life shortening after increasing the exposure

time. But until further work clarifies the situation a
precise comparison of acute and low dose rate data is
not justified.
133. The guinea-pig, the goat and dog were also
exposed for the duration of life and revealed differences from the mouse. The differences are related to thesensitivity of the various species to haemopoietic deathor, more precisely, to the dose rate level at which thesusceptibility of the bone-marrow becomes the maincause of life shortening. The guinea-pig was consistently more sensitive in two experimental series; goats
showed differences between the two sexes and anincreased response with respect to the mouse. Therewas evidence that the bending point of the curve as afunction of dose (see Figures X and XI) may occur atdose rates consistently lower than in the mouse, so thatthe maximum dose that this animal may accumulate induration-of-life experiments occurs at less than 10 R
per day, as compared to the 20-40 R per day applying
to the mouse. The qualitative response of the dog might
be similar to that of the mouse, since the dependencies
on the dose of the life-shortening effect change whenhaemopoietic or non-haemopoietic
mechanisms
influence survival. Quantitatively, the primarymechanisms of death might be neoplastic non-haemopoietic or possibly degenerative at dose rates below
about 0.035 Gy per day, while in the mouse the relevant
figure would be in the region of 0.2 Gy per day.

5.

Internal irradiation

increase as the dose decreased from 1.9 107 to 1.9 102 Bq
kg-I. A dose-related life-span shortening was reported
by Brooks et al. [B 12) in hamster injected with 90Sr (7.4
to 185 103 Bq). The 50% survival times ranged from 90
days with 7.4 104 Bq g-1 to 1100 days at 7.4 103 Bq g-1.
In this species, however, myeloproliferative diseases
rather than osteosarcoma were the most common
pathological conditions observed.
137. Another bone seeker, 45Ca, was studied in single
injections by Finkel et al. [FS], and their data wereanalysed again by Mays and Lloyd [Ml 1]. They wereable to show that median survival time from injection
to death in mice dying with bone sarcoma declined withincreasing dose owing to a progressively early
appearance of the bone tumours.
138. Sarcoma incidence in the bone tissue andlife-span shortening were evaluated as a function ofdose. dose rate and time in beagle dogs fed from midgestation to 1.5 years of age a diet containing 90Sr
[M17]. Under these conditions the observed life-span
shortening was attributed mostly to radiation-induced
tumours. Also, in the same paper a reduction of thedelay time in the appearance of bone sarcoma withincreasing activities administered was reported in dogs.
The same observation was true for the same species inthe experiments of Burikina [B13], thus confirming thata shortening of the induction period for tumours(giving rise to a shorter life span of the tumour-bearing
animals) holds true also in the case of chronic uptake ofthe nuclide.

134. Irradiation by injected, ingested or inhaledradionuclides is a special form of localized chronic
treatment which is worth considering in relation to its
effects on the life span of contaminated animals and to
the existence of any non-neoplastic life-shortening
effect. Finkel, Biskis and Schribner [F5] examined theeffect of 90Sr in CFl female mice injected at 70 days ofage with nine acute doses between 1.3 and 8.1 Bq/kg.
The same data with a more extended range of doses
were also reported by Finkel and Biskis [F3] and madethe object of a comparative analysis of life-span shortening and incidence of neoplasms. When plottedagainst dose, life-span shortening and bone sarcoma
induction were not linear over the whole dose range
observed. Life-span shortening and tumour induction
appeared to be equally sensitive indicators of radiation
damage. There was a good correspondence between life
shortening and tumour induction up to a dose of 3.3 I 07
Bq/kg but at still higher doses, in spite of a decreased
incidence of the bone tumours, life span further
decreased.

139. There is some information regarding boneseeking alpha-emitters. In a further analysis by Mays
and Lloyd [M12] of data on single injections of 239Pu in
CFI female mice by Finkel and Biskis [F3. F6] a
progressive decrease of the average survival frominjection to death (for mice living beyond 200 days
post-injection) was seen at increasing skeletal dose,even when the incidence of bone tumours at doses inexcess of 11.5 104 Bq kg-1 decreased, rather thanincreased. At these very high doses there may of course
be some question about how much a non-specificlife-span shortening might have contributed to theobserved decrease of the percentage tumour incidence.

135. Finkel's [F5] data were further analysed by Mays
and Lloyd [Mll]. Mice dying with bone sarcoma had a
median life span from injection to death which
decreased rather regularly with increasing averageskeletal dose, owing to a shorter latency time of thebone sarcoma incidence at higher doses. An effect oflife shortening induced by single injections of 90Sr (3.7
104 or 7.4 103 Bq/g) was also described by Yan Putten
and De Vries [Y2] on (CBAxC57BL)F1 hybrid female
mice and these data plotted as the percentage of thecontrol life span were rather close to those of Finkel etal. [F5].

141. The life shortening observed in dogs carrying
osteosarcomas induced by various injected boneseeking radionuclides (239Pu, 228Tb, 228Ra, 226Ra, 90Sr)
were calculated by Dougherty and Mays [D5]. The
accumulated skeletal doses up to one year before death
were computed and used as the independent variable.
In all tumour-bearing animal groups and for all
nuclides tested the log of the time from injection todeath was a linear function of the log average skeletal
dose. Thus, not only was the average life span reducedby the appearance of bone tumours (whose incidence isa function of dose) but a further reduction of the life
span was seen in tumour-bearing animals by the earlier
appearance of tumours at higher doses. Based onlife-span shortening. the approximate efficiency of thevarious nuclides relative to 226Ra (taken equal to one)was 239Pu = 6; 228Th - 8: 228Ra .. 2.5; 90Sr = 0.07 to

136. Similar observations can be made regarding thedata on rats by Moskalev, Streltsova and Buldakov[M16] as re-analysed by Mays and Lloyd [Ml!], since
the average time from injection to death tended to140. Shortening of the latency interval of tumours
induced by 239Pu injection in rats was also shown by
Bensted et al. [B14]. But in the same species chronic
administration of 239Pu-in spite of an increased
incidence of osteosarcoma, leukaemia and marrowaplasia-was reported to produce minimal changes in
the life span of the treated animals [B15].

677

0.24. These differences could best be interpreted bytaking account of the local site of energy absorption
and of the type of radiation. The surface-seeking alphaemitters are substantially more effective than thevolume-seekers.
142. In 1970 Eyring and Stover [El] examined thelife-span shortening from internal irradiation by 239Pu
and 226Ra reported for beagle dog experiments [M 18,
S24, J 1J making use of the steady-state theory ofmutation rates [SIS, S51]. They fitted cumulative
survival curves as a function of the average skeletaldose accumulated by groups of dogs injected when
young adults with various doses. There was a highcorrelation between the mean survival time and tumour
induction with the average skeletal dose. The log of thedose was proportional to the 50% survival time and theexperimental data followed two quite unrelated slopes
at low and at high doses of injected 226Ra. In the case of
2l9Pu, on the contrary, the 50% survival times followed
a linear function of dose at the low doses.

emitters (90Sr and 45Ca) or alpha emitters (226Ra, n&Ra,
22KTh, UHPu, 239Pu, 241Arn. 249Cf and 2S2Cf) administered to different animal species under a variety ofroutes, doses and dosages. Very good correlations weregenerally found between life shortening and inductionof bone tumours, thus justifying the conclusion thatwhatever reduction of life is apparent from the experiment it may entirely or almost entirely be explained bytumour induction or acceleration. except at extremely
high doses where aspecific mechanisms of death may
produce short-term mortality. This conclusion is veryclear-cut and not surprising, as selective partial-body
exposure is the mechanism operating in case of internal
irradiation and, under these conditions, non-specificdamage to the whole body cannot be expected. The
data are therefore not strictly comparable to those fromwhole-body irradiation and the above conclusions
carry little weight in respect to the problem of life-shortening specificity.
6.

143. The analysis of life shortening was also extended
to 228Ra, 228Th and 90Sr in subsequent publications [S25,
S26]. When the percentage of osteosarcoma induction
was plotted against the percentage of the life shortening
produced by each dose level of each nuclide, a life
shortening of 60% was obtained when the tumour
incidence reached 100%. At high dose levels the degreeof life shortening was similar for all live nuclides but
this similarity was not maintained at the lower doselevels. In the case of 239Pu the incidence of osteosarcoma greatly exceeded the control incidence even at
the lowest dose level where no life shortening relative tocontrols was apparent. In the case of 226Ra progressive
life shortening was seen at skeletal doses in excess of
21.2 Gy, where the occurrence of osteosarcoma was
between 92 and 100% but practically no life shortening
was found at skeletal doses between about 3.7 and 9.5
Gy, although sarcoma incidence in these groups was 10
to 20% and 42%, respectively.
144. From an analysis of data on young beagles
injected with single intravenous doses of 252Cf, 249Cf,
241Am, 2l8Pu, 228Th, 228Ra, 226Ra and 90Sr Mays andDougherty [M18] concluded that all or virtually all of
the life-shortening effect observed at medium and at
low doses of the nuclides is attributable to radiationinduced bone sarcoma. Thus, the thesis that theinduction of neoplasia is responsible for all of the life
shortening observed in the low-dose range of the experiments available was also confirmed for the case of a
medium size mammal injected with a variety of boneseeking radionuclides.
145. In the field of inhaled alpha emitters an experimental study in rats treated with 238Pu, 239Pu and 24tAm
given as oxides or nitrates was reported [M19]. Survival
time of the animals and latency time, frequency,
location and histotype of the tumours were analysed asa function of the dose rate and of the dose distribution.
An acceleration of tumour induction time (andtherefore of after-survival time) with increasing dose
and the existence of a non-neoplastic life shortening athigh doses were also apparent. Similar findings werealso obtained in dogs inhaling 2l9Pu by Bair [B16) andby Park [Pl].
146. In conclusion, a large variety of injected,
ingested or inhaled radionuclides have been studied fortheir capacity to induce life shortening. The largest
body of experimental evidence is for bone-seeking beta
678

Uncommon findings147. In some experiments involving life-time irradiation [L6] low doses of radiation led to an increase,rather than to a decrease, of the expectation of life.
Here mice were exposed to 0.11 R of gamma rays daily.
Although the increase was not statistically significant, it
was confirmed in a subsequent test where differences
between groups concerning the air conditioning and thetemperature of the animal quarters made comparisonsdifficult. Sacher and Grahn (reported by [S3]) also
noted no harmful affect of 5 R per day in threedifferent strains of mice, following cumulative exposure
to about 2500 R. Yuhas [Y3] reported life-span
lengthening when old mice (15, 18 and 24 months ofage) were exposed to 10 fractions of 140 R given over
12 days, whereas the same amount of radiation administered to 4 and 9 month old animals produced
some life shortening. Similar observations were maderepeatedly after relatively low single doses [G2, U7.
S17, E3], as may be deduced from Figure II.
148. In addition to the above cases, life prolongation
has also been reported following the interaction of
suboptimal ambient temperatures and low radiation
doses. Carlson et al. [C21] exposed male SpragueDawley rats at 25oC and 5°C to 60Co gamma-irradiation for 8 hours per day during one year. The animals
were caged individually and a parallel control group
was run at each temperature. The dosimetry was suchthat the animals in the room at 25°C received from 38
to 96 m R per 24 hour-day and the exposed ones
895-931 mR per 8 hour-day. In the room at 5°C therespective dose rates were: control, 42-149; irradiated,
897-966. Oxygen consumption, food consumption.
body weight and metabolism were checked routinely.
The irradiated animals at both 5°C and 25°C lived over
20% longer than their respective non-irradiatedcontrols, the half-lives observed were: at SoC. control
240 days, irradiated 305 days; at 25°C, control 460
days, irradiated 600 days. No explanation was offered
for this observation, except the suggestion that a mild
injury might result in apparently beneficial effect bystimulation of cell and tissue repair and repopulation
processes.
149. Trujillo et al. [Tl J reported that RF/Un female
mice showed a linear decrease with increasing age intheir ability to withstand a standard cold stress (6oC to
70c for 14 days). Mice exposed to protracted 60Co
gamma-ray exposure at 0.5 Gy per day and then

allowed to recover for 90 days showed a similar linear
decrease with increasin·g radiation exposure in theirability to withstand the same cold stress. This radiationinduced effect was considered similar to life shortening
by natural aging and was equivalent to 9.3 days per Gy.

about by unfavourable environmental conditions may
have been responsible for life span prolongation.

C.

150. In a rather more elaborate set-up Carlson andJackson [C22] studied the interaction among radiationand high temperature. The animals were divided into 8groups of 22 rats each, individually caged. Four of themwere kept at 28°C and exposed to 0.29, 0.64, 2.60 and
4.18 R per day over a period from 4 to 16 months ofage. The other four groups were kept at 35°C for thesame length of time and exposed to 0.28, 0.60, 2.57 and3.96 R per day. The age at which 50% of the irradiatedanimals died increased with increasing dose at all doselevels tested, with good statistical significance of thedata, except for two points. It was suggested thationizing radiation may have interacted with theenvironment in increasing longevity by stimulation of
the repair processes. These experiments [C21, C22] arenoteworthy, not only because they show an interaction
between radiation and ambient temperature, but also
for the finding that radiation in the region of 4 R per
day or lower has (at all temperatures tested) increased,rather than decreased, survival. As to the first point, theobservation has so far remained without confirmation;
concerning the second one, it should be mentioned that
Bustad et al. (817] working on individually caged mice
within the same exposure range but at normal ambient
temperature could not confirm the data of Carlson. The
problem therefore remains unsolved, as the different
species or environmental conditions might have been
responsible for the negative observations of Bustad.
151. Following the formulation of a theory on thestatistical nature of mortality by Sacher [S2] and by
Sacher and Trucco [S12) in which the death of anorganism is viewed as a random event arising from thefluctuating nature of its physiological performance,these authors proposed [S32] a modification of thetheory that makes it possible to account for the paradoxical observations described. Radiation (particularly
at low doses) induces a decreased fluctuation of thesignalling and control systems of physiologicalprocesses. As a result, the probability of a large fluctuation leading to an irreversible change is decreased. In
essence, the decreased variability among the exposedcompared to among the control animals, is the main
effect of the irradiation and the improved survival at
relatively low doses results from it as an occasional
consequence.
152. The above model may provide a phenomenological explanation of life-lengthening effects in
actuarial terms, but the intimate mechanisms throughwhich such effects may be brought about are still
unknown. Data showing stimulation of antibody
formation [D10. L19]. increase in phagocytic activity
and Iysosome content [T3] and activation of reparative
enzymes by relatively low radiation doses [K24, V8]can, in principle, be cited in this respect, but theirgeneral applicability cannot be decided at present.
153. Biological variability of the control and experimental animal groups and long-term changes of thebaseline reference values may have been responsible forat least some of the above observations and these cases
should probably be viewed separately from the othersin which interplay of environmental factors led to thephenomena under discussion. Kuzin [K24] consideredthat an increased resistance of the animals brought

DOSE RATE, DOSE FRACTIONATION,
PROTRACTED EXPOSURES

154. Results of other experiments are available inwhich radiations of different types were given atvarious dose rates in chronic terminated or in
fractionated exposures to animals of various species.
The experiments were sometimes made to examine theeffect of a given regime of chronic terminated exposure.
In other instances, the experiments were carried out tostudy changes in the dose rate: and in other cases inorder to compare the effects of splitting a single dose
into fractions separated by various time intervals. In allof these experiments the interplay of dose-timeparameters is extremely variable and the final effectmay be expected to be intermediate between the two
extremes of the single or of the duration-of-life
exposure. It is difficult and somewhat arbitrary toseparate all this work into various chapters: however,the following will separately consider the effect of doserate, of dose fractionation and of protracted exposure,in an attempt to draw more systematic conclusions
about the different radiobiological variables. The effecton life span of the distribution in time of low-LET
radiation has been discussed in [N14].

I.

Dose rate

155. The papers where dose rate was examined as aseparate variable in acute exposures or in the course ofchronic terminated experiments are very few and all on
mice. Vogel, Frigerio and Jordan [Vl] reported thatbetween 10 and 44 mGy min-1 of fission neutrons theeffect on life span was independent of dose rate,
although there was dependence for gamma rays in therange of 10 to 130 mGy min-1. The efficiency of thetreatment was lower at low dose rate. The experiments
were performed on CFl female mice irradiated with 13
brief daily exposures. In another series the mice were
irradiated with single neutron exposures at 80 mGy
min-1 or 2 mGy min-1 (0.36-1.74 Gy total dose).
Survival did not differ within the above dose rates.

156. Vogel and Jordan [V3, V4] irradiated the same
mice with fission neutrons and gamma rays (10 to 350
mGy min-1). Four weekly doses of 2 Gy per week of
60Co gamma or 1 Gy per week of neutrons were
employed, delivered at variable dose rates. For bothradiations, the lower the dose rate, the longer the life
span of the animals. Lindop and Rotblat [LlO] reported
on the changes in effectiveness (expressed in weeks oflife shortening per Gy) as a function of the dose rate at
the extremely high intensities of 0.77 to 1580 Gy min-1.
They showed that the maximum effectiveness (5.7 to 6.2
weeks Gy-1) was at around 10 Gy min-1, but could not
explain the loss of effectiveness at still higher dose
rates. Oxygen depletion induced by these high intensities could not have been responsible for such aneffect, as it was also seen in mice made artificially
hypoxic.
157. Upton, Randolph and Conklin [U7] and Upton,
Randolph and Darden [UlO] used variable dose rates ofgamma rays (0.8-0.01 Gy d-1) or of fast neutrons (110
to 0.04 mGy d-1) to induce life shortening on RF/Un
male and female mice (total doses of 100 and JO Gy,
679

respectively). In females, a consistent reduction of the
gamma-ray effectiveness was seen at the lowest intensities, amounting to about a factor of 3, by comparison
with acutely-delivered (0.067 or 0.8 Gy min-t) doses. A
further reduction to a factor of 6 was observed if
continuous irradiation was carried out to the time ofdeath of about 50% of the animals. For neutrons, loss of
efficiency of continuous against acute administration
was 0.9 and decreased further to 0.7 for exposures
protracted to death of 50% of the mice. In maleanimals, the loss of efficiency of the gamma rays waseven higher, amounting to 0.1 upon continuous administration and to 0.04 for irradiation protracted up to
50% survival.
158. Spalding et al. [S21] performed experiments on
RF female mice irradiated with gamma rays (0.025 to
2.5 Gy h-1, 1 to 12 Gy total dose). Within a given total
dose the mean after-survival was changed more or lessrandomly with the dose rate. Biological and environmental factors such as individual variations in radiosensitivity and cage effects rather than any identifiablephysical parameter were held responsible for theseobservations. Dose rate studies (gamma rays, 1 to 1OOO
Gy min-1, 1 to 3 Gy weekly exposure for a substantial
duration of the life span) were also reported by Willhoit
and Wiggins [W5]. Some decreased effect at the lower
dose rates was noted, but it was impossible to attributethe effect to any specific disease, owing to the lack ofpathology.
159. In the experiments of Ullrich and Storer [U8) andStorer et al. [S44] on RF and BALB/c female micelowering the dose rate of gamma rays led to a modification of the shape of the dose-effect relationship in therange 0.5 to 4 Gy from a very complex pattern at 0.45
Gy min-1 to a nearly linear shape at 0.083 Gy d-1. The
large difference in effectiveness was related to an
upward displacement of the regression line in the O to
0.5 Gy range in the high dose rate groups. BALB/cfemales showed a similar trend, in that the 0.5 Gy dosepoint was displaced upward in the high intensity curve,
suggesting a dose rate dependent injury component
which saturated at high dose rates at about 0.5 Gy,
similar to the one identified by Sacher [S2] in female
mice given 2 Gy or more. The response to neutron
irradiation of high (0.25 Gy min-1) or intermediate (0.01mGy d-1) dose rate was somewhat different. In RFM
mice the low dose rate was less effective at 0.24 Gy but
more effective at 1.88 Gy than the high dose rate. In
BALB/c mice little dose rate dependence was seen at
low doses but at 1.88 Gy the low intensity was more
effective. The results are somewhat less clear at lower
doses.
2.

Dose fractionation

160. The experiments reported in this subsection were
performed by splitting a given dose or a series of doses
into two or more fractions, irrespective of the time overwhich the total dose was administered. The dose per
fraction, the fractionation interval and the total time tocomplete the course of irradiation are variables thatinteract to produce the final effect. They cannot be
separated from each other under most of the experimental conditions used. Often the comparison istherefore between a dose given in a single treatment
and the same dose over a very protracted course of
fractionation. Only seldom is the accuracy of the datasuch that numerical protraction factors can be derived
with the necessary degree of precision.
680

161. Sacher [S2) performed experiments on the lifeshortening effect in the mouse of 400, 800 and 1200 R
given in equal fractions 5 day/week over 2 or 8 weeks.
The life shortening of mice dying from causes otherthan lymphoma decreased with increasing number offractions, even though the effect of leukaemia induction
increased by fractionation, as reported for the C57BL
mouse by Kaplan and Brown [K12]. The dose fractionation experiments performed by Curtis and Gebhard in1958 [Cl?] with lission spectrum neutrons and 250 kVp
x rays in CFl female mice did not show any change in
effectiveness upon fractionation but the authors recognized the peculiarity of this finding and attributed it tothe use of fairly large doses. In their opinion, therecovery rate from such doses would be essentiallydifferent in the x-ray and neutron groups, as comparedto the recovery from small fractional doses.
162. Survival and leukaemia incidence were studiedin RF male mice irradiated with 250 kVp x rays by
Upton, Wolff, Furth et al. [U 11]. After 150 R given in asingle exposure the life span was 15.6 months and it
increased to 16.3 and 16.5 months when this same
exposure was split into two 75 R fractions and given 2
and 6 days apart, respectively. Similarly, 450 R given ina single treatment or in 3 equal fractions at 2 or 5 days
interval changed survival from 10.3 to 10.8 to 11.1
months, respectively. These changes are small and of
dubious significance, in spite of the relatively highnumber of mice per group. They could be attributed tochanges in the incidence of reticular tissue tumours
which are by far the largest part of the causes of deathin this strain, particularly after irradiation.
163. Mole [Ml. M20, M21] reported that when 1000 R
of x rays were delivered in 10 daily fractions of 100 R
the mean survival time was shortened by 10% withrespect to controls. When the same total exposure wasdelivered in 100 fractions of 10 R each the mean
survival time was shortened by 37%. Thus, spreading agiven dose over a longer time would apparently
increase the amount of damage. The same result was
obtained on CBA mice when 750 R were given in asingle dose or spread out over several weeks. In thiscase fractionation induced a change in the shape of theage-mortality curve and of the age-specific mortality
rates owing to the appearance of more leukaemia
deaths after the protracted than after the single
exposure. It seems possible therefore that the importantfactor in this case might have been a change in the
spectrum of the induced diseases rather than thefractionation per se.
164. Cole et al. [C18] examined in the LAFl mousethe influence of 250 kVp x-ray fractionation. The
incidence of leukaemia was increased significantly
when 690 R were subdivided into 2, 4 or 8 equal
fractions separated by 8 weeks, 19 days or 8 days,
respectively. Irradiation shortened survival time in allgroups, but the largest decrement was seen in micereceiving 8 exposures of 85 R, an effect which would becontrary to expectation if leukaemia had not specifically shortened survival in this case. In contrast, observations on nephrosclerosis showed a decreased
incidence of this disease with fractionation from morethan 50% in the mice receiving the single exposure
to less than 10% in the group receiving eight fractions.
Therefore, in these experiments nephrosclerosis was
regarded as being mainly responsible for early death
after the single dose, whereas malignancies specificallyaccounted for more than half of the deaths in thefractionation groups.

165. According to Vogel, Frigerio and Jordan [VI)fractionating 2.75 Gy of neutrons into 3, 4 or I 0
separate daily exposures did not result in any significant difference of the mean survival time of CFt
female mice. Kohn and Guttman [K6) studied the effectof 520 R of 250 kVp x rays given as a single exposure orin two fractions administered 8 days apart on male andfemale CAFI mice. Specifically with respect to theeffect of fractionation. here again the results were
unclear in showing any significant improvement insurvival.
166. Vogel and Jordan [V5) examined on CFl female
mice the effect of fractionating a weekly dose (3 Gy of
60Co gamma rays or 0.6 Gy of fission neutrons) into 1, 3
or 6 equal dose fractions per week. Roth radiations
were delivered at approximately 0.01 mGy min-1 andthe treatments were continued for a total of 13 consecutive weeks, so that the mice were exposed to almost 40
Gy of gamma rays or 7.8 Gy of neutrons. The mean
survival times of the gamma-irradiated mice were notsignificantly different whether they were exposed 1 or 3
times per week. There was some indication that afurther dilution of the dose to 6 fractions per week
might increase survival but the significance of the data
could be questioned. No indication of a sparing effectof fractionation was, however. found in the neutronirradiated mice.
167. Silini and Metalli [S27] showed in a small experimental series that survival time could be increased by aschedule of fractionation where a conditioning dose of
1.5 Gy was followed by 3.5 Gy given at 7 time intervals
between zero and 48 hours. A positive regression of thedata amounting to an 8% increase in survival time was
detected. The kinetics of the phenomenon followed apattern reminiscent of the short-term intracellular typeof recovery described in cultured cells by Elkind andcollaborators [E4].
168. Grahn and Sacher [G1] tested the effects of 450
and 750 R of 60Co gamma-radiation delivered as single
exposures or in two equal fractions separated byincreasing time intervals from 3 hours to 28 days. The
regression of survival time versus fractionation interval
was negative in 3 out of 4 cases (2 doses x 2 sexes) but
none of the regressions were significantly different
from zero. The incidence of leukaemia was not consistently modified by fractionation and this disease was not
specifically associated with life shortening. in contrast
to results of other studies [G4. U 11 ].
169. Ainsworth et al. [A 7) reported that fractionationof a gamma dose of 8.38 Gy into 24 doses of 0.35 Gy
administered over 23 weeks produced a ·•sparing effect''by approximately three-fold. On the contrary, a similar
regime of fractionation with fission spectrum neutrons
increased life shortening. This is a rather unusual observation in fractionation experiments, but it is inagreement with the theoretical expectation when the
single-dose curve is, as in the case at hand, convex
upward [R 13). Histopathological observations on
pulmonary tumours could not explain all of theincreased mortality resulting from neutron dose
fractionation. Tentative explanations were offered.
based on the differential acceleration of the lungtumour appearance or on the differential killing ofpotentially transformed cells in the lung. A more recent
report [T4] confirmed the same conclusions in regard to
the actuarial analysis but did not provide pathological
data useful for their interpretation.

