UNITED NATIONSREPORT OF THE
UNITED NATIONSSCIENTIFIC COI\IMITTEE
ON THE
EFFECTS OF ATOMIC RADIATIONNOTE
Throughout this report and its annexes cross-references are denoted by a letter
followed by a number: the Jetter refers to the relevant technical annex (see Tableof Contents) and the number is that of the relevant paragraph. \Vithin each technicalannex, references are made to its individual scientific bibliography by a number
without any preceding letter.
Symbols of United Nations documents are composed of capital letters combined with figures. Mention of such a symbol indicates a reference to a United
Nations document.

Annex G

MAMRIALIAN SOMATIC EFFECTS

Paragraphs

I. SHORTENING
OF THE LIFE SPAN I N EXPERIMENTAL ANIMALS. 1
The acute LD,, . . . . ... . . . . . . .. . . . . . . . . . . . . . . . .. . . .. . . . 8
Acute effects in single organs. .. . . . . . . . . . . . .. ... . .. . . ... . 9
Recovery from whole-body exposure . .. . . .. . . . . . . . . . .. . .. 10
The experimental effect of single doses on long-term survival. .. 11
The experimental effect of single doses on short-term survival.

The experimental effect of chronic exposure on long-term
SUMV~. .. . . .. .. . . .. . .. . . . ...... . . . . . . . . .. .. .. .. . . 14

Article: "Shorfedng of life by chrortic irradiation: the ezperimental facts", by R H . MOLE

. . . . ... .. ... .. . .. . . . . .. . ..... . .. .. .. 27
Atom bomb survivors in Hiroshima.. . . .. . . . .. . . . . .. .. . .. 28

Leukemia in man. . . .

Article: "Leukentio irt Hiroshifrur City Atorrric survivors", byNIELWALD. . . .. .. . . . . . . .. . . . . . .. . . . . .. ... . .. . ... .. 33. . .. . . . . . . . . . . . . .. . . . ... . . . .. .. 34
Leukemia in children . .. . . .. . . . . . . . . . . . .. . . . . . . . . . . . .. . 35
Leukemia after X-ray therapy for ankylosing spondylitis.. . . 40
Leukemia in radiologists

Theoretical considerations for estimation of radiation hazards 47
REFERENCES

I. SHORTENING
OF TIIE LIFE-SPAN IN( b ) The intermediate period whose duration of 1.5-2
years depends on the radiation dose, and during which
practically no deaths occur;(c) The terminal period during which the population
dies out rapidly.

EXPERIYEXTAL A N I X A L S

The experintental effect of single doses
on sltort-term szwvivol
1. The short and long-term effects of whole-body exposure to a single dose of radiation have been studied
in a variety o i mammals. JVhen "survival time" (duration of life after exposure) is studied as a function ofradiation dose, the rcsults with all species have shown
fundamental similarities that may be illustrated herewith the data of a hypothetical experiment.
2. The plan and results of the hypothetical experimentare shown in table I and figure 1. The animals wereyoung adult males, 100 days old on irradiation. They
were of a species with a relatively short life span of
2% years. Slightly different results would be obtainedwith females. Greater effects per unit of radiation dosewould be obtained with immature animals or with sickanimals.
3. The mortality-time curve (figure 1) illustrates
three major periods :( a ) The acute period lasting about one month, forwhich the LD,, is 600 rein ;4. Long-term somatic effects develop during the intermediate period and some of them become "limiting
factors" for survival in the terminal period. The complete quietude of the intermediate period indicated infigure 1 is therefore misleading-the intermediate period
is, in fact, a period of increasing morbidity. The rate ofincrease may be slow or fast, depending on the radiationdose and also on various biological factors, many ofwhich are predetermined genetically.

5. The long-term decrease in life-span, illustrated infigure 1: is dealt with quantitatively in the sixth column("Days") of table I. The decrease is not proportional tothe acute mortality (column 4). The decrease can also
be expressed as a percentage of the normal life span(column 7), which in the present experiment was 900
days. It is useful to express life-shortening in per centof normal life span for purposes of comparing resultsof experiments involving species that differ in life-span.

The animals (males, 100 days old) received a single whole-body exposure on =perimentday 0. The table records the doses given to the various groups, and the resulting changes intheir median life-spans.

hdiationGroup

Num+r oflire anrmals

dare

?em

-

1 .........
2
3 .........
4 .........
5 .........
6 .........

.........

DOY 0

Long-term decrease inlife-span

Median s u w i dlime of animals
dior on day 30
dars

Day 30

Daw

0
300
500
600
700
800

100
100
100
100
100
100

100
100
82
50
11
0

Per unl of

-

~

800
710
650
600
530

90
150
200
270

-

-

&aP

A

10
17
21
30
A

The ditTerence between the datum for group 1 (800 days) and the data for other groups
in column 5 (median survival time).
The l i e span of the controls (group 1) was 900 days

6. The dependence of biological effect on radiationdose is illustrated in figure 2. In the case of acute mortality (deaths within thirty days of exposure calculated
from table I, co~umn4), the dose-effect curve shows athreshold-the first deaths occur somewhere between
300 and 500 rem. In the case of the long-term decreasein life-span (per cent of normal life-span) the courseof the curve as drawn does not show a threshold andindicates that even at the smallest radiation doses there
is some decrease in life-span (see paragraph 11).