170. Storer et al. [S44J exposed RFM and BALB/cmice to 7 weekly doses of fission neutrons of 0.067 Gy(total 0.47 Gy) or to 0.235 Gy once every 4 weeks for 28
weeks (total 1.88 Gy). Animals exposed to a
fractionated dose of 0.47 Gy had a life span notdifferent from those given single high dose rate
exposures or exposures at 0.01 mGy d-1. BALB/canimals receiving 1.88 Gy had a survival time significantly shorter than that following a single exposure.
RFM animals given fractionated treatment up to 1.88
Gy experienced the same survival as after single
exposure and a significantly longer survival thanfollowing exposure at 0.01 Gy d-1. It was concluded
that the cause of death may critically determine theeffectiveness of the fractionated exposure, although theauthors were unahle to provide an explanation for theiroh,l'f\ at in11'.

171. Data on the effect of dose fractionation on life
shortening were described by Hursh et al. [1-15] in the
Wistar male rat irradiated with x rays. Information on
x-ray dose fractionation was also reported in the same
animal species by Lamson. Billings and Gambino [L4,
L11 J. Increasing the number of fractions from 1 to 3 to
6 for the same total exposures of 120. 240. 480 R caused
an increase of life span. compared to the same exposurein one fraction. The effect was dose-dependent in that it
could be seen at the two higher exposures. Spacing of
the fractions at intervals of 3, 5, 7 or 14 days did not
influence longevity. It was concluded that fractionation
after exposure in the 1 to 6 fraction range led to 30-46%
of the sparing effect obtained by halving the total
exposure in the O to 446 R exposure range.
172. In the Wistar rat Reineke et al. [R3) examined theeffects on tumour frequency and life-span shortening of
two different fractionation regimes of whole-body xirradiation (300 R in 3 exposures over 2 months or 10 R
in 90 exposures at daily intervals) and compared theseregimes between themselves and with control nonirradiated rats. No significant differences in the overall
incidence of tumours or on tumour types wereobserved. The average survival times were 20 and 25
months, respectively. Tumour induction rates and death
rates were not different between the two groups, butsome differences became apparent when age-specificrates due to neoplastic and non-neoplastic causes werecompared. In general, all radiation effects were more
pronounced in the group receiving 300 R x 3. There wasno complete summation of the effects of the single
doses and recovery processes were more effective after
small daily exposures than after greater radiation
exposures given at longer intervals.
173. Various schedules of fractionation as well as
single exposures to 250 kV x rays were given to female
beagle dogs by Andersen and Rosenblatt [A2]. For total
exposures of 100 or 300 R, 4 equal fractions or 2 equal
fractions given at 7. 14 and 28 days interval wereadministered.
In general, differences between
subgroups receiving fractionated exposures wereapparent only in groups totalling 300 R. In theseanimals life shortening was increased when the totaltreatment time increased from 7 to 84 days. It wasestimated that the decrease in life shortening produced
by 300 R would be reduced from 23 to 10% as treatment
time increased from 7 to 84 days.
3.

Protracted exposures174. The papers discussed in this subsection pertain tochronic exposures carried out with different radiations681

on various animals. The heterogeneity of this work doe~not detract from the quality of some of the contributions in which many important conditions such as the
protraction of dose administration or the duration of
exposure (and therefore the cumulated total doses) are
the variables under examination. The common featureis that in all cases exposures were terminated before a substantial part of the animals died, thus allowing estimatesof the survival parameters under conditions in which
the "wasted radiation" component was not effective.
175. The early contributions of Evans [E2] and Lorenz
et al. [L6] are only cited here for completeness. The
paper of Mole and Thomas [M7] is a systematic investigation of life shortening in CBA mice by changing theduration of exposure to daily irradiation of 60Co
gamma rays or of fast neutrons (mean energy 0.7 MeV).
In the case of gamma irradiation. weekly exposures of

(I)

:::c
I-

350. 210, 110 and 16 R for progressively longer times (4lo JO weeks) and for the duration of life were tested.
For neutrons, 0.16 or 0.02 Gy per week for 5 to 60
weeks or for the duration of life were the conditions
tested. For both radiations, as the duration of exposure
to a given daily dose (and therefore the total dose)
increased. the mean survival time decreased. However.
beyond a given point a further increase of exposure
time and total dose produced no further effect. The
lower the daily dose, the more survival time became
independent of the total dose or of exposure time. The
minimum dose or exposure time required to produce a
maximum life-shortening effect could only be approximated. The shape of the cumulative mortality curves
depended systematically on the particular level of daily
dose and on the duration of the exposure. except
possibly at the lowest daily closes. A summary of thesedata is given in Figure X 11.

CONTROL
RANGE

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DURATION OF EXPOSURE, WEEKS
Figure XII. Mean survival times of female CBA mice after chronic terminatedand duration-of-Ille exposures to gamma rays and fast neutrons. The nominal
weekly exposures are: gamma rays, • 350 A, 0 210 A, D 110 A, "v 16 A; fastneutrons, A 0.16 Gy, T 0.02 Gy. In duration-of-Ille experiments the mean survival
time equals the mean length of exposure and therefore all points for such
exposures must lie on the diagonal slope 1, as shown. Vertical bars show therange of mean survival time in various groups of control mice. Data from Mole
and Thomas [M7]176. Mole's paper [M7] contains, in addition tovaluable experimental observations. a number of interesting points for discussion. Some pertain to theconcepts of reparable and irreparable injury. Other
points concern the problem of controlling and assessing
biological variability in long-term experiments and here
data are given for a discussion of the secular changes ofthe life span of the controls. Another observation
relates to the presence of discontinuities in the responseto chronic irradiation generated by biologicallydifferent modes of death. Data on the effect of acuteversus chronic irradiation were also reported in themouse by Curtis, Tilley and Crowley [C 19) and are
discussed elsewhere.
177. In the series by Bustad et al. [817) hybrid(C57BLxI0l) mice were exposed for 8 hours daily fromthe age of 6 to the age of 58 weeks (that is for one year)
to 0.1 R h-1 or 0.2 R h-1 of 60Co gamma radiation. The
cumulated total exposures were 290 and 480 R, respec.tively, after which the animals were taken out of the682

radiation field and followed for the rest of their life.
Although the treatment did produce some differencesin the average pattern of growth and longevity, in most
instances these differences were found to be small
relative to the variability of the normal samples.
178. Grahn, Fry and Lea [GS] also discussed the effectof protraction on mortality. showing that the risk ofdeath from all and from specific causes is quite
different if compared to acute exposure. Their data on
LAFI mice show that leukaemia death rate is reduced
by a factor of 5 or more for daily exposure levels below
20-30 R d-1. Data on all causes of death other than
leukaemia show also a protraction factor which takes
up different values (from 2 to 5) as the exposure rate
decreases from 40 to 50 R d-1 to 12 or less R d-l.
179. Spalding et al. [S28) exposed 13 groups of adultfemale RF mice to 60Co gamma rays at about 0.028 Gy
h-1 until a predetermined dose (from 4.57 lo about 0.03Gy) had been accumulated. As doses increased, therewas no accompanying increase of life shortening
because any dose had about the same effect, amounting
Lo an average of 83 days reduction of life. Assuming alinear relationship with dose in the range O to 0.47 Gy,
the effect would be about 18 days per Gy, a value which
is on the low side of those usually found for low-LET
radiation (see Table I).
180. The contribution of Russ and Scott [JU) on the
rat should only be mentioned for historical reasons.
Boche [B 11) refers to some experiments in which rabbits
received one year of treatment at daily exposures of 0.1.
0.5, 1.0 and 10.0 R. Life shortening was shown invarious ways. Similar treatments were also given to afew dogs and when the experiments were conductedwith irradiation for only a fraction of the life time atdosages below 1 R d-1 no effect on survival was noted.
This was also true for monkeys.
181. The paper by Fritz et al. [F7] on the beagle dog is
an attempt to clarify time-dose relationships after terminated chronic exposure to 60Co gamma rays. Four
exposure rates (5, 10, 17, 35 R d-1) were used and thedogs (354 in total) were removed and allowed to die ofnatural death after total exposures of 600, 1400, 2000
and 4000 R. The experiment is still in progress but theprovisional data are sufficient for a few tentative
conclusions, as follows. The LDso increased from 2.58
Gy delivered at 15 R min-t to about 30 Gy at 10 Rd-I.
Over this range of exposures the leading cause of death
was haemopoietic damage. At 5 R d-1 or lower nodefinite LDso could be determined: the haemopoietic
function continued at a nearly normal rate and survival
was sustained. The relatively high number of malignancies other than leukaemia observed among the few
animals dead up to the time of the report suggested thattumours of the soft tissues in irradiated animals weresignificantly increased with respect to controls. 1t is yet
too early to see whether a non-specific component in
the life-span shortening may become apparent at thelowest dose rates.
4.

Conclusions

182. On the whole. the modifications of the life span
induced by changing the dose rate are rather variable.
For single acute doses of low-LET beams, changing thedose rate from 0.004 to 0.4 Gy min-1 did not significantly alter the effect [S21). When the dose rate varied
between about 0.8 and about 1580 Gy min-t [LIO] theeffectiveness of the treatments differed as a maximum
by a factor of 1.6. Thus, acute treatments show little
dependence on the dose rate down to 0.004 Gy min-1.
At lower dose rates, down to about 0.01 Gy d-1, it
becomes difficult to resolve changes due to the dose
rate as such or to dose protraction over a time whichallows adaptation of the animal to the treatment. Underconditions implying irradiations for weeks or months,
the efficiency of the treatment with respect to acutedoses may drop by a factor of 10 or even of 25 forextremely low dose rates and long irradiation times
with accumulated doses involving less than 50%
survival of the irradiated animals [U7]. With suchextremely protracted irradiations the form of the doseeffect relationship may also change with various
reduction factors for different total doses [U7, US].
Modifications of the form of the dose-effect relationships are not surprising, as changes of the damage,repair and repopulation at the various doses wouldsuperimpose to changes of the biological system itself
during physiological adaptation to irradiation. All thesevariables would be expected to change profoundly as afunction of time and dose. There has been experience inchanging the dose rate in the course of brief repeatedexposures at daily or weekly intervals. For daily
exposures, a dose rate dependence of 60Co gamma
radiation amounting to a factor of 2 has been found,but not for fast neutrons. \Vcekly fractions with higher
doses and within a higher range of dose rates did,
however, show some reduction of effectiveness even forneutrons [Y3. V4].
183. In the case of neutrons, changing the dose rate
between 0.08 and 0.002 Gy min-t does not result in an
appreciable loss of effectiveness [Vl]. The data
available at lower dose rates (250 to 0.04 mGy d-1)
given in protracted exposures [U7, U8] may be interpreted to show that the reduction of effect at the low
intensities is modest, probably lower than a factor of
1.5. There may be question as to the significance ofchanges in the form of the curve within such a small
range of variation. Thus. the dependence of life shortening on dose rate is modest for low-LET radiation anddoubtful for neutrons, when treatments last a few hours
to a few days. Only when extremely low dose rates andcorrespondingly long irradiation times are involved, dox and gamma rays (but not neutrons) show consistent
reduction of effectiveness, of the order of a factor of 10
or 20.
184. Experiments performed by splitting a given dose
into two or more fractions separated by a few hours to a
few weeks [Gl. S27) have yielded little increase insurvival by the split dose. When fractionation intervalsof progressively longer duration were tested with agiven scheme, a tendency to a longer life span with anincreasing interval between doses has sometimes beenfound. but the variations observed even for very long
fractionation times are too small to make these observations clearly significant [G I, A2. S27].
185. It is very difficult to see an overall trend for more
complex fractionation patterns. In some cases [S2, A2,
A7, H5, L4, R3] dividing the dose into smaller andsmaller fractions does lead to an increased survival
time following x- or gamma-irradiation. So does theincrease in the total treatment time for the same number
and size of fractions. But in other cases [Ml. K6. M20,
C18] a paradoxical effect is observed, i.e .. an increase of
the life shortening upon dose fractionation. A changing
spectrum of the various diseases contributing to life
shortening with more leukaemia induced at longer
fractionation times has been invoked to explain theobservations. Neutron dose fractionation experiments
have also been reported on mice with unclear results.
186. In spite of the absence of a component of wasted
radiation that has been claimed to confound theanalysis, the effects of chronic terminated exposures arc
more difficult to evaluate than the experiments
involving duration-of-life exposure. In principle, forany given type of radiation, the effect to be expectedshould lie between the dose-effect relationships
obtained for high dose rate acute exposures (see Figures
I I and 111) and those operating under duration-of-life
conditions (see Figure X). However. the most striking
finding in these series is the modification of the doseeffect relationships taking place at progressively
variable dose rates. These modifications. depending on
the characteristics of the species and strains, determine
the final outcome .of any given course of irradiation.
There are not enough data on any single species toanalyse such a broad statement into any coherent
683

model as published data have essentially been obtainedon two mouse strains [M7, U7] and other series [Sl 1.
S21, L6] have contributed relatively less information.
187. These data, involving x-, gamma-ray and neutron
irradiations were analysed by Grahn and Sacher (01)and their conclusions may be provisionally accepted.
Apparently (see Figure XIIJ) the curve describing life
shortening as a function of total dose accumulated for
doses of 15 Gy or less or for protraction periods of 50days or less shows an abrupt slope transition from an
initial portion where the effectiveness of the treatment

V

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0 n~utrons, siru;le c!:i~e
CJ n~ulrons, >30°/, ol lirerirnc• gamma rcy$ 1 slngt~ !!osc'Q gommoroy~, o. 50 Gy/ d, term
6 ~ammo rays, 0, 25 Gy/ d, 1 er m
X gcmmo r.!.ys, O. 1 5 Gy / d, t e r m
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20
30
ACCUMULATED DOSE (GY)

t

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-

50

Figure XIII. Life shortening as a function of mean accumulated dose in RF female mice given
various patterns of exposure (single, chronic terminated, duration-of-life) to gamma rays andneutrons. Data from Upton et al. [U7] as plotted by Grahn and Sacher [G1]

is of the order of 20-30 days of life shortening per Gy
to a final slow-rising portion having an effectiveness of
4-5 days per Gy. This final slope applies to all
protraction periods. including exposure for theduration of life; however, the point of transition
between the fast-rising and the slow-rising segments ofthe curve is clear at 0.5 to 1 Gy d-1 but less so at intensities of 0.1 to 0.15 Gy d-1. This flattening of response
noted by Mole [Ml] and by Sacher [Sl] may be related
to the establishment of an equilibrium between
radiation injury and recovery mechanisms. which
would depend on the kinetic modifications of thetissues that are important for long-term survival [SS,Ll3. L14, L15].
188. It may therefore be reasonably expected that the
breaking point or transition in the dose-effect relationships depends also on the kinetic characteristics of therelevant cell lines, which are known to be speciesspecilic. Such an analysis makes it also quite clear thatconditions of protracted exposure may not be definedwith respect to their life-shortening effectiveness by asingle recovery constant or residual injury value valid
for all conditions of protraction and all animal species.
The neutron data would be such [Gl] that when thetransition from the fast- to the slow-rising portion of thecurve is operative. the RBE would change from 2-3 to
5-15. as a result of the change in life-shortening effectiveness.
684

D.

RADIATION OF DIFFERENT TYPES AND
ENERGIES
1.

Data

189.
The action of different radiation is manifested
through a change of effectiveness for the same amountof energy absorbed by the irradiated animal. The
spatial distribution of the primary physical events thatare responsible for the final biological effect is at theorigin of these changes. Radiobiologically, the effect ofdensely-ionizing radiation becomes evident through anincreased efficiency of the dose, by comparison with asparsely-ionizing radiation. Under well specified irradiation conditions, when a given effect may be followed
for a whole range of doses, the above phenomenon isexpressed by the "Relative Biological Effectiveness"(RBE), a factor specifying the efficiency of the test
treatment against a low-LET treatment assumed as thestandard. X rays of around 250 kVp or 6DCo gamma
rays may be used for this purpose: they are themselvesof different effectiveness, the hard gamma rays being
about 0.8 times as effective as the x rays. This Annex
does not discuss the theoretical foundations of theseconcepts which are reviewed elsewhere [KIO, R4) andare also discussed in Annex J. It considers only
evidence regarding life shortening, according to theorder of publication.

190. The early experiments on fission neutron RBE by
Henshaw [H6], Evans [E2]. Gowen [G8] and Neary et al.
[N3] will only be cited. These experiments were·analysed in the 1958 report of the Committee [Ul]which discussed all data for the chronically irradiatedrodent and summarized these in one graph [M 13] (seeFigure XIV). The percentage mean survival time wasplotted versus the gamma-ray or the fast neutron

GAMMA RAYS

-

10

OJ

R/WEEK
100

1000

100

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FAST NEUTRONS - 10-z GY/WEEK

Figure XIV. Mean survival time expressed as percentage of the control
survival, as a function of the weekly dose or exposure to fast neutrons
or gamma rays. The gamma and neutron scales are In the ratio of 1 : 13.
The symbols refer to different sets of data obtained on mice, rats andguinea-pigs by various authors, plotted by Mole [M13] and Included In
the UNSCEAR 1958 report [U1], as follows; t,, and "v [H7); 0 and x,[L6]; D [E3]; • [N3]; • and e, Neary et al., unpublished observations,+ J. F. Thompson et al., Am. J, Roentgenol. 69: 830-835 (1953)

exposure or dose rate. The data appear to be superimposable when the gamma- and neutron-scales were in
the ratio of 1 :13. From this it was deduced (in spite ofsome uncertainties in the comparison of data fromdifferent laboratories) that the RBE between fission
neutrons and gamma rays applicable to life shortening
in the rodent for chronic exposure was about 13. A
study of x rays (250 kVp. 1.85 Gy min-1) and of fastneutrons (fission spectrum, 2.7 108 neutrons cm-2 s-1)
was performed in CFl female mice by Curtis andGebhard [Cl 7) following single or fractionated irradiations. The RBE for life shortening was estimated at 1.7.
These results are difficult to interpret not only for thelack of an increase of RBE with fractionation. but also
for the low RBE value of the acute exposures.
191. When straight lines were fitted to the data ofUpton et al. [US] on LAFl mice irradiated withgamma rays or fast neutrons from a nuclear explosion,very similar RBE values of 2.1 and 2.3 were obtained inmale and female animals. respectively. Mole andThomas [M7] estimated the RBE of fission neutrons
against 60Co gamma with the same source of radiationand the same animals as reported previously [Nl, N3.
M13]. The life-shortening effects of about 0.16 Gy per
week of fast neutrons or of 210 and 110 R per week ofgamma rays were found to be equivalent both for terminated and for duration-of-life exposures. For all levelsof response the neutron data were intermediate between
the effects of these two intensities of gamma rays andnearer to those of the 110 R per week. The RBE wastherefore estimated to be between 13 and 7. but nearer
to the latter figure.
192. In a subsequent paper by the same group [N8] theRBE value was discussed for CBA mice chronically
irradiated with fast neutrons as described in [N3]. The
dose rates of the 0.7 MeY neutrons were 0.02 Gy d·l or
0.003 Gy d-1. Gamma irradiations were run al 0.16 or
0.023 Gy d-1. Complete life-table data and cumulative
survival curves were obtained in replicate experiments
and several forms of dose-response curves were postulated to fit the data. RBE values around 10 were found,with a range of estimates between 8.6 and 15.0,
according to the assumptions made. The data were
thought to be inadequate to establish whether or not theRBE depended on the level of daily exposure.
193. The RBE of thermal column radiation,
composed of thermal neutrons and hard gamma rays,
was tested against 250 kYp x rays in experiments by
Storer and Sanders [S 17] performed on Swiss white
mice. Since the neutron and the x-ray data could be
fitted by a common linear non-threshold regression of
per cent life shortening versus dose. the RBE had avalue of unity. In another series, Storer et al. [SIS]
exposed CFl female mice to neutrons or to mixtures ofneutrons and gamma rays from an atomic weapon. The
relative effectiveness of the neutrons was calculated tobe 2.6 ± 0.9. In both series the RBE values for life
shortening were in close agreement with those obtained
for the production of acute effects.
685194. In experiments by Vogel, Frigerio and Jordan[Vl] CFl female mice were exposed to daily doses offission neutrons or gamma rays at dose rates of about
0.044 and 0.13 Gy min-t. respectively. Groups ofanimals were given 13 brief exposures, each corresponding to 0.022 to 0.7 Gy d-1 of neutrons and 0.065 to
2.08 Gy d-1 of gamma rays. The neutron RBE was notincreased over the figure of 2.8 previously obtained for
acute single doses. Other experiments performed with
13 brief exposures of the two radiations given at 0.1 Gy
min-1 indicated an RBE for median survival time of
2-3. in fairly good analogy with the figure of 2.8 for theLD50130 after single exposures.
195. Curtis. Tilley and Crowley [C19] reviewed theliterature data on life shortening clue to acute or
chronic irradiation of mice with x rays or neutrons.
They concluded that acute gamma doses could be up to
4 times as effective as chronic closes. For neutrons equal
efficiency by acute and chronic exposures was the mostcommon finding. Accordingly, the neutron RBE of
about 2 for life shortening by acute doses may increase
to about 8 for chronic treatments. Chromosome
damage in the liver of animals was shown to behave
similarly and these data were thought to provide some
cellular basis for the differential action of low- andhigh-LET radiations. The data on chromosomes werealso interpreted to indirectly support the hypothesisthat mutations in somatic cells may be at the origin of
natural and radiation-induced aging.
196. Sixteen-week-old female CFl mice received 1 Gy
per week of fission neutrons for 4 weeks at dose rates of
0.01, 0.03. 0.06. 0.35 Gy min-1; or 2 Gy per week of
60Co gamma rays at the same dose rates [V3, V4]. In allgroups thymic lymphoma was the main cause of deathand its incidence was not significantly affected by thedose rate. On the basis of mean survival time or ofmortality curves, life time was reduced by about 65% by
neutrons and by about 50% by gamma rays. The
neutron efficiency was therefore higher than that of the
gamma by more than a factor of 2. The mean survival
times of both neutron- and gamma-irradiated animals
were significantly shorter with 0.35 than with 0.01 Gy
min-1.
197. Vogel and Jordan [V5, V6] compared the lethalityof fission neutrons produced by a CP-5 reactor to thatof 60Co gamma rays, both radiations being delivered atabout 0.01 Gy min-1. CFl female mice were exposed
according to a complex pattern of fractionation inwhich 13 weekly doses of 3 Gy of gamma rays weredelivered as 1. 3 or 6 equal fractions per week. Since thearbitrary RBE value chosen was 5. the corresponding
total weekly dose of neutrons was 0.6 Gy, delivered into
1. 3 or 6 fractions per week. The data showed that thepostulated RBE of 5 was too high. Upton. Randolphand Darden [UIOJ reported that with fast neutrons thelife expectancy of RF female mice was shortened by 80days per Gy, irrespective of dose rate. whereas the lifeshortening efficiency of the gamma rays decreased
from about 30 days per Gy at 0.07 Gy min-1 to about 15
days per Gy at 0.05 Gy d-1. The RBE increased
therefore with decreasing dose rate from about 2.7 to
5.4.
198. In the experiments of Upton, Randolph andConklin [U7] variable dose rates of x and gamma rays
(0.80 to 0.01 Gy d-1) and of fast neutrons (0.11 to 4 10-5
Gy d-1) were administered to RF mice. There were alsogroups treated at about 1 Gy min-1 of both radiations.
Gamma rays at the low dose rates were invariably and686

consistently less effective than at the high dose rates.
Neutron effects, however. showed less dependence on
the dose rate. The RBE evaluated on the basis of theaverage life-shortening effect (days/unit dose) was
about 3 at high dose rates and it increased to about 8
for terminated chronic irradiation. When exposure
continued until mortality reached about 50% of themice. a further increase of the effectiveness to about 14
took place. Without knowledge of the dose rate to RBE
relationships it was impossible to foresee whether
higher RBEs might be found at even lower dose rates.
Similarly, it was impossible to predict any trend atdifferent neutron energies. However, since 5 MeV
neutrons (from a Po-Be source) were essentially aseffective as the 1 MeY cyclotron-generated neutrons inspite of the much lower dose rate (3 I0-8 to 1 lo-4 Gy
min-t as opposed to 0.85 Gy min-1) it was felt thatneutrons of still higher energy might prove Jess
effective.
199. Clapp et al. [Cl2) published an experiment inwhich the effects of acute doses of 300 kVp x rays (0.5
to 4 Gy) were compared with those of 60 MeY protons(0.47 to 3.72 Gy). Irradiation conditions were such thatcomparable LET values were obtained. The protonmean LET was estimated to be approximately 1.5
keY /~Lm within the animal's body. As expected on thebasis of LET considerations, the protons RBE was 0.63
for life shortening and slightly less than 1 for allparameters, excluding the induction of ovarian
tumours. Thymic lymphoma, myeloid leukaemia andovarian tumours were increased significantly byradiation, while other alterations in the incidence andseverity of diseases were minimal by comparison with
non-irradiated mice. An RBE of 1.0 or slightly lesswould thus be applicable for most pathologicalparameters examined.
200. The experiments of Ainsworth et al. [A7] showed
differences in the shape of the dose-response relationships which were linear with gamma rays and convex
upwards with fission neutrons. The RBE was therefore
dose-dependent. On the basis of more recent data fromthe same series [T4] the RBE for both single andfractionated exposures varied inversely with the squareroot of the neutron dose over the range of doses
covered by the experiments. It was predicted that,
depending on the method of calculation. the RBE at
0.01 Gy of neutrons would be 2&-33 in male and 40-44
in female animals, for single exposures. For
fractionated treatments the extrapolated RBE values
would be 62-91 in males and 41-79 in females. Experiments are presently in progress to test the validity ofthese predictions. For duration-of-life or long-term
fractionation exposures the RBE might be between 60
and 120 ~t 0.0005 Gy of neutrons per week. varying
inversely with the -0.4 power of the neutron dose [T5].
201. The RBE of fission neutrons for life shortening.
relative to mes gamma rays varied in the experimentsof Ullrich and Storer [U8. S44] according to dose level.
In the RFM female mice treated at high dose rates thetwo-component nature of the gamma-ray relationshipproduced RBE values increasing for progressively
lower doses as the inverse of the square root of the dosein the dose range below 0.5 Gy. Such a trend would be
predicted by the dual radiation action theory of
Kellercr and Rossi [K 1OJ. At doses above 0.5 Gy the
RBE estimate (based on the ratio of the slopes of thelinear regressions fitted to the gamma-ray and neutron
experimental points) was 2.9. This value was similar tothat observed within the same range of doses on the

BALB/c mice (3.0). In the experiments of Hulse [H18]on rabbits the RBE of fission neutrons was assessed at
3.5-4.0 for longevity.
2.