7. Biological effects not only depend on radiation dose
but also on dose rate. I n the hypothetical experiment, theanimals received a single dose at 50 rem/min. The same
results would have been obtained with dose rates of 5or 500 rem/min. Below 5 rem/min., however, the effectper unit dose diminishes. In the case of acute mortality.
it does so relatively rapidly. It may do so quite differently in the case of the various lcinds of late injuries,
including those shortening the life-span.
Tlre acute LD,,
8. Recent determinations of the acute LDSO(sing!e,whole-bodyfor mature mammals are given In

table 11. Values for immature and senescent aniplals
would be lower than those tabulated. It has been pointed

TABLE
11. ACUTEX-

GMIbf-4-R4Y LDso

OF MATURE MAMMALS'
SPCCUSswine..

z ~ (rods)
r

1w310
210
Goat .........................
Dog- ......................... 240-320
Alan. ........................
300 (?)
Guinea pig.. .................. 380490
Monkey.. ....................
520&louse.. ...................... 520470
Hamster.. .................... 590-800~ ~ b b i t.....................
..
680-750....................... 790-S20........+a.e..........

NU=.& pf
dcrmnrnclrons

4
1

6
0
3
1

7
3
3
2

The original reports are listed in reference 1. All doses are
estimates for the middle-longitudinal 2xis of &e animal underconditions of approximately homogeneous soft tissue d o e distribution. The dose rates ranged from 5-60 rads/min. The LD6ois that d o e killing half the animals within 30 days of exposure.
Almost all of the deaths occur within three w e e k .

154

-

800

-

t

+ .;
I

4
B

-

HYPOTHETICAL EXPERIMENT

-

-

-

-

-

-

-

E

S

B
3

-

U

-

-

I

A

I

1

I

0 30

I

I

I

200

I

400

r

I

600

I

800

DAYS AFTER IRRADIATION
Figrcre 1. Hypothetical experiment-Cumulative mortality after a single whole-body exposure.
The dose in rem is specified for each curve.

1

100

I

I

1

I

1

I

I

-

-

80 -

-

ACUTE MORTALITY

w

-

U

60-

HYPOTHETICAL EXPERIMENT

Sr

ka

H

EU
9:

40

-

-

20

-

-

W

PC

LONG TERM DECREASEIN LIFE SPAN

-

0
1

100

I

I
300

I

I
500

I

I

700

RADIATION DOSE (REM)
Figure 2. Hypothetical experiment-Effect as a function of dose. Acute mortality shows athreshold whereas long term decrease in life-span does not.

I

out1 that the values fall into two groups. Those for the'.largerJ' mammals are in the range 200-300 rern ; thosefor the "smaller" mammals are in the range 400-800 rem.
The only monkey listed (M. mulatta) falls into the"small" animal class. The estimate for man is close to thedeterminations for the guinea pig and dog, suggestingthat studies with these species may be of speaal importance. I t is to be noted, however, that the figure for man
is speculative.
Acute effects in single orgalis
9. A very great number of somatic effects have been
described that occur within hours, days, or several weeks
of irradiation. Doses as low as 5 rem, for example, havea measurable although brief effect on the mitotic index
of the skin of mice.2 In the range from approximately
25 to 200 rern, simple qzcantitative relations between
somatic effect and radiation dose have been demonstrated
in such organs as the lymph node, spleen, thymus, testis,using both microscopic and gross methods
and inte~tine,~of examination (e.g., weighing). In these examples, restitution occurs relatively quickly, during the course ofsome days or weeks, and often seems complete.
Recovery from whole-body exposure
10. When two or more exposures instead of one are
employed, some restitution occurs during the interval(s)between them. One method to study the rate of restitution is to give a non-lethal dose on day 0 and to determine
the LD,, on various days thereafter. Suppose that theLD,, of unirradiated animals is 600 rem. Furthermore,
suppose that after 300 rern on day 0 the LD,, is :(a) 300 rern on day 1 :( b ) 450 rern on day 2 ;(c) 600 rern on day 8 :(d) 600 rern on day 20.

TABLE111. T n r ~FOR 50 PER CENT RECOVERYFROM A SINGLE THOLE-BODY EXPOSURE TO X-RAYS'

Nu&

12. The data in figure 3 are based on exposure inyouth or early adulthood. Comparable data for exposure
during middle age or old age are not available.
13. I t is Anown from clinical as well as laboratory

evidence that partial-body exposure decreases the life. spanmuch less than whole-body exposure (when theeffects of roughly similar doses in rads are compared).
There is a paucity of information, however, concerning
the quantitative dependence of the life-span on (a) theregion or organ irradiated and (b) the absorbed dose.
The data from an experiment of this type are given intable 1V.O hllore information of this kind is needed.

TABLE
IV. DECREASE LIFE-SPA-KPARTIAL Ahm WHOLE-BODY X-RAY EXPOSURE
COMPARED IN THE U O U S E ~Region cxjmscd

I t may be concluded therefore that acute recovery from300 rem was complete by day 8, since by then the LD,,
had returned to "normal", and half-complete by day 2.
Experiments of this type (table 111) have shown that therate of recovery depends on genetic factors, and therefore varies with the strain and species of animal.' The
rate also depends dn the magnitude of the dose-large
doses may. so to speak, inhibit the recovery process
per se.