Conclusions

202. The RBE experience on lire shortening refers
essentially to neutron irradiations in the mouse. For
acute doses in the region or a few tenths to a few Gy ofx and gamma rays (and equivalent doses of neutrons)
RBE figures of 2 to 3 have generally been found. The
evidence reviewed shows some increase of the RBE
upon short fractionation courses and with decreasing
dose rate down to hundredths of Gy of neutrons per
day to figures of about 5-6. More consistent changes
are found for extremely long courses of irradiation
where RBE values of between 9 and 15 are quoted.
203. From the Committee's analysis of the mouse data
in Figures II and III the RBE values that can beobtained for acute single doses of neutrons by pooling
all available experience would differ at different doses.
For acute doses of neutrons in the region of 0.01 Gy theR8E cannot be determined precisely from the data
reviewed. The predicted values might be about 10, butvalues as high as 50 might be possible. depending on
the assumed shapes of the dose-response curves.
204. The average RBE values applicable to exposures
for the duration of life may be obtained from acomparison of the curves as a function of the dose rate
shown in Figure IX. At 50% life shortening the neutron
dose rate that would give the same effect as the x andgamma rays would be about 10 times smaller than thatof the gamma rays. At dose rates corresponding to 0.01
Gy d-1 of low-LET radiation (and proportionately
lower neutron dose rates) the effectiveness of theneutron treatment would increase to about 40. Alternatively, the RBE as a function of total accumulated dosemight be calculated from the curves in Figure X where
the RBE values applying to different levels of effectwould be, between 10 and 20. It may be concluded that
the RBE values derived in the mouse by the
independent and comprehensive review of theCommittee are in fair agreement with those that may bederived from the analysis of the single experimental
series discussed in the preceding paragraphs.

E.

SPECIFICITY OF LIFE SHORTENING

205. After the overall quantitative analysis in thepreceding paragraphs. it is appropriate to review the
problem of the specificity or non-specificity of theeffect. Such a discussion presupposes the availability ofexperimental series with careful pathology of theanimals at death or serial sacrifices to investigate thedevelopment of the pathology of aging. Experiments
reported of this kind are very few and even when
pathology is reasonable, any direct comparison withsurvival is made impossible by the presentation of thedata. Therefore, the present section will be essentiallyqualitative. It will be based on the conclusions of theauthors themselves which are often unsatisfactory
owing to inadequate pathology (mostly macroscopic) or
to insufficient statistical analysis. In other cases theconclusions of the experiments were biased by themodels of action assumed in the interpretation of thedata. However, in the absence of the original data, nobetter treatment of the subject matter is possible:

206. It was mentioned in the introduction on methodology that the usefulness and precision of the lifeshortening data is often limited by the fact that
increased risk from one life-shortening disease may beoffset by the decreased risk for another. Unless efforts
are made to establish the causes of death, information
concerning the relative importance of disease states will
not be obtained and the existence of mechanisms ofdeath over and above those attributable to the diseases
normally occurring in a given species or strain will not
be proven. Identification of disease states at death or by
serial sacrifice is in itself a difficult task, but it is preliminary to an appreciation of the relative significanceof disease states. The relevant problems, particularly inrodents and in relation to life span studies. haverecently been reviewed [ H 19).
207. It is easily appreciated that the quality of thepathology and its capacity for resolving different
diseases will to a great extent condition the share of thenon-diagnosed causes of death in a given experiment.
In order to achieve good resolution. the pathologist
should have experience of the animals used. Without
going into details. it is well known that each species andstrain of experimental animals dies with a characteristic
set of pathological conditions. Data referring to themost common species of laboratory mouse [G19], rat[FIO, W6. 826]. rabbit [W7], dog [A14] and otheranimals [825) may be found in reference publications.
The variety of pathological conditions is very wide andtheir incidence extremely variable in each case. Most of
the experience available on life shortening is in themouse. where the variability of diseases between species
is by now well documented. From an intercomparisonof results in animal strains having different pathological characteristics an insight may be gained into themore general aspects of the life-shortening action.
208. Although the diagnosis of a given disease--(~combination of diseases) in an animal is founded on
objective criteria, the assessment of its significance tolife shortening is to a large degree subjective, in that it
requires an evaluation on the part of the pathologist as
to the capacity by a given disease to produce death inthat particular case. In principle one can think of anumber of chemical and clinical examinations
performed before death to aid in the diagnosis, but insmall animals such as the mouse these cannot be carriedout. Therefore, even under the best conditions ofmacro- and micro-scopic analysis. 20 to 30% of theseanimals die without an apparent cause. For them it may
be assumed (but, of course. not proven) that death isdue to true aging or physiological senescence [H19].
209. Once the pathological analysis has been
performed. the actuarial data must be interpreted in thelight of its results. In theory, correlation of the time atdeath with the occurrence of any specific disease makes
it possible to assess in a given population the contribution of each nosographic entity to life shortening.
Specificity or non-specificity of the life-shortening
effect is essentially judged on these criteria. In practice,
however, it should be emphasized that the occurrenceof multiple disease conditions, particularly in old
animals, and the problem of competing causes of death
make this exercise difficult. It may not in fact be
expected that the precision of the combined pathological and actuarial analyses may be higher than the
resolution attaching to any of the two methodologies.
210. It is commonly reported [G4, S19. C12. L9] that
correction of the data for animals dying of leukaemia
687

and of ovarian tumours, which are very common causesof death in the mouse, leads to a reduction of the large
variability of the effect between strains and sexes and toa reduction of the life-shortening efficiency of theradiation treatment. This indicates that at least part of
the reduction of lire after irradiation must be attributed
to tumour induction.
211. The first large experimental series where
pathology was of such a quality to allow analysis of
specific death causes was that of Upton et al. [U5]. The
authors could establish no clear-cut relationshipbetween shortening of life and incidence of tumours as
the dose relationships for tumour induction had
variable forms; some neoplasms increased and somedecreased with increasing dose. These data gave
impulse to the idea that radiation may cause nonspecific aging by advancing all diseases by about thesame degree for each given dose. However, a more
recent re-evaluation by Walburg [Wl], by a statisticalmethod allowing for competing probabilities of death,justified the conclusion that life shortening, which was
clearly apparent when all death causes were considered
together, disappeared when tumours were excluded
from the analysis.
212. Another set of data that was held to support thenotion of non-specific life-span shortening was that byLindop and Rotblat [L2]. The main conclusion of theseinvestigations was that life shortening was due toadvancing of all causes of death with respect to time.
without change in the relative probability of each cause.
1t would be of interest to reconsider these data with amore refined statistical test [H2] in order to assess thereliability of the conclusion. This is particularly true as
the pathology and the statistics of this experiment havebeen criticized [Wt]. The authors did recognize differences in the relative times of onset of the diseases
between control and irradiated animals. One may
wonder therefore how these data may have been interpreted, as they were then and later, to support theexistence of a non-specific effect of aging.
213. Storer in his 1965 [S20] series noted in the rangeof between 100 and 500 R of x rays a tendency of theneoplastic diseases to occur earlier in irradiated than incontrol mice. In the large series of Upton et al. [U7] andUpton, Randolph and Conklin [U9] microscopic
pathology was not performed as a rule, but the qualityof the macroscopic examination of the animals at death
was quite good. The authors felt that the death ofirradiated animals was characteristically associatedwith tumours and degenerative diseases of old age, butthat neoplastic conditions could not entirely accountfor the reduction of life. When some of these data werereassessed by Walburg [Wl] with more refined statistics.
the life shortening in the irradiated mice was negligible
if the tumour deaths were excluded, at least in the dose
range of 1 to 3 Gy of gamma rays. This indicates thattumours did contribute substantially to life shortening.
Similarly. Darden et al. [Dl] and Walburg [Wl]ascribed to thymic and myeloid leukaemia most of themortality increase observed in RF mice irradiated.
respectively, with neutrons and with x rays.
214. Grahn, Fry and Lea [05] ascribed to excess
tumour mortality the life shortening observed up to
about 4 Gy, while at higher doses the decreased life
expectancy was not accompanied by a parallel increaseof tumour incidence. Maisin et al. [MIO] on BALB/cand C57BL mice attributed life shortening at doses
below the LDso130 essentially to thymic lymphoma and,688

at higher doses, to glomerulosclerosis. Similarly,
malignant tumours at the low doses and glomerulosclerosis at high doses were identified by Metalli et al.
[M9] as the main causes of premature death inirradiated mice. In the experiments of Lamson. Billings
and Meek [L3] and Lamson. Billings, Ewell andBennelt [L5] acceleration of tumour appearance andnephrosclerosis were associated with life shortening in
the rat; and the same was true for the dog in the seriesof Andersen and Rosenblatt [A2]. according to the reanalysis of Walburg [Wt].
215. Concerning duration-of-life exposure, the paper
by Grahn. Fry and Lea [05] contains a comprehensive
discussion of the problem of specificity, based on datafrom different mouse strains. According to thisanalysis. the increment in long-term mortality at
exposure rates up to a few R per day is associated withan increment of the neoplastic deaths which canentirely account (both as increased incidence and as
accelerated appearance) for the relevant reduction oflife. At exposure rates above 6 R per day an excess
mortality from non-tumorous conditions becomesapparent. It should be added that data up to the present
from the Argonne series on the life time irradiation ofdogs are in agreement with the above conclusion.
216. Thus, the vast majority of data on rodent andnon-rodent mammals, irradiated with sparsely- anddensely-ionizing radiation and with acute or chronic
doses. when properly analysed. appear to be consistent
with the following conclusions. The life-shortening
action observed on animals surviving the acute effectsof irradiation. that is. after low-to-medium doses up to
about the LDso130, may be essentially accounted for byan acceleration or an increased incidence of neoplastic
conditions resulting in the premature death of someanimals. From doses around the LD50130-but progressively more so at higher doses-other pathologicalconditions may also advance or accelerate death andamong them the vascular changes leading to organ
fibrosis. particularly of the kidney. have been describedon irradiated animals. Atthese dose levels deaths fromother non-stochastic effects described in Annex J would
be expected. The hypothesis of a general deleterious
action of radiation formally analogous to aging could,
in principle, be entertained and, if so, it could not bedisproved. However, if non-specific life shortening isviewed as an advancement in time of diseases normallyassociated with senescence without apparent changes inthe spectrum of these diseases, no data are found tosupport such a concept. The notion of non-specificaging, based only on actuarial analogies and on superficial resemblances between irradiated and aging
animals. cannot be substantiated by accurate
pathology. Particularly at the low doses and dose rates
of interest in radiation protection there appears to be
no need to invoke any general non-specific noxious
effect, because all the experience on animals does not
require to postulate any other effect than tumour
induction or acceleration to explain the reduced life
expectancy observed after irradiation.

II.

THE EFFECTS OF BIOLOGICALVARIABLES

217. Jn this chapter the biological variables affecting
the life-shortening response to irradiation are reviewed.
The data refer to the genetic constitution of the animal
species or strain, a major determinant of the response;to the effects of age al irradiation, both in the intra- andin the extra-uterine life: and to the differential effect onmale and female animals, because special physiologicalconditions or the expression of peculiar diseases in thetwo sexes may result in a variable amount of life shortening induced by a given dose. The effect of partial
versus whole-body irradiation is considered in Section
111.D. with other modifying biological conditions.
A.

GENETIC BACKGROUND

218. Among the genetic variables, the inter-species
and intra-species differences should be consideredseparately. In the first case. the object of the analysis is
to establish a scale of sensitivity with respect to life
shortening between various mammals, analogous tothat repeatedly attempted for short-term survival (foran extensive discussion of these problems in relation to
the acute radiation syndromes, see [Bl8]). In thisconnection the problem of data extrapolation to otherspecies may be discussed. In the case of intra-species
comparisons. the problem is that of analysing thecharacter and the amount of life shortening in genetically different strains of the same species, in order tocorrelate the degree of radiation effect with some vitalcharacteristics of the strain, such as longevity, agespecific rate of death and spectrum of spontaneous
diseases. These experiments have been carried out so
far in the mouse for the availability of inbred animals
in large numbers and the relative ease of obtaining
crosses of inbred genotypes.
1.

Inter-species differences

219. It is well known that a large variability exists
among various animal species in respect to life span
and tumour incidence [825). The finding of a correlation between these two variables across various
species might in principle be of help to put generalizations in the field of radiation-induced life shortening ona firmer basis. However, in view of the disease
spectrum peculiar to each species. it can also be argued
that generalizations not accounting for specific pathological characteristics would have heuristic significancebut little practical value.
220. Attempts at inter-species comparisons in relation
to life shortening with the objective of a projection toman. were discussed and proposed repeatedly. An
approach based on the actuarial Gompertzian analysis
of survival parameters was first put forward as aworking hypothesis by Brues and Sacher [Bl]. They
envisaged that if the linear dependence of the log
mortality rate on age (see Figure I) may hold for
mammalian species of different life span, a common
origin for the curves and a time-scaling factor may bechosen in such a way that actuarial functions belonging
to various species may be made identical. Calculationsof this kind using empirical constants obtained on miceand dogs indicated that in the absence of any recovery
function the exposure of man to a continuously
accumulated tolerance dose in use at that time (0.3 R
per week) may decrease the human expectation of life
by 10%.

221. On the basis of experiments by Henshaw (Hl].
Boche [BJ 1) identified in the parameter a (the excess
death rate per week divided by the exposure level in R
per week for chronic irradiation experiments) thequantity that would be invariant for each species andmight therefore allow inter-species comparison,because it expressed the susceptibility of that species tochronic radiation action. Based on the value of such a
constant, Boche attributed about equal sensitivity to therat. the dog and the mouse, a higher resistance to therabbit and a higher susceptibility to the monkey.

222. Lorenz [L7] summarized the effects of longcontinued whole-body irradiation of mice. guinea-pigs
and rabbits. He accepted essentially the radiosusceptibility scale of Boche [811) and discussed the problem of
extrapolating the findings to man. He concluded thatman should be considered to be as sensitive as the mostsensitive animal found experimentally and on this basis
proposed that an acceptable whole-body exposure
might be 0.1 R per 8-hour day. Such an approach wascriticized by Mole [Ml3] who pointed out the relativityof the criterion and the fact that extrapolation fromanimals to man required sufficient evidence of thesimilarity between man and other animals. to giveconfidence to the process of filling the gaps in our
knowledge of human effects with experience on othermammals. Mole considered that in the absence of asatisfactory theory, efforts to define a relationshipbetween daily dose and life span for survival times ofthe order of 95% or higher of the control values werehardly justifiable. On the other hand, it is only in thisregion of effects that extrapolation is of any interest.
223. In 1955 Sacher [Sl] examined the evidence
available on seven animal species (rabbit. rat. mouse,monkey, dog, burro, guinea-pig) treated with various
acute or chronic doses and deduced for each species acumulant lethality function (see section LB.) describing
the course of injury according to a given set of
reasonable hypotheses. Regarding short-term lethality.
the conclusion was that the most and least sensitive
species investigated differed by a factor of about 10 inthe steady-state or plateau values of their cumulant
functions, while intra-species differences were within afactor of 4. However. the evidence available forlong-term mortality showed considerably less species
variation.
224. Blair [B4] and with him the 1958 UNSCEAR
report [UJJ by plotting together rat and mouse lifespan-shortening data after acute irradiation andshowing their good agreement on the basis of units of
LD5-0no, implicitly recognized the existence of somerelationship between acute and chronic survival
response in these two species and the close similarity of
their susceptibility to the Jong-term lethal action ofchronic irradiation.
225. Bochc's hypothesis [B1 l) that a given dose might
produce the same proportional life shortening indifferent species has represented the basis of many
attempts to derive life shortening per unit dose in manfrom laboratory animal data. The values proposed
varied from 1 to 5 d R-1 [Nl). In Neary's model [Nl) if
the percentage life shortening per unit dose equivalentis taken to be the same for man as for the mouse, theabsolute life shortening for the two species would be
calculated at 8 d Sv-1 of chronic radiation. Thus, aperson accumulating what was at the time a maximum
permissible life-time dose of 2 Sv would suffer a life
shortening of 16 days. instead of the figures of up to
one year calculated on Boche's (811) assumptions.
226. Spalding et al. [S21] attempted extrapolation ofdata obtained from mice that had been exposed toacute 60Co gamma doses (1.1 to 12 Gy). They found689

that if a mouse-to-man relationship of 1 day to 1 month
may be assumed, similar conditions of exposure in man
may be expected to cause a reduction of the mean aftersurvival time of 900 to 1000 days per Gy of gamma-ray
exposure.
227. Grahn and Sacher [G 1] based their extrapolations on the linearity of the log mean after-survival indays as a function of daily radiation in rad or R, formean after-survival of 25% or more of the control
values. This linear trend of the mean after-survival waspreviously shown to hold for the mouse [S4J (see Figure
XV). The coefficient of this regression is a species

So

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Figure XV. A plot of log mean after-survival as a function of
dally exposure according to equation 5 1 S0 e-k D where
5 0 Is the survival and 5 1 the survival at dose rate I. The
values of k and S0 are shown for mammalian species. Data
from Grahn and Sacher [G1]=t.:onst.int (G9] and i~ related lo the days of life lost perunit dose or the fraction or life lost per day. It may
therefore allow one. when two points referring to agiven species are known. to define the slope of thecurve applying to that species. The ratios of the coefficients of regression would then be related to the ratiosof life expectancies for non-irradiated populations or to
the ratios of the age-specific mortality rate slopes. A
radiosusceptibility scale may thus be constructed forman. dog. guinea-pig and mouse, on the basis of theslopes being in the ratio of 33:10:3:1 for life expectancies of 16 500, 4000. 1400 and 500 days, respectively.
It may therefore be deduced that the relative sensitivityof the various species (expressed in per cent life shortening for unit exposure) was approximately the samefor all species and in the ratio of: mouse = 1;
guinea-pig = 1.8; dog = 1.25; and man = 1. Similar
conclusions were also drawn by Sacher [S23, S14].
228. Grahn [G6] explored the problem of inter-species
comparison further, starting from the notion of the690

exponential decline of mean after-survival with daily
dose, which has been mentioned repeatedly (Figure
XV). By comparing the vital statistics of two selected
populations of male men and mice, he established thatthe ratio of time scale to equate the two populations is
10 mouse days = 1 man year, or 1 mouse day = 36.5
man days, a factor slightly higher than he previously
used (33:1) [Gl] and much higher than that used by
Failla et al. (20:1) [F4]. In consideration of these otherestimates Grahn selected a ratio of 1 :30 for his calculations and established that the daily exposure to induce
a 50% reduction of life expectancy in man was 0.65 R
d-1. compared with a 19.4 R d-1 in the mouse. Calculations for man and for other species showed that theguinea-pig was a relatively sensitive species in aframework defined by the mouse, dog and man. Itshould be pointed out that the life span and radiosensitivity values used for these calculations are very muchat variance with those in the I 968 paper by the sameauthors [Gl] and therefore the relative sensitivity scales
in the two papers do not correspond.
229. Mole [M2] discussed in general terms the
problem of extrapolation between species. He notedthat experimental investigations are of value when theylead to quantitative generalizations that must include
within themselves some allowance for any species
difference. Mole mentioned three possibilities in thisrespect: the opacification of the lens of the eye. which
may be inversely related to the body size or to the sizeof the eyeball: the susceptibility to the induction ofbone tumours, which may be equal in all mammals;
and the radiation sensitivity of mammalian oocytes,
which may be inversely related to the metabolic activity
or to the degree of lampbrush configuration of thechromosomes. Generalizations of such specificbiological phenomena, rather than extrapolation of
abstract matters such as mortality or life shortening
should particularly be pursued. He further expanded
these concepts [M3] and pointed out that in principle
life-span shortening may be considered to be ameaningful parameter . only when the spectrum or
diseases in different animal populations receiving
various doses is the same. In the absence of thiscondition, life shortening becomes simply acompounded but imprecise way of expressing differences in the incidence of pathological conditions thatmight be more adequately expressed otherwise.
230. An inter-species comparison of response in mice
[S4, G6] and dogs continuously exposed to 60Co gamma
rays was reported by Norris, Tyler and Sacher [N7]. It
was found in both species that plotting the log of theradiation-specific death rate (i.e .. the difference of thereciprocals of survival times for the exposed and thecontrol animals [S14, S29], see also Figure VIII) against
the log of the dose rate gave rise to a dose-responsewith a slope of 2, indicating that the excess mortality
increased with the square of the dose rate (Figure XVI).
The phenomenon was seen over the whole range ofdose rates in which damage to the haemopoietic tissues
is the primary cause of death, that is above 0.2 Gy d-1 inthe mouse. At lower dose rates in this species the slope
was 1. indicating that injury was only a function of thetotal dose accumulated and independent of the rate at
which it was given. Data available in the dog would
suggest a similar inflection taking place below 0.035 Gy
d-1, but this suggestion will have to be proven byappropriate experimentation. The only point available
for dogs below 0.01 Gy d-1 [Cl6] lies quite close to thecurve for the mouse having slope of 1, which would bein favour of a roughly similar sensitivity of the two

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DOSE RATE (10-z GY/DAY)
Figure XVI. A comparison of radiation-specific death rate In dogs andmice under duration-of-life exposure, as a function of the daily doserate, Data from Norris et al. [N7]species at the level where injury becomes independentof dose rate.
231. Grahn, Sacher, Lea et al. [G16] returned again to
the problem of extrapolation from mouse to man on theassumptions [G6J that: the Gompertz slopes for mouseand man are in the inverse ratio of their susceptibility;
the previously-mentioned ratio of 30:1 for mouse:man
applies; and the ratio of slopes or the slope
displacement has an identical relationship to the
reduction of life expectancy in both species. They thus
calculated that 2_5 Sv (i.e .. 0.05 Sv a-1 which is thepresent limit of dose equivalent for workers x SO yearsof working life) given chronically over a very long time
would produce 15 days of life shortening for an average
100 day-old mouse and about 1S months for the
average 20 year-old man.
232. At the same time Sacher, Tyler and Trucco [S50]extended their observations to 15 species of mammals
from the orders of Carnivora, Arctiodactyla andRodentia. exposed for the duration of life to gamma
rays. The survival data analysed in terms of theradiation-specific death rate showed that for all species(with the exception of the black rat) the death rateincreased as the square of the dose rate up to a breakpoint above which death rate increased linearly withdose rate. A log-log plot of the co-ordinates of the
breaking points showed a linear relationship, indicatingthat the species variation to chronic irradiation is due toa single parameter. A mathematical model based on the
induction of' cytogenetic damage was compatible withthe findings and suggested that species susceptibility tocontinuous exposure could be related to an accumulation time for damage leading to chromosome breaks.
At this level of analysis the actuarial parameters could
be linked with the study of molecular lesions as
discussed in ''Mechanisms of ageing and life shortening" although filling the gap between the two
approaches requires clearly much confirmatory work.

2.