Animaltime of puberty or young adulthood are summarized infigure 3.5 The radiation dose is expressed as a percentageof the acute LD,,, e.g., a dose of 300 rem is called 50
per cent if the acute LD,, is 600 rem. In the various
experiments, the LD,, (in r ) varied from 500 to 800 r.
The curve fitted to the points in figure 3 is on the assumption that life-shortening is directly proportional
to dose. For mice and rats it appears that life is shortenedby about 10 per cent following a "25 per cent dose".
The curve drawn through the points in figure 3 runs
straight to the origin, indicating that radiation decreases
the life-span no matter how small the dose may be. I t is
to be noted that the figure only suggests this conclusion,
but does not prove it.

ofsbainr

X-ray dose(~nn)

50 gn unt
relime(days)

Mmc
Young ................
Adult .................
Adult.. ...............
Rat .....................

1
6
1
2

260
200-400
310

7.4
1.6-3.0
12.0
4.9 and 8.5

Munkcy (M.mulotla). ....

1

260

4.8

600

Recovery measured undcr the particular conditions describedin paragnph 10. The original reports are listed in reference 4.

The experimental eflect of single doses
on long-term sr~rvival
11. Data on life-shortening in mice and rats after asingle whole-body exposure to X- or gamma-rays at the

Dose

(?em)

Control.. .................
0
Entire animal.. ........... 530
Entire chest.. ............. 720
One-half chest. ............ 570
and caudal. ............... 1140
2cm. of trunk ............. 1700

JfcdiarSins canfly
sumidtinu
digad
after czporure from Mlbd
(dous)(P 6 .05)

676
582
646
654
591
525

Yes
No
NO
Yes
Yes

-

Female mice, 170 days old when irradiated. With the doses
employed there m-ere no acute deaths. Data from reference 6.

The experiw~e+ital
efect of chronic exposure
on long-tertn sun~i-~al
14. The experimental literature on the shortening oflife by chronic exposure to radiation, and its bearing on
the ma-ximum permissible dose for man, are discussed
in the article by R. H. Mole,7 presented in its entirety
following paragraph 15. Among other details, the reportconsiders whether a threshold dose c ~ i s t sbelow which
the life-span is unaffected. The report finds the evidence
equivocal. A significant conclusion might be established
for animals if very great numbers of them were used insuch experiments. The report points out, however, thateven if such a conclusion \\-ere established, its application to the human caserequ3e a theoretical basis
to justify such an extrapolation. Such justification islacking at present.
15. Of the experimental groups referred to in paragraph 14, two (mouse. guinea pig) that received less than
1 rern per week lived a greater total number of days thantheir respective controls. In a more recent experiment8
with Sprague-Da\vley male rats exposed throughout

1

50

-

I

I

I

I

t

I

1

SINGLE DOSEDOSE IN PERCENT OF LD- 30 DAYS

Figure 3. Life shortening (percentage) in mice and rats after a single, whole-body exposure
to X- or gamma-rays. The dose is expressed as a percentage of the acute LDm The figure istaken from reference 5 where the original reports are listed.

I
I
I

adult life to 0.8 r/day of CoeOgamma-rays, the mediansurvival times were as follows :Tmpcrature ofennironmnu

Srtrpkal time (days)

CWd

5O C.. .................. 240
2S°C .................... 460

Inadiakd

305
600

Although there were only twenty-two animals per group,
the differences between the irradiated and control groups
were consistent throughout the course of the experiment.

I

1

I

Medical Researclt Coutrcil Radiobiological Research Unit
Afonric Energy Research Establishment
Hanuell, Berks., EnglandI t is probably true to say that more is known of thebiological effects of radiation than of any other environmental hazard except bacteria. Certainly the chronic
toxicity of no chemical substance has been investigatedas thoroughly as the chronic toxicity of whole-body irradiation by penetrating gamma-rays or fast neutrons.
The incentive has been obvious : the very large industrial
hazard during the mar-time development of the atom
bomb, and afterwards the increasingly widespread risk
associated with the remarkable development of atomic
energy as a source of industrial power and of a uniqueseries of military weapons. Chronic toxicity =perimentsin the strict sense must cover the whole life-span of the* UN document A/AC.82/G/R.l15:also published in Nature

180,456-460, 1957. For table 1, figures 1 and 2, and bibliographyreferred to in this article, see immediately following the arncle.

experimental animal and thus take years to carry out,
even with the relatively short-lived laboratory mouse.
The results of war-time work in the United States havebecome generally accessible in the past few
andwork carried out in this laboratory is just beginning to
A brief survey of the experimental resultsbe p~blished.~
relating to shortening of the life-span may provide a few
facts in a field of current general interest and perhaps
raise the academic question of how the results of chronic
toxicity experiments, as such, may be generalized-aquestion which needs an answer before they may be
used to help solve the practical problem of setting safe
limits to the environmental exposure of man to irradiation.