Intra-species differences

233. It is important to realize that a very large variability exists between different strains of the same
species with respect to longevity and the incidence ofleukaemia and tumours. Systematic data are available
on rodents on differences in the life span and tumour
incidence between inbred and hybrid strains. Life spanin female mice may differ between strains by nearly afactor of three and in males by more than a factor of
two [S56]. In 7 inbred strains the incidence of total
tumours ranged from 7.3 to 44% in males and from 25
to 55% in females. Variability with regard to specifictumour types may be even higher, some strains notshowing some tumour types at all [S55). In rats very
similar conclusions apply [A12. M30]. This extreme
variability points, on the one hand. to the difficulty ofgeneralizing findings in a given strain. On the other
hand, the variability makes a given conclusion verysignificant if it holds in spite of strain differences.
234. The oldest contribution to the problem of strain
differences in the response of mice to Jong-term
radiation effects is that of Gowen [G8]. He studied two
strains. the S mouse with a medium longevity and the
Ba mouse with a long life span. Upon irradiation in thecourse of a nuclear test the S mice were shown to beconsiderably more resistant than the Ba ones and thispattern of response was similar to that observed after 98
kVp x-irradiation (exposures of 20 to 960 R). There
were no good pathological observations reported, andit was argued that the resistance of the S strain to
Salmonella might at least partly account for the differences observed, although the full basis of the radioresistance of these mice was thought to be more complex.
235. Grahn [GlOJ reported on the chronic lethality offive mouse strains: BALB/c, A/Jax, A/He, C3Hl/He
and C57BL/6. The survivors of single 200 kVp x-ray
acute exposures (400 to about 700 R) were kept for691

analysis of late effect. Weighted regression lines of life
shortening versus dose showed no significant differences between the strains in either sex, although females
were more sensitive per unit dose. There was no correlation between life-sran reduction and control life
expectancy, although such a relationship could beshown in respect to LDsono, In a second series daily
60Co gamma exposures were tested at 11 exposurelevels between 220 R d-1 and 6 R d-'. covering the fullrange from acute to chronic responses. Partial datafrom crosses of BALB/c x C57BL/6 were also
included. Preliminary data showed strain differences atall exposure levels; survival times were quite variable
between strains but closely rcnected genetic differencesin control survival. The greatest life-shortening effectwas seen in strains with a high incidence of leukaemia.
236. The conclusion of a more relined analysis of theabove data [G4] was that all genotypes exhibited aradiation-induced life-shortening effect dependent on asingle common primary injury parameter. For acuteexposures the parameter could be expressed by the
number of days of life lost per unit exposure, equalling
0.28 days R-t. This parameter could then be combinedwith others to give equations predicting the life shortening for any combination of normal life expectancy,
dose, and incidence of neoplastic conditions. Aftercorrection for leukaemia and ovarian tumour
induction, life shortening for both sexes following
exposure to 570 R was 111 days and exposure to thesame LDso130 caused a constant proportion of life lostamounting to 19%. In duration-of-life experiments
mean survival time and mean accumulated dose varied
directly with control survival and therefore at eachexposure rate strains having different control survival
lost the same proportion of their life expectancy. With afew exceptions, the mean accumulated dose and theacute LDso130 were shown to he related to each other inthat each had a common relationship to the normal lifespan.
237. Gowen and Stadler [Gl l] published also a large
series of experiments in which ten different mousestrains (four pairs for each genotype) were initially
exposed from mating to death to 60Co gamma-irradiation (0.6 to 2.7 R d-1) for 22 hours per day. The design
and the analysis of this research, although involving
irradiation for the duration of life, was centred more on
the capacity of irradiation to stop the reproductivefunctions of these mice, than to shorten their life span.
238. Other analyses by the Argonne group [S5, G9]contain comparisons of the relative life-shortening
effect of 60Co irradiation to death in geneticallydifferent mouse strains and indicate the constancy ofthe slope of the relationship expressing the log mean
after-survival against exposure rate. The linearity of thisrelationship over the exposure rate range between zeroand 56 R d-1 was established for BCFl, C57BU6,BALB/c and A/Jax male and female mice [SS]. thus
confirming previous findings with the LAFl mouse[S4]. The control survival of the male and female miceof the 4 genotypes cited (8 groups in total) ranged from466 to 796 days and these differences in life span curves
were nearly parallel and were displaced from one
another by the same amount of displacement of thecontrol survival times.
239. The problem of the genotype relationship to
long-term survival has also been considered by Hollandand Mitchell [HlO] who irradiated (300 R. 300 kVp xrays) 4 strains of male and female inbred mice692

(C3Hf/Wg, C57BL/6, RFM/Un, BALB/c), C3CF1
and B6FRMF1 hybrids and a cross between these two
hybrids, C3CB6RFM. Females were shown to be, in
general, more sensitive than males by a factor of 1.5.
Within the same sex, substantial differences in sensitivity were also shown among strains. As these differences correlated well with lhe weight of the animals, it
was suggested that the variation in susceptibility to life
shortening may be at least partially accounted for by
genetically-determined differences in the maturation
rates of the various genotypes. After fission neutron
irradiation at both high (0.25 Gy min-1) or low (0.01 Gyd-1) dose rate no appreciable difference in life shortening was found between RFM or BALB/c female
mice in the experiments of Ullrich and Storer [U8].
240. Life tables for different strains of inbred andhybrid mouse strains have been reported, with data onlife expectancy for parental, Ft F2. F3 and the first
three backcross generations [G 17). These data refer to
non-irradiated animals. but they could be used inradiation work on the basis of the repeatedly citedinvariant life-shortening relationships with dose
common to all mouse genotypes (4 days per Gy or 28
days per Gy for life-time and single acute exposure,respectively [G4)). In another paper Storer [S57)reported life table data on 9 inbred and 5 hybrid strainsof mouse. non irradiated or exposed to 250 or 450 R of
250 kVp x rays. All these data may be regarded as
initial attempts to a genetic analysis of the radiationsusceptibility to life shortening in mammals. Suchattempts must however be improved considerably inorder to clarify the simple relationships of the kind
mentioned above and how these may be translated intoa variety of disease states in different mouse genotypes.

B.

SEX AND BODY WEIGHT

241. Very often in the course of the papers reviewed
mention is made of differential effects in the two sexes
for various strains of animals. To review all these observations separately is probably unnecessary as in manycases they are incidental and not particularly relevantto the main physical or biological variable discussed ineach specific paper. In this section only those papers
are reviewed where such effects were particularly wellsubstantiated and discussed. Emphasis is given tocontributions where pathological observations were
performed. in an effort to ascribe the differential effects
to diseases or conditions affecting preferentially one of
the sexes.

I.

Sex

242. In the experiments of Neary et al. [N3] the mean
survival time of the female animals was significantly
greater (P < 0.05) than that of the males. When only
the mean survival times between 30% and 100%
mortality were considered in order to exclude earlymortality, this sex difference remained evident. Sex
differences in BALB/c, A/Jax, A/I-le, C3Hf/He and
C57BL/6 mice were evident when data for female orfor male animals of all strains were pooled and fitted
by linear regressions as a function of dose. The
reduction of mean after-survival for a given dose
increment was about twice in female as in maleanimals [GlO]. Ovarian dysfunction resulting in ovarian
tumour formation was suggested as the possible causeof this difference. Grahn and Sacher [G3] also showed agreater sensitivity of the females with respect to chronic
life-shortening injury. With x rays of three different
energies the reduction of life span averaged in animals
surviving the LDsono about 37% in the female and 29%
in the male. Female mice were uniformly more sensitive
than males when irradiated with gamma rays or fastneutrons [US]. This was again attributed to the
induction of tumours of the ovary or to hormonal
disturbances. However, the RI3E for neutrons against
gamma rays was not significantly different between thetwo sexes.

10-15 and of 40-130 days the difference between sexes
was either much smaller or non-existent; at survival
times in excess of 130 days females accumulated
consistently higher doses than males. ln the large experiments of Upton et al. [U7J on RF/Un mice no obvious
effect of sex can be traced from the data. Protraction
factors in male animals irradiated with gamma rays at
low dose rates appeared to be in the same direction as
in female animals but considerably more pronounced.
Consequently, RBE data were different in the twosexes.

243. After single-dose irradiation of one hybrid andfive inbred strains of mice (200 kVp x rays, doses
between 0.85 and 1.15 times the LDso/3o) strain differences within sex were not significant. The two sexes
had, however, significantly different responses
averaging for the males 0.28 days lost per R and for thefemales 0.81 days per R (all strains pooled). Differences
tended to disappear when corrections were introduced
for animals dying of leukaemia and of ovarian
tumours. It should in fact be recalled that there are sex
differences in the induction of leukaemia among
different mouse strains [Ul4]. Life shortening in all
strains after an acute treatment about the LDso/JO
seemed to be characterized by a single parameter applicable to all strains and sexes and expressed as aconstant number. 28 days of life lost per 100 R. Combination of this primary injury term with other secondary
parameters may provide equations predicting the final
long-term effect for any combination of normal life
expectancy, leukaemia incidence, ovarian tumour
incidence and dose [G4].

247. Sex differences in the A/J strain m regard toradiation-induced life shortening (x rays, single
exposures, 150 to 600 R) were also seen by Storer [S30].
At exposures of 600 R the female animals lost nearlyfour times as many days of life as did the male mice.
Qualitatively similar results in male and female mice
were observed in the experiments of Ainsworth et al.
[A 7] and the apparent quantitative differences in
response after single and fractionated gamma-ray andfast-neutron experiments could not be attributed withcertainty to differences in body size (and therefore
absorbed doses), to hormonal unbalance resulting fromdamage to the ovaries or to differences in the
spontaneous or induced tumour incidence.

244. In the experiments of Lindop and Rotblat [Ll]the shapes of the survival curves were similar for males
and females SAS/4 mice but showed small consistentdifferences in favour of a higher resistance for males.
These differences were not such. however, to warrant a
separate analysis of the life-shortening effect in the twosexes. Moos [M14] also reported no difference inlongevity response with respect to the sex of irradiatedanimals (mice, CFW strain, 40-50 or 140-150 days ofage) in the interval of daily dosage between 2 and 256 R
d-1 of 400 kVp x rays.
245. In the series by Kohn and Guttman [K6] theanimal's sex was shown to be an important factor forlife-span shortening in CAFl mice. During much of theadult life the female animals reacted to closes below 25
Gy, although the slope of the female dose-effectrelationship between 2.5 and 4.0 Gy was less than thatof the males. Late in life the females became lesssensitive than the males. Here again. changes in theendocrine balance were reputed to be at the origin ofsuch phenomena, in the sense that the female's changes
in sensitivity may have been a manifestation of theincrease and fall of ovarian endocrine function. Such ahypothesis is in accordance with the fact that
continuous low-level treatment with oestrogen hormone
increased the age-specific mortality rate of the BALB/cfemale mouse after x-irradiation [K 13]. It is of interest
that in the CAFl strain the reduction of life span was
not correlated with the induction of ovarian tumours,
which were actually depressed and not enhanced at thedoses used.
246. Sacher and Grahn [S4] showed that LAFl female
mice after life-time irradiation were slightly moresensitive than males in the 5-10 days period of survival
but became consistently more sensitive in the 17--40 day
period. In the mice surviving during the periods of248. Holland and Mitchell [HlOJ studied life shortening (300 R of 300 kVp x rays) on four inbred maleand female mouse strains (C3H, BALB/c. RFM,
C57BL/6), on two hybrid strains (C3CF1 andB6RFMFI) and a four-way cross between both F 1
hybrids, C3CB6RFM. At the time of irradiation themice were 5-6 weeks of age. In all strains and crosses a
significant life-shortening effect was obsenred. Females
were about 1.5 times more sensitive than males of thesame strain and these data suggested a general andconstant effect of sex under all conditions. Unfortunately. the data on the various modes of death are not
yet available for a more complete interpretation ofthese observations. A higher sensitivity of RFM female
mice accounted for by a rapid rise of life shortening
over the dose range up to 0.5 Gy was also reported by
Storer et al. [S44].
249. In experiments by Moskalev et al. [M22)performed on rats treated with fast neutrons (0.085 to
5.1 Gy) or 500 MeV protons (0.28 to 10 Gy) observations on life shortening were also reported. The average
life expectancy of rats irradiated with the fast neutron
beam did not depend on the animal's sex. The data by
Rust et al. [R2] on the guinea-pig showed that thefemales were more responsive to life shortening by
chronic gamma-ray exposure. This differential effectcould not be correlated with the induction of tumoursof the female generative organs.

2.

Body weight250. Body weight as a variable affecting long-term
animal survival was investigated in mice by Holland etal. [HlO]. Within the same sex, there were substantial
differences in sensitivity among the strains tested andthese differences were highly correlated with bodyweight at 6 weeks of age. The heavier animals were lessresistant to radiation, i.e.. showing a higher degree oflife shortening. Previous analysis of body weight versus
radiation resistance based on early effects and on
mature animals had given opposite results [Ql, G12,
RSJ in that, within the same strain, adult animals with ahigher body weight were shown to he more resistant.
693

However, in adult animals body weight is thought torenect the general state of health and fitness and it isconceivable that the heavier (i.e .. the healthier) animals.
may be more resistant to a given radiation insult. If thecomparison is among different strains and on maturing
animals, given a more or less uniform state of health.
the data of Holland et al. (H 10) would be compatible
with the hypothesis that body weight may be a measureof the rate of maturation and it is not inconceivable
under these conditions that body weight is a parameter
better correlated with radiation resistance than chronological age. It may also be further suggested, as theauthors do. that some of the strain-specific differencesin radiation sensitivity already discussed in subsection
I I.A. I may be due to differences in the rate of
maturation of the various strains or to other nonspecified processes which arc in turn highly correlatedwith maturation rate.

C.

AGE AT IRRADIATION
I.

Irradiation in utero

251. The available data on life shortening induced byin utero irradiation are examined first. According toNash and Gowen [N9] who evaluated in multifactorial
experiments the life spans of 647 mice irradiated inutero with exposures of 20 to 320 R at four different
gestational ages, the reduction in longevity induced by
the radiation treatment depends on the genetic constitution and sex, as well as on the dose and on the gestational age at irradiation. Rugh, Duhamel et al. [R6]followed the long-term survival of mice irradiated with
mid-lethal in utero doses at O to 5 days post-conception(p.c.) and found no modification of the life span in
animals that survived later than 30 days post-partum.
This observation indicates that after the neonatal
period there is little permanent damage of the in utero
irradiation.
252. Non-inbred male and female RF mice were
exposed to x irradiation in utero at ages ranging from
9.5 days p.c. to 1 year of extra-uterine age. Shorteningof life span by doses of 50-400 R was more effective perunit dose at the higher exposure levels of 300-400 R
and in age groups of 40-70 days. For exposure in utero
life shortening was consistently less marked than for
exposure after birth. but irradiation with high doses inutero (300 R at 14.5 days p.c.) gave rise lo growth anddevelopmental effects in a very high percentage of lhe
animals (particularly males) which caused dealh in 6 to
7 months for causes which were not clear [U12].
253. Friedberg et al. [F8] tested the effect of rast
neutrons (0.15 Gy) on mouse embryos in the
pronuclear-zygote stage for their ability to shorten thelife span or to induce tumours in animals surviving atleast 30 days after birth. No differences were foundbetween irradiated and control animals of the same sex
for the following end-points: -mean ages at death.
cumulative mortality distributions and incidences or the
principal neoplastic diseases. Sasaki et al. [S49]observed a significant shortening of life in mice
irradi,1ted at 16-18 days p.c. with 200 R of x rays. Mean
life span was reduced by about 13% to 16%. Slightchanges of the tumour spectrum were observed, with noexcess of lympho-reticular tissue tumours. Female mice
had a higher incidence of lung and pituitary tumours,
while a prevalence of Jung and liver tumours was foundin males.
694

254. For the rat there are data by Reineke et al. [R 7).
In her experiments Wistar animals were administered asingle whole-body x-ray exposure of 270 R at 5 days
before birth and at 13, 49 and 121 days after birth.
Among other observations. life expectancy was reduced
by about 3 to 6 months and this reduction was not innuenced apparently by the age at exposure. In a subsequent paper Reineke et al. [R8] reported that 220 R fiveday~ before birth resulted in a long-term survival notsignificantly different from controls.
255. Sikov, Resta and Lofstrom [S31] studied thelong-term mortality of rats surviving at the time of
weaning, exposures of 20 or 100 R at 10 days p.c. andof 50 or 185 R at 15 days p.c. Life-span reduction
appeared to be greater in females than in males where
the effects observed were of doubtful significance. Aninteresting observation was that the LDsotJO of an
irradiation performed at 100 days of age decreased as alinear function of the dose of a previous irradiation
carried out in the pre-natal period at all developmental
ages. In the opinion of the authors such a linear dependence may imply a general decrement of fitness as aresult of pre-natal exposure.

2.

Irradiation during extra-uterine life

256. Experiments where the effect of the extra-uterine
age has been examined as a biological variableaffecting radiation-induced life span shortening are
fairly numerous and cover a variety of different species.
strains and conditions of irradiation. Kallman and
Kohn [K7], Kohn, Kallman and 8erdijs [Kl] and Kohn
and Guttman [K6, Kl4] studied the life-shortening
response to x rays of male and female CAFl mice. withspecial regard to the influence of age at irradiation.
Exposure conditions were: 250 kVp x rays at a dose
rate of about 0.4 Gy min-1 with two single doses of 2.6
or 5.2 Gy and a fractionated dose of (2.6 x 2) Gy given
8 days apart. Mice were irradiated when young (144and 164 days of age) or old (385, 550 and 730 days) andfollowed with detailed pathology at death. The age
interval covered in the mouse would correspond in man
to a range of ages between 18 and 65 years. The last
publication of Kohn and Guttman [K6] gives anaccount of the whole set of data. including a re-analysis
of other previous data obtained on BALB/c mice
irradiated at 5 months. 1.2 or 1.4 years of age. In
general. some reduction of the life span was observed,
although in some cases evidence of life shortening was
small or even absent.
257. Old adult mice tended to show less life shortening than young ones. although the difference was not
the same in all strains used owing to genetic differences.
During much of the adult life the female animals weremore sensitive to doses below 2.5 Gy. Later in life,
however, the females, at least in the CAFl strain,
became Jess sensitive than the males. The life shortening
in older animals was not associated (as in youngerones) with an increased induction of neoplasia. but
rather with a decrease. In the CAFI mice irradiation
tended to reduce the number of animals dying withtumours and the tumour-bearing animals lived as longor longer than the non-tumorous ones. Aging (bothpremature or accelerated) as such was an inadequate
explanation for these data because the irradiatedanimals appeared to age abnormally and usually diedsooner than controls, the effect depending on age at
exposure, sex and dose [K6].

258. Boone et al. [I319. 1320) on CFl female mice atages from 1 day to 18 months reported changes in life
shortening as a function of age at exposure. Moreprecisely, after 4 Gy of x rays life shortening amounted
to 40% of corols when in the age interval from 1 day to
3 months; it was then gradually decreased to 32, 14 and
7% of controls at 6, 12 and 18 months of age, respectively. Thus the life-shortening response decreased as afunction of age. This effect could not be traced to theincidence of leukaemia or of ovarian tumours whichwere evaluated separately in these experiments. In
other strains the situation may, however, be different.
In the C57BL mouse, for example, age is a condition
which alters the sensitivity to lymphoma induction.
Kaplan [K15] showed in fact on animals at 2 weeks andat 1, 2. 3 and 4 months of age that lymphoma incidence
is higher and the appearance time earlier for irradiation
at the young ages than at the older ones.
259. Upton et al. [U5] considered in detail the variable·'age at exposure'' in relation to the life-shortening
effects in both sexes on 9-12 week old mice. No differences were found of any significance for either sex andthis observation was at variance with what was seen in
the same animals with regard to early mortality, which
was highest among young animals. Moos [M14] wasalso unable to find differences between the longevity ofyoung (40-50 d) or old (140-150 d) mice within therange of doses of 8 to 128 R d-1. However, such differences were seen at exposure rates of 2. 4 and 256 R d-1,
and the old mice were less resistant under these conditions.
260. In a series conducted on about four thousand
RF/J female mice Storer [S19] examined the agedependent changes in radiation sensitivity in normal
and previously-irradiated animals. He obtained lifetable data on all these mice, about one-half of which
received at the age of 90 days 400 R of 250 kYp x rays.
The rate of mortality from all causes in the irradiatedmice showed marked departures from the Gomperlz
equation and this dose of radiation shortened the
median life span to 63% of the control animals.
Mortality rates for all causes other than leukaemia gave
reasonably good Gompertz fits to the control andirradiated populations: life shortening amounted to 24
days per 100 R under the assumption of linearity
between dose and effect. No latent period was foundbetween exposure and the time when the mortality
increase became detectable. The mortality rate ofirradiated mice was at all times higher than in control
animals. The LDso130 of the control and irradiated micetested between 120 and 560 days of age declined
linearly with age without effect attributable to theprevious 400 R exposure. The mean after-survival
following exposure to 100 R d-1 also declined with age
in a complex manner, irradiated animals being
generally more sensitive than controls. Finally,
recovery rate tested by split exposures was found to
decline sharply with age: the rates estimated in previously-irradiated animals were much lower than those in
non-irradiated animals of the same age. from all thesedata Storer [Sl 9] concluded that the tests applied werein fact measuring the damage inflicted to different
cellular systems each of which aged al a different rate,
in contrast with the notion of a non-specific life-shorteninig action.
261. Lindop and Rotblat [LI 2] made a systematic
study of the effects of age, giving small single sub lethal
exposures of 15 MeY x rays to SAS/4 mice. They foundthat radiation given at 4 weeks of age produced aneffect that was linear with dose in the range of 50-780
R. The life shortening produced by 100 R was about 4
weeks for mice irradiated at the age of 1 week; it
increased to about 6 weeks for 5 week-old animals andthen decreased steadily to a minimum of approximately
2 weeks for animals irradiated when 70-90 weeks old. A
given reduction in life time in old animals represents amuch greater loss of the remaining life than the same
reduction produced at a young age. When the effectwas expressed as a percentage of the remaining life
span the increase in response at 5 weeks of age was still
evident, followed by oscillations of the response
between a maximum of 6% and a minimum of 3%
reduction of the remaining life span.
262. In a subsequent paper [Ll 6] life shortening wasstudied as a function both of the age and of the oxygenation conditions of the animals. For animals breathing
air, assuming linearity of response at all ages, the lifeshortening effect at 1 day and at 1. 4. 8 and 30 weeks ofage was found to decrease as a function of age from 7 .6
to 2.7 weeks per 100 R. Under hypoxic conditions a
considerable reduction of the life-shortening effect was
found at all exposures. amounting to a factor of three
for mice irradiated at 8 and 30 weeks of age. However,when the mice were irradiated at 1 day or at 1 week ofage hypoxia changed the linearity of the dose-response
relationship to a convex upward curve, such that theprotection afforded by hypoxia at low doses was large
but at high doses small. The authors could not suggest afirm interpretation for such findings.
263. Johnson [J2] set up a simulated experiment where
he computed the life shortening as a function of age at
irradiation utilizing parameters and life-functions takenfrom Sacher's [S2] analysis of the LAF1 male mice
exposed to fission neutrons and gamma rays in theGreenhouse experiments [U5, F2]. Irradiation was
simulated by a displacement of the Gompertz function
on the time axis. Johnson was thus able to show that adecrease in the life-shortening effect with increasing age
was a necessary consequence of the hypothesis thationizing radiation accelerates certain of the processes
that characterize natural aging. The relationship of life
shortening to age at irradiation varies however
according to the actual form of the Gompertz function.
264. Age-dependent changes in the response toradiation (250 kVp x rays) were also observed in otherexperiments by Cosgrove et al. [C20] where LAFl mice
were given from 300 to 1200 R whole-body or
partial-body when 10 weeks or 1 year old. At any given
exposure level, a higher incidence of glomerulosclerosis
was observed in animals irradiated at the younger age.
presumably because the older animals did not survive
long enough to develop as high an incidence of thediseases. Longevity was also reduced and the incidenceof ovarian tumours increased in the young but not in
the old irradiated animals.
265. Some data by Storer [S20] in mice are of interest
to the problem under discussion. BDFl females, whenthree months old. were exposed at doses of 0, 100, 300,
500 R or 250 kVp x rays. Median survival time wasfound to be reduced linearly with exposure and theslope of the linear non-threshold regression function
amounted to a life-span reduction of 45 days/100 R.
The changes in radiation response with advancing age
and for various radiation exposures were evaluated in
two ways: beginning at various ages, samples of previously-irradiated surviving animals were tested for theirability to survive successive daily exposure of 100 R; or,alternatively, they were tested for their LD 50.
695

266. Thirty-four samples of previously exposed
animals were tested at ages ranging from 120 to 960
days with 100 R d-1 and resistance was assessed asmean survival time after initiation of this treatment.
Resistance was found to follow a long plateau (theduration of which was dose-dependent) and to decline
sharply at advanced ages. Pre-irradiated animals wereless resistant than non-irradiated control mice of thesame age and showed an earlier onset in the decline ofresistance. Since the variability in radiation resistanceincreased with age and the differences in sensitivity
between irradiated groups were reduced when therelevant comparisons were conducted at equal levels ofmortality. Storer [S20] concluded that the test treatment
was not actually measuring a phenomenon intrinsic to
the aging process but was more simply an estimate of
the incidence of diseases in the population examined.
Similarly, the LDso130 test showed that resistancefollowed the same dependence on age as after the
protracted exposure test. The conclusion was that theearlier onset in the decline of resistance of the moreheavily exposed animals was in fact correlated with theearlier onset of morbidity in these groups.

270. Ainsworth et al. [A 7] examined the problem ofage-sensitivity in B6CF1 male mice after single doses of
0.8 Gy of fast neutrons or 2.69 Gy of gamma rays. The
mice were 115. 194 or 278 days old al the time of
exposure. Irrespective of whether life shortening was
expressed as a per cent reduction of the after-expectation of life or as per cent life shortening. there wassome decrease with age of the effect per unit dose andthis was shown to be greater after gamma than after
neutron irradiation. The contribution of this change insensitivity to the "sparing" effect of fractionation
during a long course of treatment is thus proportionately greater with low- than with high·LET radiation.
Life shortening and carcinogenesis by x rays in mice
irradiated neonatally was also studied recently by
Sasaki and Kasuga [S61 J who attributed the reduction
in mean life span to the high induction rate of liver andpituitary tumours and of thymic lymphoma.

267. In addition to presenting data on CBA female
mice given acute doses of radiation (4.5 Gy of 250 kVp
x rays at four ages from 100 to 670 days), Mole [M2]pointed out some difficulties in the analysis of suchdata. If the mean after-survival time is taken as thecriterion of effect, then it is clear that the radiosensitivity of the animals decreases with age. But if it isassumed that the radiation-induced mortality depends
on the mortality of the non-irradiated animals and the
Abbott's correction is used to derive the net radiationinduced life shortening, then the curves of cumulative
mortality show little difference with age. Mole also
refers to similar unpublished data obtained withprotracted exposures to gamma rays and fission
neutrons. Such observations may imply that the lifeshortening process proceeds independently of natural
aging and thus the two phenomena are not correlated.
However. in the absence of further information about
natural aging itself, it should simply be realized that
opposing conclusions may be reached by different
analyses of the same experimental data.

271. The data available for the rat are similar to thosejust discussed for the mouse and show a dependence oflife shortening on the age of irradiated animals. Jones
and Kimeldorf [J3] treated male Sprague-Dawley rats
with about 2.2 Gy of fast neutrons obtained by the Be(p,n) B reaction. They belonged to 5 different age
groups of 1, 3. 10, 15 and 21 months. Survival rate andlife expectancy were decreased and the age-specificdeath rate was increased by comparison with shamirradiated litter-mate controls. The magnitude of theseeffects was inversely related to age at exposure frompost-infancy up to middle age (10 months). At older
ages there was no discernible change in life span withrespect to control rats. In the opinion of the authors
these data may be compatible with Ncary's theory [Nl]postulating an induction period in life which may be
shortened by various treatments and an ensuing period
of development. which would be relatively constant induration. In the male Sprague-Dawley rat the period ofdevelopment would begin in the age range of 10 to 15
months.

268. In experiments by Yuhas [Y3) the sensitivity wasstudied of 4 to 24 months old C57BL/6J female mice tothe life-shortening effects of 1400 R of 300 kVp x rays.
Radiation was given in 10 equal fractions within 12
days. In the 4 months old animals the resulting life
shortening amounted to 148 days but in older animals
the same dose was considerably less efficient: in fact,
life shortening amounted to only 30 days at 9 months
and at the three oldest ages (I 5, 18 and 24 months) there
was actually a lengthening of life of the order of 53 to
65 days.

272. In a subsequent paper [J4] the relevant data fortumour induction were reported. There was an excess
proportion of animals with one or more palpabletumours (compared to the control groups) after
exposure at all except the oldest age (21 months), in
spite of a significant life shortening only after exposure
at the three younger ages. The percentage of animals
with palpable tumours was higher in all groups (evenfor the group exposed at 21 months) in comparison
with the control tumour-bearing animals. It should berecalled that this strain of rats has normally a very highincidence of radiation-induced tumours, particularly of
the skin and skin adnexa, which may have altered to an
unknown extent any more precise estimates of life
shortening.

269. The decreasing response with increasing age
confirmed previously-reported data by Lindop andRotblat [L12], Kohn and Guttman [K6], Jones andKimeldorf (J3]. The data also confirmed the life
lengthening in mice irradiated at very old ages. The
compatibility of these findings was tested in relation to
five different hypotheses. The data could not be
accounted for in terms of insufficient time forexpression of injury; or of the identity of normal andradiation-induced senescence; or of selective changes
in the population of mice induced by early mortality;
or by normal "attrition". They were instead consistent
with the hypotheses that the sensitivity to the inductionof certain diseases decreases with advancing age.
696

irrespective of the time required for their expression;or, alternatively, that radiation given in old age may
have a therapeutic effect on some neoplastic growths inthese animals.

D.

CONCLUSIONS

273. From all the data reviewed it may be concluded
that among the biological variables determining thelife-shortening response to irradiation there is sufficient
data for discussions on the genetic constitution and on
the influence of sex and of age at irradiation.
274. It is easy to understand that different species may
show a different response in relation to the longevity ofeach species and to its specific physiologic and pathologic characteristics. It is less easy to trace a common
parameter or a set of parameters from which one canevaluate the sensitivity of a species and thus construct asusceptibility scale for inter-species comparisons or
extrapolations. The analysis of survival parameters
according to the actuarial model of Gompertz; thecalculation of semi-empirical parameters such as theexcess death-rate divided by the exposure rate inchronic irradiation experiments; the evaluation of thelife-shortening effect normalized as a percentage of thecontrol value and as a function of the acute LD50130;
the hypothesis of a common life-shortening effect perunit dose normalized according to the respective life
span of the species compared; were all criteria
proposed in order to achieve the scopes mentioned
above. On the basis of one of these parameters approximate scales of radiosensitivity were in fact proposed,of which the majority were obtained from gamma-ray
chronic irradiation data (see Table 3). Most of thesedata agree in showing that the rat, the dog and themouse are about equally sensitive, while (on the basis ofvery scanty data) the rabbit would appear to be lesssusceptible and the monkey, the goat and theguinea-pig perhaps more sensitive in terms of life lost
per unit dose. Susceptibility for man is reported in one
case to be higher (perhaps by a factor of two) and inanother case to be similar to that of the dog and themouse. It does not appear from the data that the differences between the various mammalian species tested isvery large and the range within which all species may
be included may possibly be a factor of two in both
directions (taking the mouse and the dog to be in the
middle of an ideal radiosusceptibility scale) or about afactor of five over the whole range of radiosensitivity ofthe species tested.
275. Intra-species or inter-strain variability has also
been studied in the mouse, the species where different
genetically-homogeneous strains are more easily
available. When adequately looked for. differences
between various strains (for the same sex) were easily
observed. Little formal genetic analysis of the radiosensitivity parameters has been attempted and most of thedata refer to irradiation for the duration of life. In
general the amount of life shortening is correlated withthe control mean survival time, in the sense that the
proportion of life lost per unit dose is similar for thevarious strains having different life spans. Life shortening is also correlated with the expression of thepathological characteristics of the strains, since animals
prone to the development of leukaemia and of ovarian
tumours (the cases which have been more thoroughly
analysed) show a greater amount of life shortening perunit dose. It is possible that the differences in responseof the various strains may also reflect the maturation
rate of the genotypes irradiated, as some data on thecorrelation of the response with the weight of maturing
animals would suggest. When allowance is made for allthese variables the mouse appears to respond according
to a basic parameter, whereby the number of days lost
per unit exposure for acute single doses equals 0.28 d
R-1. On this basic dose-response relationship all thefactors mentioned above (in addition to other factors
for sex and age) combine to give the final compoundedvalue of effect for each particular situation.
276. In a few cases of the data reported, either nodifference or small differences in sensitivity to life
shortening were reported between male and female
animals. In most other cases however invariably ahigher sensitivity of the female animals was observed.

The sensitivity factors reported were between 1.5 and 4.
Ovarian dysfunction induced by irradiation and theincidence of ovarian tumours were generally reported
to cause this differential effect. which tended todisappear when the data were appropriately corrected
for the incidence of tumours of the genital tract or ofleukaemia. The conclusion to be drawn from the vast
majority· of the data is that. within strain, sex has aconstant effect which is mostly manifested by anincreased incidence of tumours of the female genitaltract.
277. The data for the rat show no obvious difference
in results for either sex, while the results for theguinea-pig, in analogy with most data for the mouse,show an increased sensitivity of the females attributableto tumours of the genital tract. Body weight may also bea biological variable of interest in the final expressionof life shortening, but it appears to be of rather minor
importance.
278. With regard to the effect of age, after allowancefor other conditions influencing reduction in longeyity(genetic background and sex) most data show that
irradiation in utero of the mouse produces less marked
life shortening than irradiation during post-gestational
ages. There may even be no long-term effect at all on
the irradiated animals, particularly those surviving
irradiation at the early gestational ages. The experiencein the rat shows some reduction of the life span for
irradiation of the foetal animals, but the effects
observed are of doubtful significance and in any casenot substantially different from the effects of the same
doses given soon after birth.
279. With regard to the effect of extra-uterine age. thedata are rather numerous but only pertain to the mouseand the rat. In both these species irradiation late in life
produces-allotherfactors
being
invariably
equal-less life shortening than treatment at younger
ages. ln the one case where no effect of age was found[US] the range of useful ages examined was too shortfor any effect to be seen. In some instances the
reduction of life shortening with age is preceded by aphase or increased susceptibility of the animals up to
the time of sexual maturity [L12]. In other cases irradiation in old ages may even produce (for moderately
high doses) an increase, rather than a decrease, of theduration of life [Y3] or no change with respect tocontrol [13]. The change in sensitivity between young
and old animals may be up to a factor of three when thelife shortening per unit dose is considered; if the effectis evaluated in terms of the percentage loss of theremaining life span, this amounts to a few per cent. In
some experiments a correlation may be establishedbetween the degree of life shortening and the inductionof tumours or of nephrosclerosis, but in other cases nosuch correlation may be found.
280. lf life shortening is primarily or exclusively due
to the induction of excess tumours. each of which has a
distribution of times of expression, the age-dependenceof life shortening may be due to the influence of latency
on the life tables of the irradiated population. Thus,
because of competing risks, some lives will be overbefore the induced cancers are expressed. an effectwhich obviously increases with the age at exposure. No
specific test of this possibility has been reported in theliterature. It may, however, account for all age-dependence. If it should only account for part of it, then theremainder may be attributed to a decreased susceptibility of certain pathological conditions. Another possi697

bility is that radiation in old age may have a therapeutic
effect on some (presumably neoplastic) conditions
already under development at irradiation. Caution
should be used in the analysis of data from experiments
in which animals were started on irradiation courses atvariable initial ages as different analytical approaches
to the data, in addition to implying different hypothesesof action, may lead to variable conclusions as to effectof age on the animals' radioscnsitivity.

III.

MODIFYING FACTORSA.

PHYSICAL TREATMENTS

281. Among the treatments that modify the life-shortening response to irradiation those of a physical,
chemical or pharmacological, and biological nature arereviewed in this chapter. It should be realized that
information on these subjects is very heterogeneous andnot suitable for generalized conclusions. A review onlife shortening. including also some original data.
centred on various chemical and biological modifying
factors, has been recently published [A 16]. Among thephysical treatments, those referring to irradiation given
in combination with low- or high-temperature treatments have already been reviewed in subsection T.B.6.
282. In experiments by Gambino et al. [GB] LongEvans female rats were irradiated over the whole bodyor only on the adrenals with 500 R and then exposed
for three hours daily to ooc. Reduced longevity wasamong the effects (retarded growth, cataract. fur
greying, tumours) seen at long term in the whole-bodyirradiatcd (hut not in the adrenal-irradiated) rats. It
amounted to about 20% of the normal control life span
and it was not modified by the cold treatment. Other
effects were also not modified, except perhaps for aslight reduction of the accelerated tumour onset seen inwhole-body irradiated animals. Interpretation of thesedata is made difficult by the fact that the cold treatment
as such has produced life-span reduction and changed
the spectrum of diseases with a prevalence of intlammatory pulmonary conditions and a relative decreaseof neoplasia [Hll).
283. Some information is also available in regard to
the modifying effects of a specific stress on long-term
mortality of irradiated animals. Ordy et al. [U1]irradiated C57BL/10 mice on the brain with 5 Gy of 20
MeV deuteron beam with a highly significant decreasein longevity of the irradiated animals. They also
observed a reduction of the late mortality in the
animals undergoing periods of daily stress (cold.
electrical shock, or both). Such an effect appeared to bestatistically significant in some. although not all, groupsof animals and was observed irrespective of whether
they had been irradiated or not.
284. Reineke et al. [R9] submitted Wistar rats at 120
days of age to starvation for 9 days, water deprivationfor 6 days or forced swimming. Animals that had
passed through such severe stress before irradiation(280 R of x rays, single dose), lived longer than thosereceiving irradiation only. The differences in thesurvival curves were significantly different in three outof six possible comparisons .. No influence of stress wasobserved on the tumour incidence. There was also no
obvious difference in the swimming ability and in the
decline of this ability with age between normal miceand mice irradiated with a single acute dose of 2.24 Gyof x rays at 20 weeks of age [N12].

698

B. PHYSICO-CHEMICAL AND
PHARMACOLOGICAL TREATMENT
I.

Anaesthesia, oxygen and hypothermia

285. The effects of hypoxia induced by various treatments will first be examined. Lindop and Rotblat (Ll 2)
showed some protective action of anaesthesia against
early and late death. Protection appeared to decrease
with close rate in the interval 4.8-1620 Gy min-t.
Protection could not be ascribed to low oxygen tensionin tissues by the anaesthesic drug. because there was nosummation of effects by the anaesthesia and close rate,particularly at the high dose rates. In other series ofexperiments Linclop and Rotblat [L12. Ll6] showed thatwhen SAS/4 mice, anaesthetized with 20-60 mg/kg of
Nembutal and breathing nitrogen 30-50 second, were
exposed to a beam of fast electrons (15 MeV. 400 Gy
min-1) they had a considerably reduced life shortening,in comparison to other animals exposed in air. The
protective effect of hypoxia was influenced by the age
at exposure in that a dose-reduction factor of about 3
due to the nitrogen breathing was observed in animalsof 8 and 30 weeks of age. In mice of l day or I week ofage the shape of the close-life shortening relationshipwas changed from linear to curvilinear. giving rise to alarger protection factor at low doses and a very small
one at high doses.
286. Hypoxic hypothermia was also tested by
Hornsey [H 12) with respect to the possible modificationinduced by this treatment on life span. While
hypothermia induced at the time of irradiation offeredconsiderable protection (a factor of about 2.8) to thehaemopoietic system whose failure is responsible forthe early death of the animals, it did not protect to thesame extent against long-term death. For the same close
administered to normal and to chilled animals the
expectation of life was greater for the latter, but thenature of the data did not allow any precise estimate of
the protection factor afforded by hypoxic hypothermia.
Thus it appears that the protection by hypoxia alreadyshown against the acute radiation effects extends also
to the long-term effects. although perhaps not to thesame degree.

2.

Chemical radioprotective drugs

287. On the subject of chemical radioprotection
Maisin et al. [M32] reported that mercaptoethylamine[MEAJ (HJ mg/rat, given 5 minutes prior to irradiation)
was active in reducing the mortality rate during the firstmonth post-irradiation but was incapable of modifying
the late rate of mortality following irradiation of thehead (1000-2000 R) or of the abdomen (900-1500 R).
This drug was also without effect on the late mortality
following irradiation of the abdomen and of the wholebody with 600 R. In another series of experiments.
MEA (425 mg kg-I d-1) and 2-aminoethylthiosulfuric
acid (1000 mg kg-1 d- 1) were administered in thedrinking water to Swiss mice that were exposed for theduration of life to 6°Co gamma rays at dose rates from lto 5 R h-1. Mortality data were indistinguishable fromthose of controls drinking tap water and it wastherefore concluded that neither of the drugs (which areactive in the prevention of early mortality) had aprotective action against chronic irradiation effects at
drug levels accepted by the mice [A8].
288. Cosgrove et al. [C23) tested the effect of theradioprotective drugs aminoethylthiouronium (AET)

on (101 x C3H)Fl female mice following a wide rangeof x-ray exposures (300-1800 R) with or without
parallel treatment with isologous bone marrow
drug treatment was found to have a marked protective
effect against early lethality, but its effectiveness inprotecting against a reduction in longevity was
equivocal. No effect was found on tumour induction,
nephrosclerosis and lens opacities while induction ofthymic lymphomas and greying of the fur were reducedby the drug treatment. Thus AET protected against
some bur not all long-term somatic effects and in nocase the dose reduction factor approached thatobtained against the acute lethal effects of radiation(40-50%). In another experimental series performed onmale and female LAFl mice by the same workers [C20]administration of AET before irradiation led to some
reduction of kidney sclerosis but was again without
effect in regard to the induction of tumours of the ovaryor to the greying of the fur.
289. An attempt to maximize protection against 9
MeV irradiation was reported by Shewell and Wright[S33] who combined four different methods ofprotection: administration of cysteamine before irradiation, irradiation during nitrogen hypoxia. and administration of syngenic bone marrow and of antibiotics
after irradiation. The LD50130 for the protected mice
(C3H/Bi, 15 weeks old) was increased by a factor of 3.8
with respect to unprotected animals and this factor
persisted throughout the long-term follow-up of themice surviving early lethality. Greying of the hair andepilation also gave a dose-reduction factor of 3.8. but
the appearance of radiation cataracts did not conformto the same pattern. lt was therefore concluded that theprotection afforded against the different effects hadvariable dose-reduction factors for each effect tested.
290. In Nelson's [NlOJ experiments irradiation
followed various fractionation schedules: 80 R atintervals of 1 day up to total accumulated exposures of
640-1920 R; 80 Rat intervals of 3 days for the whole
life span; 160 R at intervals of 1, 3 and 7 days up to
exposures of 480-1760, 1600-3250 and 2880-5760 R,
respectively. Cysteamine at 4 mg per day for 24 days orat 4 mg per day twice a week was used as a chemical
protector. The drug treatments by themselves, as well as
the injection of physiological saline twice a week for thewhole life, modified drastically the mean and mediansurvival time of the irradiated animals. However,cysteamine unequivocally protected against mortality.
The magnitude of the protective action depended on
the accumulated exposure and on the time interval
between fractions. At low accumulated exposuresradiation injury was insufficient to show significant
differences between protected and control animals,
while for high exposures radiation injury was
supralethal. The effect of fractionation intervals wasoften variable. No single dose-reduction factor could bederived from these experiments since the values of thisfactor vary in each series with exposure. fraction sizeand fractionation interval. However, cysteamine wasshown to protect not only against the acute injuries but
also against fractionated doses in the sublethal range.
Any more precise assessment would be unwarranted
owing to the toxicity of the drug and to the adverse
effect of the administration procedure which influenced
the survival of the animals rather substantially.
291. Yuhas [Yl] reported that the radioprotective
agent WR-2721 [S - 2-(3-amino propylamino) ethylphosphorothioic acid] protects against acute death
more efficiently than it can protect against the lifeshortening effects of radiation. although the exact

extent of this protection could not be directly andprecisely estimated. It has, however. been shown [06]that the ability of the drug to protect against life shortening varies with the size of the dose of radiation.
292. Storer [S30] investigated on A/J and C57BL/6J
male and female mice the effect of four radioprotectors
administered i.p. 15 min prior to irradiation. They
were: paraaminopropiophenone (PAPP) at 40 mg/kg,
rnercaptoethylamine (MEA) at 200 mg/kg, amynoethylthiouronium (AET) at 200 mg/kg and 5-hydroxytryptamine (5 - HT) at 100 mg/kg. X rays of 300 kVp were
given acutely at 150. 300. 600 R to the control animals
and at proportionately higher exposures to theprotected mice. Dose-reduction factors in the region of
1.5-1.8 were found for the various drugs with respect to
the LDsono of the x rays and the drug treatments had no
significant effect on the longevity of the non-irradiatedmice. Within the range of exposures tested, mean
survival time decreased as a function of dose (withsome sex and strain differences in the amount ofresponse) with concave upward relationships, although
the hypothesis of linearity could not entirely berejected. The pooled data (all strains and sexes anddrugs together) for control and for protected mice
showed that mean life shortening was a curvilinear
function of dose both with and without drugs and thatthe radioprotective treatment did afford some
protection against life shortening. However, the extent
of protection varied with strain, sex and drug. PAPP
was found to be the most effective, follO\ved by MEA.
5-HT and AET. The average dose-reduction factor for
all agents and mouse groups was 1.35. All this showsthat protection against life shortening is qualitatively
and quantitatively different from protection against theacute lethal effects and results from a complex interaction of factors depending on strain. sex. drug anddose of radiation.
293. Other experiments on the subject of chemical
radioprotection were reported by Maisin et al. [M8,
M23] and summarized in Maisin et al. [MlO, M24].
BALB/c and C57BL mice were given 100-2000 R acuteexposures of 250 kVp x rays; causes of death wereclassified among 12 different groups and analysed forcompeting risks of death. In the BALB/c strain life
shortening had a linear dependence on dose. except
perhaps at very high doses. When AET or a mixture ofradioprotectors (glutathione, cysteine. AET. MEA and
5-hydroxytryptamine) were administered prior toirradiation with various schedules of administration,
they showed a significant protective action against latedeath. Under the hypothesis of linearity, the dose
reduction factor for AET was estimated to be 1.23 ±0.05 and that for the radioprotective mixture 2.1 ± 0.2,
which values are significantly smaller than those
applying to acute lethality (1.7 and 2.8 respectively).
Radiation-induced shortening of life was attributed tolymphoma,myeloid
specific
diseases(thymic
leukaemia, glomerulosclerosis, non-tumorous lesions of
the lung). Protection was most effective against thymic
lymphoma, but was also discernible for leukaemia andnephrosclerosis. In the C57BL mouse the data,
although less complete, were essentially similar.
294. Maisin and his collaborators [M24] performed
also another experiment where the mice were given
fractionated treatments. Using a variety of different
doses and fractionation intervals they showed for theirradiated-AET-protected mice a dose-reduction factorof 2.1 at 50% life shortening. Radioprotectors decreased
significantly the incidence of thymic lymphoma, but699

did not modify other causes of death. A paper was also
reported on the same subject by Philip [P2]. In this case
AET (300 mg/kg body weight) or 5-HT (75 mg/kg)
were given i.p. 10 min prior to irradiation with 400 R(250 kVp x rays) to young Swiss female mice. Single
exposures of 100, 200 and 400 R were also given to
normal. non-protected mice. Life-span shortening.
incidence of thymic or myeloid leukaemia, and theoccurrence of tumours of breast, ovary, lung and uterus
were the end-points evaluated. Dose reduction factorsof 1.7 for AET and 1.4 for 5 - HT were calculated forlong-term survival. These values were close to thoseobtained for short-term survival. For the induction of
all tumours the respective dose-reduction factors were
1.5 and 1.4; for the induction of thymic lymphoma 1.8
and 1.6.
BIOLOGICAL TREATMENTS

C.
I.

Bone marrow transplantation

295. Syngeneic marrow transplantation was not very
effective in protecting against reduction of longevity in
Cosgrove's et al. [C23] experiments. This treatment
inhibited the induction of thymic lymphoma. inaccordance with other data [C13, K16, I12, C24] but did
not alter the incidence of glomerulosclerosis, solid
tumour induction (ovary, breast. lung, uterus) or lens
opacities.
296. Experiments on the late somatic effects insyngeneic radiation chimaeras were performed by
Covelli et al. [CB] on (C57BL x C3H)Fl male mice.
Bone marrow treatment was effective in increasing
survival of the animals within 60 days, but the mean
and median after-survival of the mice irradiated with
9 Gy of x rays were not influenced by the number ofcells injected (in the range of 8 104 to 1 107 cells/mouse). Irradiation with 9 Gy of 250 kVp x rays
followed by bone marrow treatment was very effective
in decreasing the incidence of reticulum cell sarcoma inlong-term survivors but led to an enhanced incidence ofother tumours (particularly of the malignant ones) bycomparison with untreated animals. Irradiated bonemarrow-treated animals had a greatly enhanced andaccelerated appearance of nephrosclerosis which wasby far the most important cause of death between 600
and 700 days of treatment under these conditions.
2.

Other treatments

297. In order to examine further the frequently
reported finding of a greater sensitivity of the female
animals to life shortening (see section Il.B.) Holland etal. [H13] investigated the effect of ovariectomy on RFM
mice. Castration had little effect on overall mortality
rate. both alone or in combination with irradiation (300
R). It had. on the contrary, significant effects on
specific spontaneous or radiation-induced diseases, as
it reduced the incidence of lymphosarcoma andpituitary, harderian and adrenocortical adenoma and it
increased the incidence of lung adenoma. For two otherdiseases, septic metritis and severe glomerulosclerosis,
castration interacted with radiation in nullifying theincreased incidence brought about by radiation.
Although not strictly comparable, these findings seemat variance with those of Hamilton et al. [H 14] who
exposed LAFl mice to 145 R d-1 and found thatfemales had a greater sensitivity than males, judging by
survival time. However, when the females were ovari700

cctomized their survival became closer to, although still
lower than, that of males. Thus, acute survival might beinnuenced by ovariectomy, as opposed to Jong-term
survival.
D.

PARTIAL-BODY IRRADIATION
I.