Daily irradiation has been given to animals in a variety
of ways. for details of which the original reports should
be consulted.'-' The more important experimental features are summarized in table I. There are two importantdifferences between the experimental arrangements ofHenshaw et aL3 and Evansz on one hand, and those ofLorenz et aL4 and of this laboratory on the other. I n thefirst two sets of experiments, the animals had to betransferred individually each day from their living cages
to the irradiation boxes and back again. and each daily
dose of radiation was given in a few minutes. In thesecond two sets of cxpenments, the animals mere irradiated in their living cages, undisturbed by additional
handling with its accompanying traumatic effects, andthe daily dose of radiation was spread over 8-24 hours.
In general, the experimental animals were examinedture of the data, it would be difficult to have a clearer experimental demonstration of the existence of a threshold.
(2) The biologist, almost as a reflex, attempts to fit
a Gaussian cunre to quantitative data. Such a curve isshown as a dashed line in figure 1, and clearly fits all theexperimental data very well. The meaning of the fit atweekly doses of less than 10 r., where none of the points
differs significantly from the base line, is less clear.
( 3 ) Boche (1946, 1954)' suggested that shortening
Reszclts ar~dtheir ittferfiretaiiotz
of life-span was proportional to the total accumulated
By chronic irradiation is meant daily irradiation five,dose,
six or seven days a week at dose-levels which allow surt - to = kdt
vival for at least six months. All the experiments on
where t and t,were the mean life-spans of irradiated andchronic irradiation for the duration of life which havecontrol animals, d was the daily dose of radiation andever been carried out, so far as is known, are referred tok was a constant. This curve (k = -0.04 for gammain table I and, where possible, shown in figure 1. The durays) is shown in figure 1 as a dotted line, which also
ration of life of an irradiated group of animals has beenfits all the experimental points very well.
expressed as a proportion of its corresponding control
and plotted against the weekly dose of radiation on a
Curves 1 and 2 are empirical : curve 3 has some claim
logarithmic scale. The results from this laboratory are
to a theoretical basis. the idea that the bigger the totalshoum in black symbols. They provide the first dirkt
dose of radiation the bigger the effect, that is, the shorter
experimental comparison between gamma-rays and fast
the mean life-span. For daily exposures which kill inneutrons for chronic irradiation, where the dose of fastless than six months, however. the converse is found toneutrons was measured in terms of energy absorbed in
be tr~e.'~~*l'This is not as paradoxical as it may seem,tissue. The relative biological efficiency factor for theonce the importance of recovery processes is apprecifast neutrons used as compared with cobalt gamma-rays
ated; but it makes data on the effects of high daily doses
was 13.
(on shortening of life by much more than 50 per cent)This factor has been applied to the other two fastof little value in helping to decide which is the best ofneutron experiments, where the fast-neutron dose wasseveral curves, each purporting to describe the effects
measured in arbitrary units and where a somewhat unof low daily doses.
certain conversion factor (table I) has to be used forCurves 2 and 3 are clearly so dose together that overestimating the tissue dose. In this way the results of a l ltheexperimentally determined range they cannot be disthe experiments with fast neutrons as well as those withtinguished.
(The possibility that this algebraic similarity
gamma-rays from other laboratories have been plotted,
has
a
much
wider
biological significance is being investiusing open symbols, together with our own results ingated.)
Each
curve
appears to fit all the points better
figure 1. The agreement, when mice were used as experithan
thestraight
line
of curve 1, but this may be a spurimental animals, is remarkable, and suggests, in spite
ous
consequenceofexperimental
uncertainties. In twoof the various uncertainties in the comparisons, thatexperiments the exact conversion factor from arbitrary
chronic irradiation shortens the life of mice in a reprounits of fast neutrons to rads is unkown (see above)
ducible manner.
and factors numerically different from those used (tableI t should be noted that there are eight experimentalI) but just as plausible (see literature) would make thepoints at weekly doses of less than 10 r. or its equivalent
fit look less good. There seems to be no intrinsic reason
in neutrons, and that the duration of life in none ofwhy different mouse strains should behave identically,
these experimental groups was significantly different
and the curvilinear arrangement of the experimental( P 2 0.05) from its control.
points may merely reflect differences of strain andof dose.
The experimental results have bee11 put down as they
were obtained. hfore sophisticated analyses of some ofEach of the second two formulations indicates that~ * ~pur* ~ ~ ' ~there is no absolute threshold for shortening of life bythese results have been made e l s e ~ ~ r h e r e . ' ~Thepose of such analyses has usually been to find some reguchronic irradiation. The apparent threshold suggested
larity in the results which would all~urextrapolatioils to
by curve 1 may be thought of either as an absolute o r as
daily doses smaller than, and to species other than, thosean effective threshold, depending on whether shortening
used experimentally.
of life is considered in proportional or absolute terms.
If time is necessary for the effects of daily irradiation
to show themselves. and if this time is longer the lower
Three curves have been fitted to the mouse data andthe daily dose, then an effective threshold ntwt be
are shown in figure 1.
reached at a dose-level which takes longer than the life( 1) The straight line which provided the relative biospan to produce its effect. If so, each species would be
logical emciency factor of 13 from our second experiexpected to have its own threshold. and the longer thement (Xearq. ei d.,11, table I ) is clearly a good fit to its
natural life-span the lower this would be. The only releresults, and is.also reasonably close to the only experivant esperimental data are those of Lorenz ef al.' on
chronic irradiation of guinea pigs and these are included
mental group in our first experiment with a markedly
decreased sun-ival-time. The simplest interpretation of
in figure 1. The effect of 1.1 r dzily was possibly greatersuch a linear relation is that there is a threshold of bethan in mice (though still not significantly different fromtween 1 m d 2 r. daily below which no shortening of aits control) and the apparent threshold possibly a little
mouse's life will be produced by daily irradiation. This
less. The difference in life-span between mice and guinea
may be considered confirmed by the repeated experimenpigs is probably not large enough to decide the point,
tal failure to find a demonstrable shortening at n~eeltly and in an event there are no confirmatory data for guinea
doses of less than 10 r. (see above). Considering the napigs as there are for mice.
daily and the time of death noted. Post-mortem examinations to determine tumour incidence and the cause ofdeath were usually made, but the =perimental reports
cliff er very greatly in the detail with which these findings
are given. For this reason, and since shortening of lifespan is often considered the most sensitive experimental
index of the toxicity of chronic irradiation, survival-timeis the only experimental end-point considered here.