Mouse

298.
Although selective partial-body exposure may,in principle, be a good method for the study of thepathogenesis of the individual causes of death responsible for life-span shortening, data on this subject arc
comparatively few. In the mouse Kallman et al. [K7]reported on CAFl females exposed to 250 kVp x rays.
Partial-body irradiation was performed bilaterally on
the thorax (weight of irradiated tissues about 7.6 g); on
the right hemithorax (3.5 g) and on the pelvis (5.0 g).
Three hundred and 500 R given to the whole body
produced an appreciable shortening of life.
Partial-body exposure on the chest or on the pelvis wasmuch less effective than whole-body irradiation interms of tissue dose units. The smallest whole-bodydoses were more effective than the larger per unit dose
but the reverse was true in the case of partial-body
exposure. In the partial-body exposure of one region
the loss of life per unit absorbed dose (dose per unit
volume of tissue) was not a constant in these experiments.
299. Boone [B8, B9] worked on mice of the samestrain and sex irradiated on the whole-. lower- or
upper-body with x-radiation in single doses.
Whole-body irradiated animals (150 mice for eachgroup) received 1, 2 or 4 Gy, shielded animals 2, 4 or 8
Gy and shielding was adjusted in order that the total
weight of the tissues included in the irradiation fields
would be the same. The integral dose to shielded
animals was therefore equivalent to that received byunshielded ones receiving one-half of that dose.
Inspection of the data showed a non-linear dose-effectrelationship in all cases, with upper convexity.
Whole-body exposure was most efficient for inductionof life shortening; shielding of the lower body least
efficient; shielding of the upper body was intermediate
between the two. The only pathological data given were
those referring to overall leukaemia and they are insufficient for any conclusion. Also, the significance of thedifferences observed between control and treatmentgroups and between the treatment groups themselvesappears dubious.
300. Cosgrove and Upton [C25] exposed RF female
mice to 250 kVp x rays, under Nembutal anaesthesia
and the conditions studied were: irradiation on thewhole body with 100 R or 300 R; 300 R to the upper,
middle or lower third of the body: non-irradiatedcontrols. Life shortening was appreciable after 100 or
300 R given whole-body but survival of the shieldedgroups was slightly, if at all, different from that of nonirradiated controls. Whole-body irradiation at both
exposure levels increased the incidence of thymic
lymphoma and in the 300 R group myeloid leukaemia
was also increased: but none of the diseases wasincreased in shielded mice. Since partial exposure of
any third of the body to 300 R produced less life shortening than did 100 R to the whole body, the effect was
not correlated with the integral dose.
301. The experiments of Cosgrove, Upton et al. [C20]
on LAFl female and male mice are more concerned

with the induction of ncphrosclerosis than with life
shortening, but were performed on partially-shielded
animals. They showed that shielding of the kidney
prevented the induction of glomerulosclerosis andexposure of the kidney alone was as effective as
whole-body irradiation for induction of this disease.
Longevity was reduced by irradiation of the wholebody or by exposure of the lumbar area to 1200 R at 10
weeks of age. but not when the same dose under thesame conditions was given at 1 year of age.
Partial-body exposures below 1200 R gave an insignificant reduction of the mean age at death.
302. Sato, Tsuchihashi and Kawashima [S34] reported
that whole-body, head or trunk exposure to 400 R
induced significant life shortening in ddN female mice
irradiated when 10 weeks old with 200 kYp x rays.
Lower-body exposure to the same amount of radiation
did not result, on the contrary, in any reduction of thelife span. Per volume dose. life shortening was
maximum for the head exposure. Gompertzian plots ofall groups were linear. but they did not bear any simple
relationship between partial- or whole-body irradiation.
Other experiments on ddY female mice [S60] yielded
dose-effect relationships for life shortening by wholeor partial-body irradiation. Mean survival times
following whole-body exposure decreased by about 7%
per Gy. A dose of 1 Gy to the head or the lower body
produced 8.5% and 9.7% shortening, respectively. but
there was almost no further reduction up to 7.6 Gy.
After irradiation of the trunk with 1.9 Gy life shortening amounted to about 14% of the control value andbeyond this dose to about 1% per Gy.
303. An analysis of causes of death was carried out
only for part of the experiments mentioned above.
Histological data are available for animals receiving 6
Gy whole-body, 8 Gy on the head. trunk or lower body,or for non-irradiated controls [S43]. The increase inincidence of all tumours and of malignant lymphoma
was significant in the whole-body exposed group. Head
exposure enhanced the induction of tumours of thepituitary gland; trunk exposure that of ovarian tumours(with a depression of malignant lymphomas); lower
body exposure gave the same tumour spectrum as thecontrol. Judging by the mean after-survival of micedying for the same cause, an earlier appearance of allcauses of death (and particularly of the lymphoma) in
irradiated than in control groups was apparent. The
larger life shortening produced by the whole-bodytreatment was attributed to the high incidence oflymphoma and to the early appearance of lymphomas,lung and mammary tumours. The lower incidence oflymphoma in the partially-shielded mice was responsible for the low life-shortening efficiency of these treatments.

2.

Rat and hamster

304. In the rat Maisin et al. [M23] and Dunjic et al.
[D7] performed a study of the mean duration of life of ahomozygous strain exposed under various conditions.
They found that 600 R given whole-body gave a
reduction of life span of about 41%; 850-1000 R to theabdomen alone reduced the life span by 18-34%. There
were also groups irradiated over the thorax only
(600-3000 R) or over the head only (600-2000 R). The
survival curves had distinctly different shapes
depending on the region of the body exposed and on
the various modes of death showing at characteristic

doses: pulmonary and oesophageal syndromes forthorax irradiation and delayed head or oropharyngeal
syndromes for irradiation of the head. The authors
suggested that the survival curve after whole-body
irradiation could be a composite of the survival curves
for partial irradiations of various types, an explanationthat fails to account for the life shortening at doses far
lower than those responsible for the modes of death
mentioned above.

305. In other experiments young female Wistar rats
were irradiated on the whole body or on sections of it(head. upper abdomen. whole body except the upper
abdomen) with a single exposure of 1000 R of 250 kVp
x rays under anaesthesia and therefore under slightanoxia. Mean and median survival times of the groups
receiving partial- or whole-body exposure were all
reduced compared to controls. Life shortening
observed after partial-body irradiation was in approximate proportion to the weight of the irradiated tissues.
Nephrosclerosis was not seen unless the upper
abdomen was included in the irradiation field and.
except for the kidney, the spectrum of diseases
observed at death in control. partial-body orwhole-body irradiated animals was very similar.
Inflammatory diseases of the thoracic organs andbenign and malignant neoplasrns predominated [L17].
306. The results of Taketa [T2] were also obtained in
the rat (adult male Sprague-Dawley, 9-11 weeks old)and involved exposure of the intact abdomen exclusiveof the gastro-intestinal tract (which was surgicallyexteriorized and shielded) to 13, 35 or 50 Gy. A dose of
13 Gy to the intact abdomen resulted in 100% of theanimals dying within 4 days of exposure. The same
dose given to the abdomen without the intestine
allowed survival of the animals to a mean life span of
262 days. But an increase of the dose to 35 or 50 Gy
under the same conditions shortened the life span of therats to 82 or 33 days, respectively. Results with thelower or the upper abdomen irradiated separately (withexteriorized and shielded intestine) were less clear.
307. Carsten and Innes [C26] working on female ratsof the CFN strain irradiated with 250 kYp x rays
showed that 6.5 Gy given to the lower body or 13 Gy
administered to the upper body had a life-shortening
effect of about 90 days (against a control value of about
700 days). The effect was statistically different from thecontrol life span. but was very similar for the two treatments. Mammary adenofibromas developed in 60% of
the normal aging mice. Acceleration of these tumours
was induced by irradiation of the lower. but not of theupper, body. These tumours were a major cause ofdeath in both the irradiated and the non-irradiated rats.
308. Chinese hamsters were irradiated whole- or
partial-body with 250 kVp x rays [K11J. Judging by thelife span, the upper half of the body appeared more
vulnerable than the posterior half and the response to
the whole-body exposure was largely determined byirradiation of the anterior half. This observation seems
quite unique to this species and at variance with dataobtained in the mouse [K7. 88. C25] and in the rat [D7,L17]. A significant increase of the incidence of tumoursin irradiated animals was seen only for the ovary.
Progressive capillary glomerulosclerosis was observedin all animals examined and this was accelerated byirradiation.
701

E.

CONCLUSIONS

309. In conclusion. it appears that stress of a rather
non-specilic nature (cold. starvation, water deprivation,
physical exercise. electric shock) may have someinfluence on the life span of the irradiated animals,
owing presumably to some interaction between theeffects of stress and of radiation exposure. These data
are, however. too few, the treatments tested too unspecific and their underlying mechanisms too obscure to
warrant undue generalization. Hypoxia induced byvarious techniques invariably results in protection
against the life-shortening action of radiation, but theextent of this protection is probably less than that
produced by the same treatments against acuteradiation effects.
310. Treatment shortly before irradiation with anumber of radioprotective chemicals (MEA, AET,
5-HT, cysteamine, PAPP and others) affords a certain
amount of reduction of the life-shortening effect, bycomparison with irradiated untreated controls. The
nature and the dose of the drug; the dose of radiationin relation to the form of the relationship and to its
possible modilication by the drug treatment; the strain
and sex of the animals; are all variables that may tosome extent modify the final outcome of the drugradiation interaction. The effect on longevity of thesedrugs is often smaller, sometimes marginal, bycomparison with the effect produced by the same drug
treatments on early mortality: dose reduction factors in
the region of 1.4 to 1.8 may be derived. Some protective
effect is also found with fractionated courses oftreatment but not with duration-of-life exposures andlow drug levels. The protective action of a single drug
may cumulate with the effects of other drugs and withthe action of concomitant treatments like anoxia, bonemarrow transplantation. antibiotics. Whether theprotective effects of the drugs on the life span operates
through a decreased induction of tumours or of othernon-specific conditions is not clear. However. theincidence of some diseases such as kidney sclerosis(which is responsible at medium-to-high doses for life
span shortening) may be decreased by the action ofradioprotective drugs.
311. Isologous marrow infusion acts essentially on
short-term lethality: late survival is not correlated withthe size of the marrow inoculum or with the amount ofmarrow shielded. The only long-term effect thatappears to be affected by transplantation or shieldingof haemopoietic cells is the induction of thymic
lymphoma or of myelogenous leukaemia. These data,
together with other findings [P3, S35, S36] may beviewed as evidence that marrow exhaustion does notcontribute to natural aging or to radiation-induced
life-span shortening.
312. The only generalization to be gained from theexperiments where whole- and partial-body irradiation
were compared is that partial-body exposure in therange of medium-to-low doses is less effective (both perunit dose and per integral dose) than whole-body irradiation for induction of life-span shortening. Experiments where doses of many Gy are given to sections of
the body are clearly unsuitable for studies on thepathogenesis of life shortening, because under these
conditions localized destructive lesions to the irradiatedorgans are decisive for survival or death of the animals.
Data are unsuitable for other lirm conclusions on thecauses of death contributing to the loss of life-time. It
appears however that inclusion of the kidneys in the702

irradiation lield is a prerequisite for induction or acceleration of nephrosclerosis, a disease that in all strains ofrodent tested and at doses of a few Gy largely contributes to life-span shortening. The tumour spectra andthe pathogenesis of each tumour type are too variable
for any meaningful generalization. In cases where
leukaemia contributes substantially to the reduction oflife, the lower incidence of this disease resulting fromthe shielding of the hacmopoietic system [K12, K16, 12,
C24] could explain the low efficacy of the partial-body
irradiation in respect to life shortening.

IV.
A.

THE HUMAN DATAINTRODUCTION

313. In this chapter the evidence for a non-specificlife-shortening effect in the human species is discussed.
The evidence available comes from three different
sources of epidemiological studies: groups of people(radiologists.
radiology
technicians.
physicians)
exposed occupationally during their professional life;
patients who have undergone radiation treatments forpathological conditions, mostly for tumour therapy orfor control of ankylosing spondylitis; a large number ofsurvivors of the A-bomb experience in Japan in 1945
and a few hundred people exposed in the Rongelap
fallout accident in 1954. The data will be discussed
separately, since the conditions of the exposure aredifferent in the three groups and the characteristics ofthe sample size and of the epidemiological observations
are also quite different.
314. The studies performed on humans are subject toa number of limitations, mostly related co the lack ofany control over the variables in question. In general.
the sample size is small for effects which have often amarginal incidence over the whole population studied.
The life span study on the A-bomb survivors,
numbering about 80 OOO irradiated persons. is an
exception. Often the time elapsed between irradiationand the epidemiological survey is insufficient to reveal
effects which take a very long time to develop. In thecase of radiotherapy patients there is the concomitantpresence of an important disease which causes a
decrease .of survival completely unrelated to theradiation exposure and induces a prevalence of
associated disabling conditions altering the spectrum
and the time of occurrence of the causes of death
expected in a normal population.
315. Finding suitable control groups to match theirradiated group is always a problem: the distributionof ages. the geographical location, the differences in thesocio-economic status and in the living and working
conditions between the control and the test sample areoften quite large. When the effects to be studied aresmall the choice of an appropriate control group may
often be decisive in order to assess their presence andmagnitude. Although in many cases corrections can beapplied to allow for obvious differences, a subtle
difference may remain unrecognized and may thus alter
to an unknown extent the interpretation of the data. In
all cases differences in the composition of the control
and the test sample. difficult to be recognized add
variability to the data and uncertainty to the conclusions.
316. Jn retrospective studies the accuracy of therecords is often a problem. For some groups (physicians, radiotherapy patients) the high standard of the
medical care makes the records on causes of death very

useful and well documented. But in other instances
records are poor and causes of death only approximately known. Uncertainties may apply only to someand not to all causes of death and the ability of theepidemiologist lies in identifying these sources of errors
and properly allowing for them. Radiation dose records
are mostly uncertain or unavailable; as in the case foroccupational exposures where presumptive evidence
must often be used instead of more precise statementsof dose. In these cases no analysis of dose-response.:
relationships are possible, but only contrasts of broad
categories of exposed versus unexposed groups. At theother extreme. doses in the treatment volume are very
well known for radiotherapy patients. but may not beeasy to estimate for all tissues of importance outside thebeam.
317. Radiation dose distribution in time is often
unknown and variable within the ascertained orpresumptive period of occupational exposure; theradiation beams are often of very low energy andtherefore likely to be absorbed superficially; irradiationof the hands. arms or upper part of the body makes the
sample of occupationally exposed individuals very
inhomogeneous. And. in addition to the abovementioned factors. the acute. fractionated or chronic
conditions of the exposures make it difficult to compare
the results of the various series. The interplay of allthese variables would naturally call for multifactorial
types of analysis. which however have not been specifically applied to the field of life shortening.

B.

DATA FROM OCCUPATIONALLY EXPOSEDPEOPLE

318. Following a number of papers where an
increased rate of leukaemia in radiologists, ascompared to other medical practitioners, had alreadybeen reported [M25, M26, U13], in 1947 Dublin andSpiegelman [D8] published some preliminary data on
United States physicians during the period 1938-1942.
showing essentially that physicians experienced thesame longevity and mortality as a male test group of thesame age in the United States. No evidence of diseases
associated to radiation exposure was found in thatstudy, but in a subsequent paper [09) this research was
extended to the mortality of medical specialists during
the same period. Among 175 146 medical doctors listed
in the American Medical Directory in 1940. 37 610 (or21 %) were classified as full-time specialists. During thefive years covered by the study there were 12 419
doctors who died in the age group 35-47 and 2029 ofthese (or l 6.3%) were medical specialists. The mortality
ratio from all causes for specialists was 78%, taking thedeath rate of all physicians to be 100%. Radiologists
were reported to have a mortality ratio of 0.90. dermatologists of 0.98. pathologists of 0.60. Radiologists
showed a high rate of mortality from cancer andleukaemia and among 95 recorded deaths of radiologists leukaemias were higher than in any otherspeciality.
319. In 1956 Warren [W2] reported on 82 441 physicians dead during the period 1930-1954 inclusive. He
found that physicians had a mortality rate about thesame as that of the general adult population. In 1950 in
the United States the average age at death for a maletest group having reached 25 years of age was 65.6
years. Radiologists died on the average 5.2 years earlier
than other non-exposed physicians, who died at 65.7
years. Also. the non-radiologists known to be exposed

to radiation did show some life shortening (they lived
on the average 63.7 years) although less than that ofradiologists. Failla and McClement [F4] estimated thatradiologists received an accumulated exposure that
could vary from rather low values to about 1000 R, witha possible whole-body exposure of 500 R in 35 years ofpractice.
320. Warren [W2] found that deaths from leukaemia
among physicians were 120 over the period 1950-1954,
which rate was about three times that for the generaladult population. During 1930-1954, 0.63% of thedeaths from specified causes occurring among nonirradiated physicians were due to leukaemia, against a
2.33% among other specialists having had some contact
with radiation and 3.65% of leukaemia deaths in radiologists. Also, the average age at death of physicians
dying from leukaemia was 60 years. whereas radiologists with leukaemia died on average at 55.8 years. Not
only radiologists and medical specialists exposed tosome radiation had a shorter mean life span than othernon-exposed doctors, but they seemed to die younger
from practically every cause of death, neoplastic.
degenerative, infectious or other stated or non-statedcauses. This suggested that radiologists were subject tosome factor lowering their resistance to disease andhastening aging. The fact that other specialists exposed
to some radiation had mortality values intermediate
between radiologists and non-exposed physicians was
taken as a further evidence that such a common
causative agent may be radiation.
321. In a subsequent paper Warren [W3] added two
years to his previous series and compared the life spanof radiology specialists (averaged over periods of 5
years) with the duration of life of the United States
male population at large. He found that the mean age atdeath of radiologists before 1945 was less than 60 years,
while after that date it increased progressively toapproach by 1955 the average age at death of thegeneral male population. This observation implied thatduring the period 1930-1955 there had been a lower
rate of mortality of the radiologists as compared to theaverage male population. so that, in spite of a generaltendency to an increased life span. the average age atdeath for the two populations compared had by the endof the period come very near.
322. Seltser and Sartwell [S37] examined the comparability of the groups in Warren's [W2] study. in order to
see whether there might be other differences that could
account for the apparent life shortening of the radiologists, compared to non-radiologist physicians. They
tested the hypothesis that the observed differences
might result from an unequal age distribution among
the samples under comparison and found in effect thatthe age distribution of radiologists differed from that of
the other physicians: radiology being a relatively new
medical specially. there were proportionately fewer
radiologists in the older age groups where the mortality
intensity was heavier. And when the expected age
distribution at death was recalculated using data from1940 and 1950, it was concluded that radiologists wouldin fact be expected to die at younger ages. just because
there were proportionately fewer elderly radiologists.
This finding raises some doubt on the comparison
method adopted by Warren [W2]: it shows that the
average age at death is in this particular case amisleading parameter, while comparison of age-specificdeath rates in the two groups would be a more reliable
method of analysis. Seltser and Sartwell. however. did
not prove that the exposure to radiation of radiologists
had no effect on their life span.
703

323. Similar reservations about the method used byWarren [W2] were expressed by Lewis [L18] in a review
on radiation-induced leukaemia. He pointed out after
appropriate calculations that a difference of at least 6
years in excess in the life span of radiologists would be
expected by comparison with other non-exposed physicians, solely on the basis of differences in the age
distributions among the two samples compared. If thiswere true, radiologists might have had a slightly longer
life span than other non-exposed doctors.
324. At approximately the same time the results were
published of a survey on British radiologists by CourtBrown and Doll [C27]. The study concerned life expectation and cancer mortality among 1377 male radiologists, mostly diagnosticians. who had been members ofspecialist societies in Great Britain during 1897-1956. It
proved impossible to assess the exposure to radiation ofthis group: it was simply assumed that the average dose
received prior to 1921 (when the first recommendations
on radiation protection were issued) was high, whereas
the average exposure of those registered as specialists
after that date had been likely to be within the limits
recommended.
325. Mortality data were calculated from the
population at risk at each age and in each year. The
expected numbers of deaths were first estimated byassuming that mortality might be the same as for all
men in England and Wales in the same age groups andover the same time period. Expected deaths were also
calculated according to those expected in the uppersocial class or in the medical class as a whole, withsome corrections concerning the relative mortality ofpeople in various social groups aged 65 or more. Bysimilar methods the number of deaths to be attributed
to all types of cancer (appropriately corrected for
occupation and social class) were obtained. All the data
were kept separate for radiologists registering before orafter 1921.
326. With regard to life expectation. the observed
deaths were 463. fewer than expected on any of theassumptions mentioned, which would have been
between 499 and 525. If deaths attributable to cancer
were excluded. the relative differences between
observed and expected cases became more marked andapproached statistical significance. Thus, there was noevidence that occupational exposure to radiation
caused a detectable non-specific shortening in the
expectation of life. As to cancer mortality, a significant
excess was found among radiologists entering practice
before 1921, the excess being confined to tumours of
the skin and pancreas (and possibly to leukaemia). No
excess mortality from cancer was found in thoseentering radiology after 1921, although the time elapsed
up to the completion of the study was insufficient toensure that the cancer hazard had been totally
expressed.
327. The study on British radiologists was recently
updated by Smith and Doll [S59] to include observations up to the beginning of 1977, by which time about
55% of the 1338 persons had died. A reliable estimate ofthe dose received by these individuals proved impossible, but it was calculated that those entering theprofession between 1920 and 1945 might havecumulated a whole-body dose of the order of 1 to 5 Gy.
As in the previous study. the mortality of the radiologists was compared with that of all men in England andWales, all men in the upper social class and all male
medical practitioners. Radiologists entering the704

profession before 1921 had a 75% higher cancer death
rate than other medical practitioners. Leukaemia,
tumours of the pancreas, Jung and skin were significantly elevated. The cancer death rate among those who
had started the profession after 1920 was not significantly elevated. Data were not available to examine
non-cancer mortality by individual causes. However, it
was confomed that the overall non-cancer death rate
among radiologists was significantly lower in two outof three comparison groups than that of other classes
under comparison. Thus, an extension by 20 years of
the study provided no support for the concept of a nonspecific life-span shortening.
328. Seltser and Sartwell [S38] returned again to the
problem of mortality of radiologists of the UnitedStates, in comparison with other medical specialists.
Their new study covered the period 1935-1958, during
which the mortality experience of 33 616 members ofseveral United States medical specially Societies wasanalysed, in order to test the hypothesis of a possible
increase in mortality due to occupational radiation
exposure. The Societies were selected in such a way that
their members had a postulated high (radiologists)
intermediate (internists in general) or low (ophthalmologists and otorhinolaryngologists) rate of exposure toradiation. The mortality experience in these groups
conformed to the above hypothesis and the median age
at death was about 5 years greater among the lowestexposure than the highest-exposure groups. The method
followed for the comparison was to determine personyears of exposure, specific for age and calendar time,
and to relate these to mortality. There were three
periods along which comparisons were made:1935-1944; 1945-1954 and 1955-1958.
329. Comparison of matched and paired subjects forlow- and high-exposure groups were also carried out
and they gave results consistent with those of groupcomparisons. The differences in mortality increased
with age but decreased with calendar time for all except
the oldest age classes. There was no excess mortality ofradiologists in the 35-49 classes of age over the period
1945-1958, suggesting that by that time the hazards had
been controlled. The increased risk of mortality was
distributed over a number of assigned causes of death.
In the Societies with a postulated high exposure
mortality due to cancer, cardiovascular-renal diseases
and all other causes combined was increased.
Leukaemia showed the highest ratio of observed/
expected deaths at all ages combined. In general. withthe exception of leukaemia and other cancers, themortality ratios were highest in the oldest groups of age.
The excess of leukaemia and all cancers combined was
greatest during the last working years and the excess inother causes during the post-retirement years.
330. From the above data Seitser and Sartwell [S38]inferred that occupational exposure to io111z111g
radiation on the part of radiologists had in the past
produced a non-specific life-shortening effect. But thevalidity of this conclusion depends on the demonstration that the groups compared are similar in all
respect, except for radiation exposure. The authors
examined certain characteristics of the samples
compared such as the geographic distribution of thegroups, the region of residence. the size of the living
communities, the birth-place: none of these comparisons revealed any difference among groups. Exclusionfrom the comparisons of the first five years after themembers had joined the Societies, in an attempt lo
eliminate a possible selection due to persons with poor

health not joining the profession [C27], did not modify
the conclusions. And the same was true for anotherpossible cause of selection due to the unfit persons notentering the profession with the highest radiation risk.
Factors known to affect the survivorship of otherpopulations (smoking, diet, alcohol consumption,family longevity) could not be tested, but were notdeemed to have caused significant differences among
the population groups tested.
331. Seltser and Sartwell commented on the fact thatthe reduced survival (about 5 years) among radiologists
for the years 1935-1944 was remarkably near to thatobtained by Warren [W2]. This occurred in spite of thefact that the method used by this latter author (but not
his conclusion) was criticized by Lewis [Ll8] and by thesame Scltser and Sartwell [S37]. Whether Warren [W2]reached the right conclusion with the wrong method, ornot, the results from his and from Seltser and Sartwell's
study are in any case in good accordance.
332. The differences with respect to the negative
findings of Court-Brown and Doll [C27) could first be
explained, in the opinion of Seltser and Sartwell [S38],
by the methods of analysis. The absence of acomparison between medical specialists in the British
series would be a weakness, since specialist physicians
have a more favourable survival experience than males
in the general population, at least in the United States.
Also, the numerical adequacy of the British data might
be questionable, since with groups of the order of 1000
persons a life-shortening effect of as much as 10 years
could go undetected, even if present. Other differencesof substance may have regarded the more careful andearlier adoption of safety measures in the United
Kingdom than in the United States; the fact that in the
United Kingdom most radiological practice was carriedout in hospitals and therefore much of the exposure
might have been taken by radiology technicians and notby the specialists; the wider use of fluoroscopy than ofradiography and also the greater number of films used
per radiological examination in the United States thanin the United Kingdom [V7]. It should be pointed out,
however, that both the United Kingdom and the UnitedStates series agree in showing that since adoption ofradiation protection limitations any hazard attributableto radiation can no longer be documented.
333. Two papers from Japan on a small group ofradiology technicians were also reported. In the first
one [K 17] estimates of radiation injuries such as
leukaemia, cancer of the skin and tumours of the innerorgans were carried out but no mention was made oflife-span shortening associated with the exposure of thisgroup of people. The second paper [K 18) reported thatduring the period 1933-1963 there were 52 radiology
technicians dead in three Japanese prefectures. The
corrected death rate corresponding to this number was
significantly higher than that in the population at large
employed in similar professions and aged over 15 years
in 1955. There was some tendency of the death rate toincrease with increasing occupational exposure. but nocorrelation with the age at which exposure first began.
Except for skin cancer which was significantly higher,other causes of death were similar in this group as in
the general population. Life expectancy in each age
class was shorter than in male persons of comparablesocial and working conditions which were over 15 yearsof age in 1951 and 1952. A life-span shortening
amounting to 6.6 years in the x-ray technicians wasfound, corresponding to an estimated loss of 0.92 d R-1.