,iThe data for guinea pigs do show that species differences occur. Bochel suggested on. admittedly tenuous
evidence, that the constant k (curve 3) is a t , where a isthe same for all mammals. If this were true, the mouse
data should not agree so well, since to for the different
mouse strains differed. If the mean mouse t, is 600 days,
a = 7 s le5(rather different from Boche's own estimate)! and this has been used to construct the theoreticalcurve for guinea pigs (at, = -0.09 curve 3, figure 1 ) ;the fit to the experimental points is poor.

In any event, too much should not be read into theresults because of the nature of the experimental material. First, the results have all been espressed in termsof mean survival-times. This is really a rather unsatisfactory parameter to use, as may be seen from figure 2,
which illustrates the shape of the mortality curve of
normal control female CBA mice. The shape of thehuman mortality curve in the more materially advanced
human civilizations is similar. but that of mice with ahigh spontaneous incidence of leukemia may be very
different.'3l2 The mean survival-time and its statistics
are markedly affected by the occasional early deaths andno great precision in mean survival-time can be expected.
A small decrease in mean survival-time could occur
either because of a small increase in the frequency ofearlier deaths or because of a small reduction in life-spanof the upper two quartiles. In fact, an analysis of causeof death in relation to duration of life is imperative inorder to see whether irradiation decreases life-span byincreasing the frequency of particular causes of death
which kill earlier than the average, or merely by making
all causes of death kill at an earlier age.0
Second, the nature of a chronic toxicity experimentusually, if not invariably, makes it impossible to randomize treatments and to ensure that the only difference
between experimental groups is the treatment being investigated. F o r example, if animals are arranged at different distances from a source of radiation, the animals
will occupy different parts of a room for their whole
lives and it will be impossible to be sure that environmental temperature, humidity, degree of air movement
and other relevant factors possibly not even thought ofare exactly the same for each different dose-group. Thus
the differences in, say, mean survival-time between different groups, mill be due to the differences in radiationlevel plus any other relevant environmental differences.
This is not just a theoretical point. Differences of theorder of 5 per cent in the mean survival-time of female
CBA mice have been found during the past few years
not only between different "lots" of controls but also
between two sets of randomly chosen controls kept, so
far as could be, in the same environment but some 20
feet away from each 0ther.O The apparent increase insurvival-time at the lowest daily dose used by Lorenz
et al.' (figure 1) may well be due to the fact that the
animals at this dose-level were kept without air conditioning in a different room from all the other groups,
including the controls. Such variability is to be expectedby the biologist, but it should also enjoy caution in extrapolation of the results of analysis of intrinsically in=act data.
Replication on a sufficiently large scale, though often
completely impractical, could overcome this particulardifficulty. I n fact, however, replication is almost completely lacking from the =periments listed in table I.
The logic of experimentation is that experiments arerepeated and give the same result. Yet with the esceptionof a still unfinished investigation,^^ no one concernedwith duration-of-life irradiation experiments has everrepeated his esperiment even once--for whi& there areperhaps understandable reasons. The nearest to ppetition so far has been the two =periments carried out inthis l a b o r a t ~ r y , ~where* ' ~ although the same mouse strain
was used the radiation doses were different. Fromthis
point of view the value of figure 1 is to demonstrate thatan esperiment has been done, that is, that the same result
has been obtained several times over.
Lastly, it should be pointed out that in all the experiments considered here irradiation has been for the durntion of life. This may not be the most appropriate experi~ +well' ~ as olderq4.16
ment to carry out. R e ~ e n t , ~ * asevidence has shown that, in some circumstances at least,
not all radiation is of equal value, the first of a series ofdaily doses having proportionately greater effects inshortening life and inducing leulcemia than the later
daily doses. This is presumably one aspect of the time
factor: time is needed for the effects of irradiation todevelop to the point where biological damage can bed e t e c t e ~ l . ~ ~and/or~ ' + - ~ ~the reactivity of the biologicalobject may change with age." But if the phenomenon istrue of weekly doses of less than 50 r., which has not yet
been demonstrated, formulae which give equal weight toeach of a series of doses as Boche's, cannot be properly
estrapolated. Further, if at relatively high daily doses
much of the radiation is wasted, so far as producing aneffect is concerned,ll then an observed linearity of response against total dose (curve 3, figure 1) may imply
a decreasing ability of radiation to harm as the daily
dose decreased.
There has also been very little work yet on the problemof whether the effect of chronic irradiation is alteredby changing the distribution in time of, say, a constantweekly dose. The data of table I and figure 1 suggest thatit matters little whether a daily dose is given in a few
minutes or spread out over many hours; but other as~ ~ * ~ ~ that the deyet uncompleted o b s e ~ - v a t i o n s suggest
layed effects of irradiation may depend as much on theway the irradiation is given as on the total dose. I nthese experiments there was no wasted radiation: on
the contrary, as much time as possible wvas allowed forthe full development of any damage that radiation may
have caused. Such experiments may give a relation between shortening of life and dose of radiation very
different from those shown in figure 1, and indeed thismight well be anticipated by anyone aware of the normal
complexity of biological phenomena. Dose-response
curves should not be extrapolated without fully realizing
the nature of the =perimental material on which they
are founded.

Possibilities of extrapolation
It should first be emphasized how unusual it is to pay
any attention to the ends of a biological dose-response
curve. Normally, the aim of the biologist is to work In
the middle ranges and, if irregularities appear at theends, this is regarded as just to be expected, not necessarily deserving investigation.
The current maximum permissible level of radiationfor occupational exposure of man, 0.3 r. weekly (Recommendations of the Intenlational Commission on Radiological Protection), is indicated in figure 1. Extrapolation suggests that this dose-level would shorten the liyesof mice by nil, 0.02 or 0.2 per cent, depending on whlchof the three curves described earlier is taken to becorrect. As already shown, the experimental data on
chronic irradiation at low doses are not sufficiently exact
to distinguish between the curves, and the adequacy of
fit at high levels of irradiation seems quite irrelevant.
Thus the value of any attempt at extrapolation must
depend on whether there is some theoretical reason for
preferring one mathematical form to another. When thisquestion is settled, there is the additional problem of
extrapolating from one species to another.
One principle of selection often used nowadays ingeneral discussion on radiation as it affects mankind, andat first sight self-evidently sound, is to take the mostpessimistic assumption suggested by experiment or
theory for the relation between dose and effect. Lorenzs
used a very similar criterion when discussing the effects
of daily irradiation on the difficult tissues and organs ofdifferent species. He concluded that man should be considered to be as sensitive as that species of animal foundexperimentally to be the most sensitive. Clearly this is
no absolute criterion; as the range of species examined
is widened, the apparent sensitivity of man must decrease. A consistent use of this criterion would involve
denying the possibility of chemotherapy, or of selective
killing by pesticides. I t does not seem realistic to maximize pessimism as a means of choosing the best doscresponse curve.
The most plausible reason for thinking that species
differences among mammals in their reactiolls to irradiation are likely to be smaller than in their reactions tochemical agents is that the penetration of radiation into
cells is not affected by the series of permeability barriers
which every chemical agent has to pass before reaching
the site of its acti~n.'~The uniformity of the acutely
killing dose for all mammals gives supporting evidence.
However. the chronic toxicity of radiation would be expected to depend on a balance between the continuing
damage produced by the radiation and the ability of theirradiated animal to keep pace with the damage by repair.
The ability to repair and its rate must depend on manyof the structural and metabolic features which distinguishstrains and species, and, for this reason, strain andspecies differences in the dose-response cunres forchronic irradiation might be expected. Some of the ex-perimental facts can best be understood in this way.6

An alternative view is to assume that the chronic toxicity of radiation is due to processes where repair ofdamage does not occur, like genetic mutation. It may
then be plausibly argued that the genetic material of all
mammals is very similar, both physically and chemically,
and that therefore dose-response curves mill in general
be the same for all species. Such a view would suggestthat damage should be proportional to total dose, as in
Boche's formula (curve 3, figure 1). and u-ould beconsistent with the somatic mutation theory of carcinogenesis and the iact of carcinogenesis by ionizing radiation. But there are difficulties in the way of equating
damage and total dose, as already suggested, and reallyvery little evidence in support of the mutation theory ofcarcinogenesis, The theory is an easy one to accept: buteven with the most recent advances in technique its
testing seems almost impossible to envisage. However,in the experimental animal there is no simple relation
between carcinogenesis and dose of radiation, and formouse leukemia there is good evidence of the great importance of an indirect mechanism.lg Rforeover, theexperimental evidence suggests that radiation shortens
life apart from inducing cancer, and this is not easy tounderstand in terms of mutation.
If the results of animal experiments are to be carriedover to man, there must either be very good evidence
that all mammals behave alike, or sufficient human evidence of similarity with experimental animals to inspire
confidence in the process of filling the human gaps fromanimal experience. I t will at least be generally agreed
that experimental dose-response relations which cannot
satisfactorily account for all experimental results are
scarcely worth applying to the human case. I n the absence of a satisfactory theory, it seems pointless to
expend the enormous experimental efiort required todefine the relation between daily dose and life-span formean survival-times of 95 per cent and more of thecontrol: it is only in this region that extrapolation to
man is of any particular interest.
I urould l i e to thank my colleagues for allo\ving me
to make use of unpublished material.

TABLEI.
Of preceditrg paper by R. H . Mole".

Unit of irradiation cxbos~trc
LYPf ofdose Symbol
inadratwn(conansion
Dwofion used i a
G-Gamma rays fubr to Days/of daily Fie. 1
N=fast nc:rfro,rs
rods)
wcrk
dose
Smrrcr andRrfncncr

t%:nn:.dJicuscsbai?:

Shf0f

irradiation(dous)

lif~-s9cn

fiom

sfor;ofminutesminutesOn

Evans (ref. 2). . . . . .. .

5

minutes•

Lorenz et d.(ref. 4). . . Radium G
Neary et al. I (ref. 6). . Graphite N
reactorGraphite N
Neary ct al. I1 (ref. 13) . .. reactor
G[Wo
Thompson d d.(ref. 16). . 6JCo
G

8 hr.
7
6-7 1 6 2 4 hr.

0

rad

7

1 6 2 4 hr.

A

r.
r.

7
7

24 hr.
21 hr.

+.

Henshaw rt al (ref. 3). . . ./z$hite( reactor.

Lorenz el a1 (ref. 4).

.. Cyclotron N K (2.5)
r.
...
.. . .
rad.... . . RadiumGr.

{c$males

4%

28-42

- . 52-85

CBA

0

CBd
Rats (SpragueDawlcy, females only)
Guinea pigs
(hybrrd)

{

hr.

820

hledin-

475
420

500

hIediallb

75-95

703
780

240
500

&rean
Meado

90-120

585

42+

Mean

137-196

1,372

112

Mean

only)

LAP- 2

replingsunidtimc

-.

?

{ziss
.