334. Another paper on the mortality of Japaneseradiology technicians was made available to theCommittee [S53]. During the period 1955-1965 thenumber of these technicians was estimated to be 74 721
and the observed number of deaths in this group was 91(for male Japanese of the same age classes 325 were
expected). Leukaemia deaths did not exceed the
expected value, although the relative risk of leukaemia
was an order of magnitude higher for people who had
been employed for over 29 years. Seventeen deaths
were registered in 1964 and 1965 (80 would have been
expected for male Japanese of the same age classes)with an average age at death of 47.7 years (against 48.0
expected). The estimated exposure ranged from 9 to 37
R during the ten years of observation. Since there wereno significant differences between observed andexpected values, it should be concluded that radiationinduced life shortening was not proven in thispopulation sample.
335. New data on the effects of ionizing radiation onradiologists were reported in 1966 by Warren andLombard [W4]. The study comprised 5982 certified
radiologists which were compared with all physiciansof the United States in 1949-1951. with the malepopulation of the United States aged over 25 years in1950 and with a group of 3176 Massachusetts dentists.
Although the number of certified radiologists increased
more than three-fold from 1940 to 1960, their mean age
did not change at all and remained between 46 and 47
years. The mean age at death of radiologists was 55.8
years in 1934-1939; 59.3 years in 1940-1949; 64.5 years
in 1950-1959 and 70.1 years from 1960. The rate of thisincrease was higher than that of the general malepopulation, so that, from 1960 on, the two curves
expressing the increase in the average age at deathversus time crossed with each other. The life shortening
observed in preceding years could not be attributed toany one cause in particular, such as leukaemia, but was
the aggregate of shorter life spans associated with manycauses of death. Leukaemia had a higher risk (about 5
times) among radiologists than among the malepopulation at large, but it occurred rarely and only
after a number of years of occupational exposure. It
was more common in radiologists than among the malepopulation at large, but it occurred rarely and only
after a number of years of occupational exposure. It
was more common in radiologists after 40 years of age,but more common before 40 in the general population.
In recent years the excess incidence of leukaemia inradiologists decreased. From the above findings
Warren [W4] concluded that radiation protection
measures had been effective in providing adequate
safeguards for the radiology specialists.
336. Miller and Jablon [M27] searched for lateradiation effects among men trained as radiographersin the United States Army during the Second World
War. The mortality experience of this group of people(6560 persons in total) was compared over the period
1946-1963 with that of other groups trained by the
Army as pharmacy (1522 persons) or medical laboratory technologists (5304 persons). It was difficult toascertain the radiation dose but it was concluded fromancillary evidence, in the absence of more complete
records, that they received substantially greaterradiation than did patients exposed to x rays fordiagnosis. Causes of death were investigated and in
only 1 out of 16 possible comparisons between exposed
and non-exposed groups there was a statistically significant difference of any interest in the present context. It
referred to an excess of tumours of the respiratory tract705

which was elevated among radiographers: however, thedifference between expected and observed values wasdue in part to the low mortality rate from this cause ofdeath in the control samples. No significant excess ofleukaemia was found among the radiographers, but in astudy of this size a two- to three-fold increase in the riskof leukaemia could have gone undetected. No information on life-span shortening was reported as such.
337. There was yet another report from Japan on themortality and causes of death of radiology technicians
during the period 1966-1972 [K19]. Among thesetechnicians affiliated to the Japanese professional
association there were during the above-mentioned
period 134 deaths, a number much lower than expected,
owing probably to some inadequacy of the survey. Outof these deaths, 6 were due to skin cancer and 2 toaplastic anaemia and these numbers were significantly
higher than would be expected to occur among the
population at large. Leukaemia was found in 5 cases.
indicating no significant difference with the number
expected. Concerning the average age at death, 52.7
years was the value found among radiology technicians,
while the expected value would have been 48.6 years. A
very recent evaluation of the doses absorbed by persons
dying from neoplastic and non-neoplastic causes wasreported [A17]. Statistical tests to investigate a possible
relationship between dose and mortality showed nocorrelation for the majority of causes of death frommalignant tumours and for the cancer versus noncancer causes.
338. The mortality rates of United States radiologists
in comparison with other medical specialists were reexamined by the Johns Hopkins University group[l\128, M29] in two reports published in 1975 up to a
total follow-up of 50 years. The comparison regarded
male members of the Radiological Society of North
America who were contrasted with fellows of theAmerican College of Physicians and members of theAmerican Academy of Ophthalmology and Otolaryngology. The information through 1954 available fromthe previous study by Seltser and Sartwell [S38] was
updated for new members and decedents up to 1969.
Deaths and causes of death were traced for 99.5% of
the decedents. The persons under comparison wereabout 30 OOO among all Societies for a total number ofdeaths of about 6500.
339. In the first paper [l\128] the mortality rates fromall causes were calculated by the life-table method ofanalysis with age- and time-adjustments of the death
rates in such a way that cumulated rates could becompared within any 10 year cohort and acrosssocieties. No specific study of the influence of life style
was included in this or the following [M29] study.
Mortality from all causes depended on the decade ofentry. During 1920-1939 death rates of radiologists
were higher than those of any other specialist group forboth cancer and non-cancer causes. The differential
between the rates for radiologists and other specialists
was lower in the 1930-1939 cohort and it disappearedin the 1940-1949 cohort. So did the graduation of death
rate radiologists > internists > other specialists which
was noticeable in earlier periods. Removing the deaths
from cancers in the 1940-1949 cohort led to a disappearance of the difference between radiologists andnon-radiologists noticed in earlier cohorts. The allcancer mortality rates for radiologists were higher thanthose of other specialists up to the decade ending in
1949. The next decade had not aged sufficiently to show
the expected peak of cancer mortality in the 60-64706

years age group. It was pointed out that self-selection of
the persons entering any one group and the life styleafter entering the specialty would have little influenceon the data: thus, the presumed radiation exposure of
the specialists under comparison would appear as the
only reasonable way to explain the mortality differences and their trend over time.
340. In a companion paper [l\129] the specific causesof death contributing to the excess risk of mortality inradiologists were examined. In the 1920-1929 cohort
the radiology specialists, in addition to the previouslynoted cancer mortality [M28]. showed also the highest
death rate for diabetes, cardiovascular-renal diseases.
stroke, hypertension and suicide. After this early period
radiologists ranged highest among other comparisongroups only for cancer mortality. The excess ofleukaemia observed in the 1920-1939 cohorts subsequcnlly disappeared. During the same period, however.
lymphoma mortality. particularly multiple myeloma,
increased significantly in radiologists entering theirprofession in 1930-1949. Except for this latter finding,which was discussed in relation to possible effects ofradiation on the immune system, the data reported
confirmed and extended previous observations. The
authors were aware of the peculiarity of their findings,
as radiologists of the United States are the only humanpopulation where life-shortening effects of radiation,over and above those related to an excess tumour
induction, have been observed. They .specificallycommented on this point and reaffirmed the validity of
their observations. They also added [M28] that it may
be premature to state conclusively that such an effecthas disappeared in the 1940-1949 cohort. since
relatively few persons in this cohort (193 out. of 1011)
had passed through the ages when mortality is higher:
examination of an additional 5-10 years period might
be required to determine whether such an effect has
been reduced through a decrease of the occupational
exposure.
341. More recently Polednak et al. [P4] reported on themortality of a group of women employed in the dialpainting industry in the United States. A cohort of 634
subjects working in this industry during 1915-1929 wastraced from employment lists. Mortality in thesesubjects was compared on the basis of death certificateswith the general mortality rate of a comparable female
test group. An increased death rate was observed incomparison with the expected rate in the exposed
population (240 cases versus 188.5 expected).
342. Bone cancer (22 cases versus 0.3), cancer of nonspecified sites (18 versus 2.6), cancer of the colon ( I 0versus 5) diseases of the blood and haemopoietic organs(4 against 1) and external causes (31 against 10.1) werealso increased, as compared to the general population.
Mortality from selected causes was also examined as afunction of the year of first exposure, time period of
observation and age at first exposure. The mortality
ratios from all causes and a\l cancers in women
exposed after 1925 were lower than in women exposed
in 1915-1924, in good agreement with the fact that thework regulations for the dial painting industry cameinto operation at about that time. Large-scale measurements of radium burden on these women were begun in
1954 and an anlysis of the relationships of radium bodyburden to mortality was performed only on women
alive in 1954 who had been measured at least once
between 1954 and 1975. Only 360 women in the groupwere available for an analysis as a function of dose andtherefore the comparison with respect to cause-specilicmortality was performed between two groups: subjects
with a body burden lower than 1.8 MBq or those with aburden of 1.8 or more MBq. Mortality ratios from allcauses higher than 1 were observed only in the groups
with the higher body burdens (1.91). Among these, allmalignant tumours, bone tumours and other unspecified neoplasms were also significantly elevated. Among
women with less than 50 µCi body burden, tumours of
the large intestine were the only significantly increased
cause of death.
343. Another paper by Stehney et al. [S39] is more
specifically concerned with the possible presence in thisgroup of women of life shortening ascribable to causes
other than bone sarcoma and carcinoma of the headsinuses. The study was performed by the life table
method using comparable age- and time-specificmortality rates for females for the comparisons. There
were 1235 women exposed before 1930: they were on
average 20 years old at employment and about 44% of
the persons in the group had died by the end of 1976.
The observation times thus covered a period of between
45 and 60 years. Regarding death from all causes. 529
deaths before the age of 85 were observed versus 461
expected and the cumulative survival of the group was
significantly less than expected, starting at 10 years
after employment. When mortality rates for bonesarcoma and head carcinoma were subtracted from themortality rate for all causes, there was no significant
difference at the 5% level in the total population (455cases observed against 460 expected) or at any of thetime intervals considered. A correction for the effect ofcompeting risks was also made on the data after
exclusion of the radium-related tumours and thedifference between observed and expected survival was
similarly non-significant also under these conditions.
When calculations on the expectation of life were
performed at one year intervals from zero to 59 years
after the first employment, differences between
expected and observed mortality were again notapparent. The conclusion from this study is that when
radium-tumour deaths are removed from the exposed
sample the average survival is indistinguishable fromthat of the contemporary control group of the same age.
Thus. to the precision obtainable with such a small
sample size, only the radium-related tumours contributed significantly to life shortening of this population,with no evidence of non-specific effects.
344. The epidemiological data on uranium miners inCzechoslovakia [K.25]. the United States [A13] andCanada [G18] are discussed in Annex L in connection
with the combined action of radiation and tobaccosmoke on lung tumour appearance. The problem of life
shortening has not been addressed specifically inpublished work on these series. However. to the extent
that standardized mortality rates may indicate theprevalence of death mechanisms or causes, the data
available can not be interpreted to show non-specificlife shortening. The Hanford series [M31, G20] and thePortsmouth Naval Shipyard Series [R12] are similarly
negative in respect to any such effect having been
observed in the employees of a large atomic plant andof a nuclear shipyard.

C.

DATA FROM RADIOTHERAPYPATIENTS

345. Doses administered to patients surviving radiotherapy are rather well known and may be taken as theindependent variable against which any possible life
shortening may be tested. The limitations with thisgroup of people are due to partial-body exposure andto the possible effects of the disease initially requiringradiotherapy. The relevant data should thus be taken
critically. Sorensen [S40] studied 184 patients treatedfor cancer of the uterine cervix in 1922-1929 in
Denmark. surviving for at least 5 years after treatment
and having been followed for the 20 years thereafter.
Sorensen found that survival was not correlated withthe stage of the disease at diagnosis. Each patient loston average 3.5 years of life by comparison with themortality experience of the female Danish population.
This excess of deaths was exactly accounted for by
patients who died during observation time for a recurrence of the neoplasia and there was no evidence that
irradiation as such had decreased the survival rate of
the patients without recurrence.
346. Newell [Nll] attempted to establish some correlation between integral radiation dose and longevity in
217 women treated by radiotherapy at Stanford
University in 1924-1947. The patients affected bycervical carcinoma in stages I and II had survived for
10 or more years after treatment. Radium treatment
alone or radium in conjunction with x rays were used in
the therapy. From the data Newell concluded that nolife shortening attributable to radiation had occurred in
the patients. The data were also evaluated independently by Kohn et al. [K20) who had access to theoriginal records: their c-0nclusion was the same.
347. A third series was reported by Kohn. Bailar andZippin [K20, Zl] on about 500 cases of cervicalcarcinoma treated with x rays and/or radium obtained
from two cancer registries in the United States. These
women were treated prior to the age of 55 and survived
at least 5 years after treatment. By the time of the lastreport about 38% of the women had died and this fact
limited objectively the weight of the conclusions. The
patients were grouped according to the stage of thedisease at the time of treatment and according to theregional dose delivered. There was no evidence ofradiation-induced life shortening. It was also reported
that the incidence of leukaemia appeared in thesepatients to be lower than among patients treated forankylosing spondylitis or for metropathia haemorrhagica.
348. Indirect information of a negative nature may bederived from a study of nearly 3000 children irradiatedin infancy to shrink their allegedly enlarged thymus.
These infants were followed in time and compared with
about 5000 non-irradiated siblings. In spite of afour-fold increase in tumours. particularly of the
thyroid. among the irradiated subjects, the report [H 15]
shows good agreement between observed and expected
numbers of death. This indicates the absence of excess
non-specific mortality, which may not in any case be
surprising in view of the small portion of the body
irradiated. The data of Peters et al. [PS] on 61 patients
given local irradiation to suppress stomach hyperacidity after partial gastrectomy are inconclusive as tothe presence of non-specific life shortening.
349. In 1965 Court-Brown and Doll [C28] reported ona sample of 14 554 persons (12 161 man and 2393
women) treated for ankylosing spondylitis with one ormore courses of radiotherapy at various centres in the
United Kingdom during 1935-1954. These patients had
been followed for periods varying from 5 to 25 years up
to the end of 1959 with reasonably good records of the707

treatment; adequate follow-up information in 98% of
the cases were available. The number of expected
deaths in these patients if they had suffered only anormal mortality rate were computed from the numbersof person-years at risk for each sex, age group andcalendar period and they were multiplied by the sex
and age-specific mortality rates for each corresponding
period. These calculations were performed for allcauses of death, all cancers. the principal types ofcancer and the respiratory diseases. The total death rate
among the patients was abqut 1.8 times as high as thecorresponding national death rate. When the various
causes of death were analysed separately, the following
observations were made.
350. In the test sample (by comparison with thegeneral population) deaths attributable to arthritis andother forms of rheumatism were very high (about 100
times on average); deaths attributable to clinical conditions known to be associated with ankylosing spondylitis were on average 2.9 times more common; deaths
from conditions attributable to irradiation (aplastic
anaemia. leukaemia, cancers other than leukaemia)
were about two times as common; deaths due todiseases from which the mortality could be similar tothat of normal population had a prevalence of 1.3. Thislatter increase regarded all conditions examined andthe total experience was sufficiently large for it to behighly significant. When mortality was examined as afunction of the post-irradiation period, all causes ofdeath other than cancer and aplastic anaemia were in aconstant relationship to the expected mortality. In
contrast, for leukaemia and aplastic anaemia mortality
increased within the first 5 years of observation andthen fell off; deaths from cancers of heavily-irradiatedsites were increased approximately two-fold at 6-15
years after treatment. Many different types contributed
to this excess, in a rough proportion to their natural
incidence. Deaths from cancers originating in otherlightly-irradiated tissues were not increased significantly.
351. The interesting observation in the present context
is the increase in deaths due to non-specific causes andnot grossly related to spondylitis or to irradiation. The
authors [C28] pointed out a number of reasons thatmight account for this finding. Firstly, non-specificdeaths might contain a small proportion of rare conditions related lo spondylitis (lesions of the aortic valves,
regional enteritis, proneness to accidents). Secondly,
patients in this group carry other conditions known to
be associated with spondylitis (amyloid degeneration,
nephritis) that might decrease resistance to non-specificcauses of death. Thirdly, the inaccuracy of thediagnoses at death, the possible effect of drugs and theuse of imperfect death-rate values for the calculation of
the expected numbers of deaths were discussed as otherpossible reasons. Finally, the constancy in time of theratio between the number of deaths observed other thanthose presumably related to radiation over the expected
number calculated from national mortality rates
suggested that the above excess mortality was likely to
be dependent on the spondylitis itself and unrelated to
the form of the treatment.
352. The 1965 study of Court-Brown and Doll [C28]included many patients who had been treated with xrays more than once. This fact could complicate theinterpretation of the late effects of the overall
treatment, since subsequent irradiations may havecontributed to the excess of death observed. A very
recent study by Smith and Doll [S62] reports on about
708

14 OOO patients with ankylosing spondylitis given asingle course of x rays between 1935 and 1954. They
were observed for an average follow-up time of 16.2
years, after a mean bone marrow dose of 3.47 Gy. The
numbers of deaths expected by cause were estimated bymultiplying the person-years at risk by the corresponding age- and sex-specific mortality rates forEngland and Wales. Mortality from all causes
combined in the test sample was 66% greater than formembers of the general population. Although the study
was mainly concerned with cancer mortality, it did
show that there was also a substantial excess of deaths
from non-neoplastic conditions. which appeared to be
associated with the spondylitis itself, rather than its
treatment. However, the excess of deaths fromleukaemia and cancers of the heavily irradiated sites inthe test sample was attributable to radiation exposure.
The authors concluded that, on the whole. the data did
not support the suggestion that radiation could produce
a non-specific effect of life shortening affecting death
rates from causes other than cancer.

D.

DATA FROM A-BOMB SURVIVORS

353. The effect of radiation on aging and life shortening in an Oceanic population irradiated in 1954 wassummarized in a report by Conard [C29]. A number ofchanges connected with aging was investigated andamong them the opacification of the eye lens, thepresence of chromosomal aberrations in perypheral
lymphocytes, immuno-haematological and nephrosclerotic changes. Regarding life shortening in particular,
the number of persons exposed was too small to allow
any reliable assessment. The population under study
includes. in fact a control group and two irradiatedgroups of 334 persons in total, exposed to a maximumof 175 R from fission-product gamma radiation.
354. The study of the A-bomb survivors in Japan, is
providing information on long-term radiation effects,
including life shortening, that will eventually form themost extensive source of data on the human species.
The earliest reports of the A-bomb series are particularly concerned with the description of the sample [B21]
and with mortality from all causes [J5] and from
specific causes up to 1960 [J6. A6].
355. The report covering the period up to 1966 [B22]was based on the T-65 dose estimates and included
16 356 deaths among about 109 OOO people, comprising
irradiated and control groups. When malignant
neoplasms were excluded from the analysis, there was
no evidence that radiation might aspecifically shorten
life and the excess mortality of the irradiated sample
could best be explained in terms of disease-specificeffects, particularly leukaemogenesis and, moregenerally, cancerogenesis.
356. Mortality data from the Japanese sample up to1970 [J7) allowed the following conclusions. Althoughlate radiation effects on human mortality could to somedegree resemble non-specific manifestation of accelerated aging, the most notable effect remained by far
the induction of tumours and leukaemia. The authors
could not conclude with certainty on the absence of anexcess mortality, for example, from diseases of thecirculatory system or from cerebrovascular conditions:but it appeared most unlikely, if there was indeed any
excess, that it could approach the excess of tumour
induction.

357. The problem of longevity in irradiated humanpopulations with special reference to A-bomb survivors
up to 1972 was reviewed by Anderson [A9]. He
concluded that evidence for a tumour-independent
shortening of life was equivocal and, in his opinion, thisexperience would be at variance with other reported
experience in man. For this reason, judgement on theinterpretation of the Japanese data should be reserved
pending further evidence. However. from their reviewof thirty years experience with the A-bomb survivors(02]. Finch and Beebe [Fl] could find no convincing
evidence for a generalized increase in mortality fromnatural causes other than cancer, in contrast with therequirements of the hypothesis of accelerated aging.
358. A re-examination of the mortality experience of
A-bomb survivors up to September 1974 was performedby Beebe, Land and Kato [86). The number of deaths
from non-neoplastic diseases, whose increment could in
principle be suggestive of a non-specific life shortening,
was at the time about 14 OOO among 82 OOO survivors. In
the irradiated sample, cerebrovascular diseases, othercirculatory diseases and diseases of the digestive systemshowed no evidence of an increase. Deaths from
diseases of blood or blood-forming organs were apparently increased, but difficulties with the diagnosis madethis finding uncertain. All other non-neoplastic conditions were apparently unaffected.
1950-54r----·-,
1955-56•

I I

1959-62359. When all diseases except tumours and diseases of
the haemopoietic system were pooled together, their
combination produced no further evidence of a
relationship to radiation dose. Although the sample
group in the Life Span Study could indeed be regarded
as a highly selected group. there was no evidence that
selection due to survival from early effects, as suggested
by others [S41. R 10). might have favourably influenced
the subsequent mortality. ll was concluded therefore
that the views that ionizing radiation may causepremature aging in man or that the carcinogenic effectis only a part of a more general acceleration of aging
find no support in the Japanese experience: radiation
effects on long-term mortality do not appear diffuse but
rather specific and focal and principally cancerogenic.
360. The latest available analyses of the mortality
experience of Hiroshima and Nagasaki survivors
should also be reported for completeness [B23. B24),
although the information contained in them is essentially that discussed in Beebe, Land and Kato [B6).
These contributions showed that age-specific death
rates for all non-tumorous causes (taken at 4-year
intervals and adjusted for city and sex within each time
period) separately calculated for the group receiving
0-0.09 Gy and that exposed to 1 + Gy were superimposable (see Figure XVII). This finding, as repeatedly
pointed out, cannot be reconciled with the hypothesis

I I

1963-66

II

1967-70

1 r 1971-74

1000

I
iOO

10

I

1 + Gy0-0.09 Gyl~~•,_.I
O· 1 O· 20· 35. 50 O· J 0- 20· 35· 50 G· 1C· 20· 35· 50 (I. , O· 20· 35· 50 0· 10· 20· 35- 50 O· 1 O· 20· 35· 50
9 19 3..\ 49 + 9 19 34 49 + 9 19 34 49 + 9 19 3,i 49 • 9 19 34 49 + 9 19 34 I,') +AGE AT THE TIME OF THE BOMBING
Figure XVII. Death rates (per 100 OOO persons per year) from all diseases except neoplasms by age at the timeof the bombing In Hiroshima and Nagasaki, during the period 1950-1974, plotted for each 4-year period separately for the group receiving 1 + Gy (heavy llne) or 0--0.09 Gy (light llne). The rates were adjusted for city andsex within time periods. Data from Beebe, Kato and Land [824]that radiation may accelerate natural aging. but rather
shows that any life shortening present in the sample isassociated with cancer induction. The results shown in
Figure XVII did not change even when the observations were extended up to 1978 on the same cohort[K23). The survival curve excluding deaths frommalignant neoplasms for this cohort does not differ bydose over the whole period 1950-1978 [K23]. However,
it is important to note that the most pronounced
putative effects might be expected among the younger
age groups where to date relatively few deaths from
non-malignant causes have occurred.

361. The contrast between the Japanese data and thedata on occupational exposure of radiologists of theUnited States and their mortality prior to 1950 was
specifically discussed in the last publications [823, B24),
particularly in view of the most recent evidence ofMatanoski [M28. M29). It was pointed out that either
the contrast groups in the occupational experience(radiologists against other medical specialists) wereconfounded by factors other than irradiation or that
there are intrinsic differences in the nature of theradiation response between the Japanese survivors andthe radiologists of the United States. Since the latter709

hypothesis would be against a massive body ofevidence collected on other mammals, one should
logically be inclined to favour the first interpetation,
particularly in view of the much more reliable
experience from Japan. which is now based on about
20 OOO deaths among about 80 OOO A-bomb survivors.
362. Mention should also be made of an up-to-date
report concerning the mortality experience of children
exposed in utero to the A-bombs [K21]. There were 203
deaths among 1923 subjects during 1945-1976. The
mortality ratio increased with dose in both cities. The
increase was linear with dose in children dying within
the first year of exposure, particularly within the firstmonth; however, there was no increase between l and 9
years and only the suggestion of a further increase after
10 years of age. The excess mortality was significant
only for children exposed during the third trimester ofpregnancy, but loss of the embryos and foetuses might
have been present in an unknown percentage ofpregnancies before term. Regarding the causes ofdeath, no information was available for 55 persons (outof a total of 203 deaths) most of whom died within one
year after birth: loss of this information was due to theconfusion in the official vital statistics reporting system
which arose immediately after the war. The sample size
is yet too small and too young for any conclusion about
a possible excess death from non-specific causes.

E.