.*

a c r 3 8 o o 0,

irradiario~r
-

6
6

G
r.
N r. (2.0).,..,.A>

5-0.ofonimals

blean survival times calculated from data provided by Hollaender and Stapleton (1948, personal communication) have beenused in fig. 1.
b Mean survival-time of the two strains combined were also
reported and have been used in fig. 1 because standard errors
were also given. However, irradiation stopped when 8-30 per centof an experimental group nxs still alive, so that the mean survival
times include variable proportions of radiation-free time.
There were real st. differences in control life-span and pm
sibly also in the effects of irradiation. The data have been pooled
to make thcm comparable with those of the other authors.
The data of Henshaw (ref. 7) have not been included because
the mean life-span of his controls %as less than a year. The dataof Boche (ref. 1) have not been included for a variety of reasons:his monkeys had tuberculosis, his mice salmonellosis; the dogs
and rabbits were irradiated in small numbers and irradiation
stopped after two years, long before the end of the natural lifespan; irradiation of the rats also ceased after two years when
16-36 per cent of the lower level and control groups were still
alive and were filled, which prevents estimation of mean survivaltimes.
Evans's X-ray data (ref. 2) have not been included becausemean survival-times were not given. The control life-span was
not given by H a p and Simmons (ref. 5). In each of Sacher's(ref. 5) and bfole s (ref. 1I ) experiments with daily X-irradiationof mice, one experimental group survived about seven months;
they are omitted because no groups surviving longer are available and because the relative brological efficiency for X- t ogamma-rays for chronic irradiation is not known.

BIBLIOGRAPHYFOR PRECEDING PAPER BY R. 13. MOLE

14. Mole, R. H., in "Progress in Radiobiology", edit.
J. S. Mitchell. B. E. Holmes and C. L. Smith(Oliver and Boyd, Edinburgh, 1956).
15. Mole, R. H., Brit. 1.Radiology, 30, 40 (1957).
16. Thompson, J. F., Tourtellotte, W. \V., Carttar.
M. S., Cox, R. S., Jr., and Wilson, J. E., Anrer. I.
Roentgelzology, 69, 830 (1953).
17. Mole, R. H., Proc. V I Int. Haematology Congress,
Boston (in the press).
18. hlole, R. H.. Brit. J. Radiology, 26, 234 (1953).
19. Kaplan, 1-1. S., Carries, W. Ha,Brown, M, B.,andHirsch, B. B., Cancer Research, 16, 4 2 (1956).

1. Boche, R. D. (1946), cited by him in "Biological
Effects of External Radiation" (edit. H. A. Blair),
N N E S VI-2 (McGraw-Hill. New York, 1954).
2. Evans, T. C., Nucleonics, 4, 2 (1949).
3. Henshaw, P. S., Riley. E. F., and Stapleton, G. E.,Radiology, 49,349 ( 1947).
4. Lorenz. E., Jacobson, L. O., Heston. W. E.. Shimkin, M., Eschenbrenner, A. B., Deringer, Margaret
K., Doniger, Jane, and Schweisthal, R., in ''Biological Effects of External X- and Gamma-Radiation"(edit. R. E. Zirkle), NNES IV-22B (McGraw-Hill,
New York, 1954).
5. Sacher, G., I.
Cancer Inst., 15, 1125 (1955).
6. Neary, G. J., Munson, R. J., and Mole, R. H..
"Chronic Irradiation of Mice by Fast Neutrons"(Pergamon Press, London, 1957). In the press.
7. Henshaw, P. S., J. Nat. Cancer Inst., 4,513 (1944).
8. Lorenz, E., in "Biological Effects of External Xand Gamma-Radiation'' (edit. R. E. Zirkle, NNES
IV-22B (3IcGratv-Hill, New York, 1954).
9. Blair, H. S., "Peaceful Uses of Atomic Energy",
11, 118 (United Nations, New York, 1956).
10. Sacher, G., Radiology, 67, 250 (1956).
11. Mole. R H., I. Nut. Cancer Inst., 15,907 (1955).
12. Sampford, M. R., Biornetrics, 8,13 and 307 (1952).
13. Neary, G. J., Munson, R. J., Hulse, E. V., and Mole,
R. H. (unpublished observations).

at.

11. LIFE SHORTENING EFFECTS IN M A X
16. Data were examined relating to the mortality of
medical specialists in order to learn if those exposed to
X-rays had a shortened life-span. In one extensive
analysi~,~utilizing the mortality data for specialists 3574 years of age who died during 1938-1942, the nrortalify
ratio was calculated for each specialty. The mortality
ratio is the ratio of the number of deaths observed to thenumber that specialty would =perience if subject to thespecific death rate calculated for all physicians. These
mortality ratios are given in parentheses in the last coluinn of table V. I t is seen, first. that specialists havq alower mortality than physicians in general ; the specialist
mortality ratio is only 0.78. Secondly, the various specialties appear to have different mortality ratios, from
0.99 to 0.62.
17. The mortality ratios of the various specialties
were r e c a l ~ u l a t e dusing. ~ ~ the death rate for all special161

ists instead of all physicians (table V). The ranking of
the mortality ratios by this method agreed with that ofparagraph 16. Eight specialties had mortality ratios
greater than unity, but in no case was the difference
statistically significant.
18. The extent to which repeated small exposures to
X-rays shorten the life of man is a matter of speculation. In the past, radiologists were so exposed, but fromthe mortality statistics it cannot be demonstrated thatthe life-span of this group of mcdical specialists has beenshortened relative to that of other medical specialists1'
although this has been suggested.*?I t is known, however,that the incidence of leukemia is increased in these men.