CONCLUSIONS

363. The data on occupationally-exposed groups ofworkers do not lend themselves to complete dose-effectanalysis and. in the absence of precise dose evaluations,conclusions must rely on comparisons between groupsof exposed and non-exposed individuals. Under thesecircumstances, the homogeneity between the control
and the test samples is critical because in many series
the effects are marginal and their statistical significancemay depend on the choice of controls.
364. The data on radiologists leave no doubt thatparticularly in the early days of radiology leukaemia
and cancer were indeed induced in these persons.
Observations in favour of this conclusion have been
confirmed in all studies [09. W2, W3, C27, S38, W4,
M28, M29]. However, in some instances a higher
incidence of neoplastic conditions was not accom- ·panied by an increased death rate and shortening of life
[D9, C27]. while in others [W2, W3, S38, W4) there wasa true loss of life amounting to 5 to 6 years, following
exposure for the whole working life. Not all of this life
shortening may be accounted for by leukaemia andcancer induction. and other non-neoplastic conditions
contributed to it. Some of these may have been due tonon-stochastic damage, such as skin necrosis, leading todeath in the earlier series. There is no way to derivefrom the data, as there is no knowledge of dose. anapproximate value of the life shortening per unit dose.
There is unanimity in the conclusion that the inductionof neoplastic conditions, accompanied or not by life
shortening, has disappeared in more recent years,
presumably after the adoption of radiation protection
measures.
365. True shortening of life has only been reported ina series from the United States [W2.W3,W4.S38).
Reasons to justify the absence of life shortening amongradiologists of the United Kingdom have indeed been
given and the absence of effect could be accounted for710

by objective reasons and on methodological grounds. It
has been pointed out that with samples of the order ofl OOO persons prevalence ratios of the order of 2 to 3 forleukaemia and life-shortening effects of the order of 5
to 6 years can hardly be resolved. It should also be
realized that induction of neoplasia is not necessarily
linked to life shortening. Within the large limits ofvariation cited above an excess mortality ratio of 1.5 to
2.0 could be compensated by a lower rate of death fromother causes, leaving the death ratio from all causes
unchanged with respect to controls [S42].
366. In spite of the small sample size (about 1200
persons) the data on the mortality experience of dial
painters convincingly showed that the only causes ofdeath significantly contributing to the life-span shortening in these women are bone sarcoma and carcinomaof the head sinuses, tumours known to be specific risks
for 226Ra and 228Ra exposure. To the precision possible
with such sample size. therefore, non-specific mortality
was not seen, in spite of the known presence of nonstochastic injury in these subjects, for example, in thebone. On the other hand, exposure under these conditions was localized and not extended to the whole body.
367. The experience on the radiology technologists.
both from Japan and from the United States, is considerably more limited (and therefore much less significant) than that on radiology specialists. However. on
the whole, it does not appear in contrast with the latter.
Here again. induction of leukaemia and of some formsof cancer were often seen [Kl 7, K 18, M27, K 19]; in one
case life shortening was reported [K 18), but not inothers.
368. What may safely be concluded from the data on
occupationally-exposed pioneer radiologists is thatneoplastic diseases, particularly leukaemia and skincancer. are real effect. Some life-span reduction may
also have been present in these persons who were presumably exposed to high doses; however, this effect
was reported unanimously to have disappeared in more
recent years in radiology specialists entering theirprofession after the radiation protection rules havebeen in operation. If this conclusion is true. it should
logically follow that within the range of doses recommended since that time (that is for exposure rates of 1 R
per week as a maximum) no reduction of life span canbe expected and any residual prevalence of leukaemia
and tumour induction would be insufficient to cause astatistically detectable shortening of life.
369. In principle, radiotherapy patients have anumber of favourable characteristics for epidemiological studies (knowledge of the dose, good standardof medical follow-up) which might counterbalancesome negative aspects (small samples, death associatedwith the primary disease). In practice, the three small
series available on women surviving radiotherapy foruterine cancer [S40, Nl 1. 21) have yielded negative
answers in respect to life shortening. The size of thesesurveys is certainly inadequate for any firm conclusion.
but a negative finding would not be unexpected underconditions where only a small fraction of the body wasirradiated. It is known from animal experimentationthat life shortening is less likely to be observed afterpartial-body exposure (see section 111.D).
370. The experience on the ankylosing spondylitis
patients [C28) does show at a first sight a small but
significant
prevalence of unspecilic mortality.
However, a thorough analysis of the causes of death,discussion of the epidemiological evidence and consideration of the time-course of the excess mortality raisesome doubt on the reality of this observation. On thesegrounds a dependence of the excess non-specificmortality on the spondylitis itself cannot be rejected.
Thus, the survey seems inadequate to validate theexistence of a radiation-induced non-specific shortening of life.
371. On the whole, therefore, the evidence comingfrom radiotherapy patients is negative for the presenceof the life-shortening effect under discussion.
Naturally, the weight to be attached to these data isrelatively smaller than that applying to the surveys on
occupationally-exposed people and much less than thatcarried by the studies on A-bomb survivors.
372. The incidence of leukaemia and various othermalignant tumours is increased among the survivors of
the A-bombs. These diseases arc associated with ameasure of life shortening and appear to accountentirely for the observed shortening of life in the
exposed groups. irrespective of dose. The absence ofsignificant non-specific life shortening is importantbecause this conclusion is based upon a large amountof data on person-years at risk. However, the limited
experience in connection with the younger age groups
where few deaths have occurred should be kept in mind
in this regard.
373. The negativity of this survey is remarkablebecause the modality of the irradiation (acute, highdose rate) would be expected to produce a maximum oflife shortening by comparison, for example. with the
low dose rate occupational exposures. Also. theabsolute amount of radiation absorbed over the wholebody (of the order of 1 Gy or more, but for 90% of those
exposed below 2 Gy) should also have produced asubstantial life-shortening effect. But since there is noevidence to support the hypothesis that a selection of
the early survivors might have favourably influenced
the subsequent long-term mortality experience [R 10),the conclusion must be accepted that up to the present
time there is in this large sample of persons no evidenceof a diffuse non-specific effect of life shortening. Any
long-term effects are, on the contrary, very specific.
focal and essentially cancerogenic.
374. In conclusion. the evidence concerning a nonspecific radiation-induced life-shortening effect in man
has been reviewed in the preceding paragraphs. This
review has produced essentially negative answers.
except for the pioneer radiologists of the United States.
The data from this group of people are. however, incontrast with a massive body of data in experimental
animals where such a non-specific effect, particularly at
low-medium doses of radiation, cannot be substantiated. The data on the pioneer radiologists · of theUnited States are in contrast with the much larger bodyof information on the A-bomb survivors. In the latter
situation. the degree of life shortening observed can be
accounted for by the increased prevalence of a variety
of malignancies, although data on the survivorship ofyounger age groups are still limited. It may be noted inthis connection that the early radiologists that experienced a degree of life shortening were exposed at a
relatively early age.
375. Pending further evidence therefore. it should beconcluded that radiation-induced life shortening in
man is essentially due to the induction of specificneoplastic conditions. Non-specific effects on the life

span, suggested in one instance. have not been provenbeyond doubt: the weight of these data is therefore
insufficient to modify the above conclusions.

V.

GENERAL CONCLUSIONS

376. The Committee has reviewed in this Annex mostof the existing data in animals and man on the subjectof radiation-induced life span shortening and has
considered the effect thereupon of the major physicaland biological variables. The analysis of the Committee
has been centred particularly around the possible
existence of non-specific mechanisms of premature
death. the dose levels at which these mechanisms might
operate and their possible relationship to the physiological processes of aging. A non-specific life-shortening action and an aging effect of irradiation wereclaimed in earlier times on the basis of gross experimental observations of irradiated animals. The
Committee believes. however, that a critical reappraisalof previous findings and the availability of more
precise and significant new information have now
made these concepts untenable.
377. The Committee has briefly reviewed the current
concepts concerning natural aging and the possible
mechanisms at the molecular. cellular, tissue andwhole-body level that might be responsible for senescence. The Committee has also examined the interactions between such mechanisms and their expression inan animal population as statistical events causing the
population's extinction in time. It has concluded that
there are at present great difficulties in defining aging
in ways other than by actuarial parameters and that it is
impossible to decide whether the changes revealed byexperimental observations in senescent animals are thecauses of aging, effects of aging or indeed aging itself.
The Committee has therefore decided to confine thisAnnex to the analysis of life shortening as such,pending further clarification of the notion of aging.
378. All available data consistently show that
irradiated animals do experience on the average ashorter life span than their non-irradiated controls.
However, the notion that such an effect may be due tothe same spectrum of causes taking normal animals todeath (although appearing earlier in time) may not be
substantiated by experimental evidence. Thus, the ideaof a non-specific effect of irradiation superimposableonphysiological aging becomes conceptually
improbable and logically unnecessary. This is particularly true at doses below the mean lethal dose where life
shortening may be accounted for solely on the basis ofradiation-induced tumour induction. Under these
conditions life shortening becomes a compounded butvery imprecise way of expressing by actuarial values theacceleration or higher incidence of tumour appearance
in an irradiated animal population. However. at doses
well in the lethal range a non-specific component of life
shortening may become apparent. which may besubstantiated by diffuse damage to the capillary bloodvessels or to the connective tissues.
379. The Committee has reviewed and independently
analysed the existing life-shortening data on micesubmitted to a single acute dose of radiation of both
high- and low-LET. While in each given experimental
series the dose-effect relationships could be of manydifferent forms. pooling many series resulted in an711

apparently linear relationship for low-LET and an
apparently convex upward relationship for fast neutron
exposure. The different forms of the two relationships
cannot be explained at present. but the fact that a linear
function of dose may reasonably describe life shortening in a highly non-homogeneous population where
different strains, ages and sexes are represented hasinteresting practical implications. Information on othermammalian species such as the rat, the hamster and the
dog have also been examined in comparison with themouse to which most data refer.
380. Single acute irradiation is undoubtedly an easy
and efficient way to induce and study life shortening,
but long-term irradiation at low doses is the most
relevant exposure condition in practice. The existingdata on rodents irradiated for the whole duration of
their life was examined by the Committee as a functionof the dose rate and of the total cumulated dose. for
exposure to electromagnetic beams. The lower efficacyof the long-term as compared to the single-dose
treatment has been confirmed for x and gamma rays. In
the case of neutrons, long-term treatments have in someinstances shown reduced life shortening compared withsingle doses and in others increased life shortening,particularly in more recent studies. Under long-term
conditions of exposure phenomena of apparent life
lengthening have been reported whose significance has
also been discussed. The special case of chronic
exposure to many injected. ingested or inhaled radionuclides has been studied but has revealed no life shortening in excess of that attributable to the induction of
specific tumours caused by the various nuclides.
381. A variety of observations exist in experimental
animals concerning the effect on life shortening
induced by changes in the dose rate, dose fractionationand chronic exposure terminated before death of theanimals. The Committee has reviewed this informationand has concluded that all these treatments, but each toa variable degree, result in a level of life shortening
which is intermediate between that of the acute and of
the life-long treatments. Repair and repopulation
mechanisms are operating under such circumstances.
These mechanisms appear to depend markedly on dose
and time parameters as well as on a large number ofbiological variables, following complex relationships.
382. A linear relationship for gamma rays, assuggested in paragraph 379 implies no dose rate dependence. Therefore fractionation of the dose orcontinuous irradiation at low dose rates should not
reduce life shortening per unit dose. This however is atvariance with the Committee's conclusions about theexperimental observations (paragraphs 380 and 381 ).
Thus a linear-quadratic relationship which can provide
for the observed effects and which is equally likely
according to the analysis in paragraph 95, might bepreferabletoa simplelineardose-response
relationship. At low doses and dose rates the form of
the response would be essentially linear in either case,but not with the same slope.
383. For neutrons, the convex upward shape of thedose-response relationship for single doses intrinsically
implies an increased effect when the dose isfractionated or when low dose continuous irradiation isused. As has already been noted, the experimental
results with neutrons have been mixed. In some cases,
life shortening appeared to be reduced by lengthening
the exposure, in other cases (particularly in more recent
experiments) it is increased by fractionation. It is712

possible that real differences in dose-effect relationships for different tumour end-points do exist, and thatthese account for the complexities observed in the life
shortening response for different strains or species.
384. The RBE of fast neutrons up to 14 MeV, as
compared to low-LET radiation, has been assessedfrom published data and from the Committee's own
analysis. For acute doses in the region of 0.01 Gy or
neutrons, the RBE cannot be determined precisely. The
predicted values could be about 10, but values as highas 50 might be possible, depending upon the assumed
shape of the dose-response curves. Low-LET radiation
appears to be about seven times less effective in studies
with duration-of-life exposure than it is for single
exposures. At low dose rates and duration-of-life
exposure neutrons could be 20 to 40 times more
effective than low-LET radiation.
385. The vast majority of the data reported on rodent
and non-rodent species of mammals submitted toradiation of different types delivered at various dosages
appeared, when appropriately analysed, to beconsistent with the notion that life shortening after
doses up to about the LDso130 can be accounted foressentially by an acceleration or an increased net
incidence of tumours causing premature death. No data
were found to clearly support the concept that radiation
may advance in time or accelerate the appearance ofdiseases normally associated with senescence, without
any change in the type and the relative incidence of
these diseases.
386. The spectrum of radiation-induced diseases andthe consequent life shortening depend largely on thespecific physiological and pathological characteristicsof the irradiated animals. The Committee has reviewed
the evidence pertaining to the changes in life shortening
seen in different species of animals. Such data had beenobtained in the hope of constructing a scale of radiosensitivity values to aid in the extrapolation of findings
from animals to man. The conclusions to be derived
from such data may, however. hardly be taken as usefulgeneralizations in view of the large differences pointed
out above. Comparisons between strains of the same
species, the mouse, have also been attempted and haverevealed interesting regularities in the life-shortening
response, in spite of the strain-related specificities. The
formal genetic analysis of these findings is not yet suffi.
ciently advanced to allow the identification of thecommon principles underlying the precocious death ofanimals through a variety of specific causes.
387. Extensive data led the Committee to conclude
that the sex of the irradiated animals is also a significant variable affecting the susceptibility to life short·ening: female animals are in general more sensitive
than males, mostly owing to their higher rate of genitaltract tumours and leukaemia in mice. As to the effect ofage, irradiation in utero seems to produce usually lesslife shortening for a given dose than irradiation during
the post-natal ages. Irradiation early in extra-uterine
life also produces, all other conditions being equal,
more life shortening than treatment in older ages.
Physical conditions (temperature. stress), chemicaltreatments (oxygen. radioprotective substances) andpartial-body irradiation have been studied in respect totheir influence on life shortening. The presence and theextent of these effects have been assessed by theCommittee.

388. Data derived from irradiation of human subjects
were the object of special attention in this Annex. They
were obtained through epidemiological investigations
carried out on persons exposed in the course of theirprofessional life (radiology specialists or technicians,
dial painting workers), on patients treated withradiation for various pathological conditions (tumours,
ankylosing spondylitis) or on survivors of the atomic
explosions in Japan. The Committee has investigated
the reliability of the different series from the point ofview of exposure conditions. dose assessment, methodology of study and significance of the conclusions.
389. With regard to occupational exposure, it hasrepeatedly been shown that a component of life shortening observed in radiology specialists exposed in the
United States during the early days of clinical radiology
cannot be accounted for solely on the basis of tumour
induction. Such a component has apparently disappeared at about the time when radiation protection
recommendations limiting exposure to less than 1 R per
week came into practice. Analogous investigations
carried out on a group of British radiologists wereunable to reveal such an effect. Numerous other studies
conducted on radiology technicians or on dial painters(these latter series carry less weight due to the smaller
size of the groups) were also negative for the presenceof non-specific life shortening. The Committee
therefore concluded that the existence of such an effectis doubtful under the conditions of the above studies or.
more conservatively, that exposures to 1 R per week orless does not cause any detectable non-specific shortening of life in man.
390. With regard to medical exposure. investigations
on patients treated with localized radiotherapy forcancer of the uterus did not reveal any life-shortening
effect. A survey on spondylitis patients was inadequate
to validate the presence of life shortening associated to
the radiation treatment rather than to the disease itself
requiring radiotherapy. Although the importance to be
attached to these conclusions is limited by the modalityof the treatment (partial-body) the conditions are also,
in general. against the notion of non-specific life shortening.
391. The epidemiological series in man which carries
by far the highest degree of significance and reliability
for the numerosity and the accuracy of the observations
is that on the A-bomb victims. For the last thirty years
and up to the present stage of the observations thisseries has indisputably shown that there is no evidenceof life shortening that could not have been explained byan increased appearance of leukaemia and solid
tumours.
392. In essence, the review of the Committee has been
unable to substantiate in experimental animals and in
man a non-specific effect of life shortening below themean lethal dose. While the presence of such an effectcannot be excluded for higher doses, there is no firm
evidence that diffuse non-specific mechanisms causing
premature death in the irradiated animals may be
operating at the low doses and dose rates of significance to the radiation protection of man. On thecontrary. long-term radiation effects arc very specificand essentially cancerogenic under these conditions. In
the light of present data, a higher incidence of tumours
fully explains the life shortening seen in the irradiatedpopulations.

VI.

RESEARCH NEEDS

393. Given the above conclusions, the Committee
believes that experimental research specificallydesigned to analyse the physical and biologicalvariables affecting radiation-induced life shortening
only should not be assigned high priority. It is,however, advisable that the collection of data on life
span might proceed in parallel with other experiments
planned for different purposes. in particular for the
study of induction of neoplasia. Specific recommendations as to the general strategy and the detailed topics to
be followed in this field have been issued in previous
reports of the Committee. In order that the best use
might be made of data on life span shortening obtainedin the course of long-term experiments. these data
should be collected and analysed according to methodological needs repeatedly discussed in the precedingtext.
394. For the actuarial analysis of the data, use of thefollowing methodologies is recommended:(a)Analysis of mean and median ages at death andsurvival times following standard statistics. both asabsolute parameters and relatively to the control
values:(b) Analysis of the extinction curves of the irradiatedversus the control population;(c) Analysis of age-specific mortality rates mirradiated and control groups;(d) Corrections of the life-shortening data to accountfor the effects of competing diseases by methods
which have been shown to enhance the capacity todiscriminate between specific and non-specificcauses of death:(e) The use of multifactorial models in the analysis ofcomplex physical. physiological and pathologicalinteractions.
395. Attention has been repeatedly drawn to the factthat in order to assess specificity or non-specificity oflife shortening detailed clinical surveillance during lifeand pathological examination of the animals at death isnecessary. Although the assessment of causes of death
is difficult in animals. it is essential if the data to begathered arc to be of the most use. Serial sacrificeexperiments, whether included in life-span studies ornot. would be particularly valuable to investigate theevolution in time of the diseases contributing topremature death. Attention should also be drawn to therenewed importance of interspecies extrapolation, notonly for life shortening but for tumour induction as
well, because of the lack of human information forsome types of radiation, including neutrons. In thisregard experiments in species intermediate in life span
between mouse and man are of special importance.
Questions of particular interest at this time relate to thesensitivity of embryos to life shortening and to tumour
induction among the different species.
396. The Committee's recommendation for a low
priority to be assigned to research solely on radiationinduced life shortening derives from the opinion thatsuch an effect may be explained at low doses and dose
rates by tumour induction. with addition. at higher dose
rates, of specific non-stochastic effects described in
Annex J. It is perfectly compatible with the wellestablished fact that gaps still exist in knowledge of thelife-shortening effects of radiation in mammals. The
713

Committee has identified many areas which could
profitably be explored among which are:(a) The analysis of physical and biological factors
contributing to the life-shortening effect incomplex regimes of long-term irradiation;(b) :he analysis of the causes leading to an apparent
life lengthening for irradiation at low doses anddose rates and the innuence of biological variability or repair phenomena thereupon;(c) TI1e problem of RBE. particularly at low doses
and dose rates, of radiations of different qualities;(d) The dose levels at which non-stochastic effects aswell as tumour induction might become of importance in the causation of death after whole orpartial-body irradiation;(e) The extent and mechanisms of life shortening after
pre-natal irradiation;(f) The innuence of modifying factors. including
radiosensitizing and radioprotective treatments;(g) The role played by the different pathologicalconditions in determining the form of the doseeffect relationship for life-shortening;(h) The comparison of life-shortening effects indifferent species.
397. The Committee believes that the collection ofdata about the effect of radiation in causing or contributing to deaths in men should continue to be given thehighest priority. This applies not only to the series on714

the atomic bomb victims which will undoubtedly befollowed with care, but to all other groups and particularly to those undergoing occupational exposure and topatients treated by radiation for benign diseases and forcancers with a good prognosis. The final conclusions
drawn from such data will be of immediate relevance tothe knowledge and prevention of radiation effects in
the human species. This recommendation is made sincefurther knowledge is needed regarding deaths from
non-stochastic damage, in addition to cancer induction.
at as wide a range as possible of both dose and dose
rate.
398. The loss of life expectancy by affectedindividuals in whom a tumour has been induced byradiation is an important factor in risk estimation. It
involves a knowledge of the frequency of induction ofeach tumour, the average latent period and the averageage of the population at risk. The lost time per affectedindividual can then be used as a basis for comparisonof hazards between occupations involving exposure toionizing radiation and, for example, lost time due toaccidents (fatal and non-fatal) in a range of industries[I4]. These estimates can also be used to derive an
average loss of life span for the entire population at risk
from a given average dose. lt would be useful to havedirect estimates of the life shortening per unit dose forpopulations such as the Japanese survivors, when theseare feasible.

Ta b l e
Life shortening after single acute who 1e-bodi x- or ~an111a-rax t rea tmen ts
Speciesand strain
Mouse
Tosfrains
8AF1

Sex

Radiation

M
M
M
M

98 kVp x
80 kVp X
135 kVp X
250 kVp x
80 kVp x
135 kVp x
250 kVp x
250 kVp X

F
F

CAFl

F
F

Swiss
CFl

F
F

Percentage Range of Days lost Fonn of Ref.
1ife lost percentage per Gy or curve
per Gy or shortening
per 100 Rg/
per 100 R
4.2
4. 2 a/
4.9 a/
4.6 a1
6.7 al5.2 a/
6. 1 al
3.2-6.3

30.2
30.4
27.2
39.2
32. l
39.2
19

15
24
29
27
35
34
43
21-42

?

250 kVp x
4.7
garrrna
2.6
from weapon
x rays7.8-10.9

0-30
8-37

19
25

11-31

?

RF

ga!llna
5.0 b/
from weapon 6.3 o/
M 200 kVp X d/ 4, l
F
- 5.4
M+F
15 MeV x
5.4
F 250 kVp x
9.J
F 60-Co ga11111a 4.7
M 250 kVp x
F 60-Co ga11111a
F 300 kVp x
4.1 e/F 300 kVp X
5.9 eJF
300 kVp x
1.1

et

3-45
10-51
23.2
30.6
5-44
36.5
28-85
3-31
5-29
3-32
7-38
6-32

37 c/
47
28
81
40
45
25
56-3
15-2
23 e/
29 eJ
75

LAfl

M+F 60-Co gamma 2.5 e/

7-29

15

85CF1

60-Co garrrna 5.3
F
5.3
M 250 kVp x
2.5
M 250 kVp x
7.3
M 250 kVp x
9.8
F
137-Cs gamma 9.6 e/
M
6. 1 e/F 137-Cs gamma 7.0 e/
M60-Co ga11111a 5. I e/
Fs.2 e/

5-42
6-43
0-9
0-66
0-48
0-38
0-20
0-14
0-40
0-45

45
48
22
54
68

M

LAF!

6 strains
SAS/4
RF /J
RF
RF /UnC57BL/6L
A/J(CS 7BLxC3H)
BALB/cC57BL
RFM
BALB/c
B6CF1
Rat
rutar

~gle

M

F

M

z1

39 e/
42 e/
43 ~/

linear

IG2)
rG3]

?
?
?
convex[K7]
upward?
linear [ Sl 7]
1inear ;s1aJ
convex [B8;upward?
concave :us]
upwardconcave :G4]
upwardlinear [Ll]linear? [S19]linear f S21]
convex [U7]upwardconvex fYl]
upward [Yl]convex 'Cl2]
upwardconcave '.GS]
upward1inear [A7]1inear1inear? [C13]linear? (MS]1i near? (MS]complex (S44)
1i near?
1i near? rs44J
1inear [T4]linearM
FF

250 kVp x

4.2-4.9
2.8-4.0
250 kVp x f/ 0.4

7-29
4-24
39

35-41
15-22
28

1inear?
1i near?

ru1

F

250 kVp x

3-24

284

1inear?

(A2;

6.7

fHS~

a/ Data derived on the hypothesis of linearity from experiments at the Lo level.
50
Figures obtained at the LO level.
Figures derived from Grahn 50and Sacher rGJ].
al Average for all strains.
·e/ Data derived on the hypothesis of linearity.
T/ Data derived from a single exposure of JOOR given under 5 % oxygen.
~/ .11.s given by the authors.
fi/

,1

715

Table 2
Life shortening after single acute whole-body neutron treatments
Speciesand strain

Sex Radiation

Mouse
Swiss

F

CF!

LAFl
CF!
RF /Un

BC6Fl
RFM
B6CF1
Rat
Guinea-ei9
a/
o/

£I

Percentage Range ofDays lost Form of Ref.
life lostper Gy or percentage per Gy or curve
shortening
per 100 R':./
per 100 R

therma 1
columnF weaponneutrons
M weaponF
neutronsF
fissionneutrons
M 1 MevF
neutrons
F 14 MeV
neutrons
M fission
FneutronsF
fissionneutrons
M fission
Fneutrons
M fission
neutrons
M fission
neutrons

4.7

0-30

19

1i near

[Sl7]

4.7

8-30

37

linear

[S18}

6.7
15.6
22 !I

9-23
9-39
9-45

79
6

concave
upward1i near?

[US]

9.0-18.0
8.4-14.9
6. 7 a/

19-28
33-47
9-26

21-6
11-3
40

[U7)

35. 9 b/

7-26
9-31
4-25
0-20
0-25
0-31
22

300- 90390-110convex
upwardconvex
upwardconvex
upwardconvex
upwardconvex
upward

45-77
42-70
10 !I

6

?

[Vl]

[DI]
[A7]
[UBJ
[T4)
(KB]
[K9]

12

a/

12-16

?

- 100

fK8]

rK9'
J

Estimate derived from a first-approximate assumption of linearity.
Estimate derived from data at the smallest dose of 0.2 Gy.
As given by the authors.

various animal s ecies
rnn

Irradiation condition

Chronic x-irradiation
Acute x- or
y-irradiation
Chronic y-irradiation

716

Approximate sensitivity
Moresensitive

More
resistantMonkeyRat, dog and mouse
Rabbitabout equal
Rat and mouseabout equa 1
Guinea-pig, rat, dog
and mouse about equal
Man, dog and mouseabout equal
Dog and mouse about equal
Mouse

Man

Chronic y-irradiation

Guineapig

Chronic y-irradiation
Chronic y-irradiation

Goat

Refs.

~Bll J

[Ul]
[Gl J
[S23]
[G6)
[N7)
[H9]

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