the incidence rate of cancer to radiation dose and to timeafter exposure. For introduction, the method of calculating the incidence rate and the influence of certain
variables on it will be discussed briefly.
20. The prevalence of cancer may be defined as thenumber of cases per unit of population at a specified
time, e.g. 15 cases per 10,000 on January 15.
21. The cancer incidence rate R may be defined as
the number of new cases per unit of time and population
occurring during a specified interval of time, e.g., 5 per
10,000 per annum. Alternatively, it may be said that an
estimate of the probability that an individual in the
population will acquire a cancer equals 5/10,000 or 5 x
lo-' per annum. R is an important statistic in the calcu111. CANCER
IN M A N
lations to be made below.
19. It is generally agreed that the incidence of can22. The total effect of exposing a population to radiacer* in man can be increased by exposure to ionizing tion is estimated in terms of the total number of cases,
radiation Quantitative data will be considered relating ,,'- induced per unit of population. If the rate after
exposure is constant at R, and if prior to exposure it*Cancer is a generic term and, as used here, includes leuwas
constantly R,, then (R-R,,) is the number of extra
kemia and all forms of so-called neoplastic o r malignant disease.

FAST

NEUTRONS

rads / week

Figrrre I (of preceding paper by R H. Mole). Mean survival-time (per cent of control) andweekly dose o i radiation (logarithmic scale).
The symbols are given in table 1. The curves are numbered 2s in the test, where they are
discussed. The gamma and neutron scales are in the ratio 13 :1 (see t e s t ) .

AGEFigure 2 (of preceding paper by R H. Mole). Cumulative mortality of female CBA mice(four different control groups 1951-54). All times plotted from same starting age of 70 days.

Rank

1.
2.
3.
4.

5.
6.

7.
8.
9.
10.
11.
12.

Specially

Obseror4 &allrr

Expected & a l hMoriality rafi*

Tuberculosis.. ..............................................
Dermatology ................................................
Roentgenology and radiology. ................................
Anesthesiology..
Orthopedic surgery, proctology, urology and-idustrial surgery.. ..
Neurology and psychiatry.. ..................................
Public health.. .............................................
Suwry ....................................................
Obstetric3 and gynecology.. ..................................
Eye, ear, nose and throat ....................................
Internal medicine and pediatrics.. .............................
Pathology and bacteriology.. .................................
Au

43
60 (58)b96 (91)b
17
199
142
99
360
112
502
378
38
2.046

34.2
47.8
82.4

1.26 (0.99)
1.25 (0.98)
1.16 (0.90)- (0.88)
1.11 (0.86)
1.07 (0.83)
1.OS (0.83)
1.04 (0.81)
0.96 (0.75)
0.96 (0.75)
0.89 (0.69)
0.79 (0.62)"
1.oO (0.78)............................................

The ratio of (observed deaths i n a specialty at ages 25 to 74
years) t o (expected W h s a the basis of age spccifi deollt rates ja
all specialists, 1938-1942). The ratios a-ere calculated from data
made available by Dr. &I. Spiegelman. The figurs in parentheses
are the published9 mortzlity ratios for specialists based on the

-

179.1
133.0
94.3
346.7
116.3
523.4
423.6
48.1

age specificdeath rates for all ph sicians (instead of all specialists)a t ag-et 35 to 74 (2,046 deathsf Note that the ranking of themortality ratios is the same for both methods of calculation.
b Omitting deaths from leukemia.
Pathology only.

cases per unit of population per annum. In a period of
T years,
Nx = (R - R+)T
(1)
Although simple in principle, the use of equation ( 1) issomewhat difficult in practice. First, R is not a constant,but varies with times. In general, exposure is followedby an initial period during \~+ich few if any radiationinduced cases occur. The duration of the initial period
may be shorter after large doses than after smaller ones.
Thereafter, depending on the particular cancer studied
and the nature of the population, there will be a second
period during which the vast majority of radiationinduced cases occur. This period might last for five years
or for twenty-five. We are now only in the process ofIcamin what the duration of such periods may be.
Second y, precise values of R, may not be available. In
the case of some kinds of cancer there is some evidence
that R. is changing relatively rapidly (e.g. leukemia).
F o r these, it would be necessary to estimate the changes
in R, as a function of time independently of the changes
in R. Thirdly, the numbers of radiation-induced cases
actually dealt with are very small, as will be seen below.

f

3.Having obtained a method for estimating N,,it
becomes feasible to investigate how N, depends on thedose of radiation, D. Is N,, for example, a simple linear
function of D, is it a non-linear function or is there athreshold dose below which radiation is without effect?
Before a t t a c h g such a problem, it is important to notethat the same dose may result from a single exposure,
multiple exposures, or a long period of continuous exposure. Such differences in dosage may lead to majordifferences in the end results and therefore must be
esplicitly dealt with when making comparisons or
ex-trapolations.
24. It is worth special note that the factor of time hasentered the problem in more than one way. I n equation(1) paragraph 22, there is the term T, often referred toas period at risk. In paragraph 23, the role of time indosage is considered ; this may be referred to as periodrclder exposure. The period under exposure may lastfor only a minute and thus be an insignificant fractionof the years at risk. On the other hand, in the case oflong-lived isotopes, for example, the period under exposure may be a matter of many years and thus partiallyor even completely overlap the period at risk.

wise expressed? Should the integral absorbed dose beconsidered ?
(b) Tettrporal factors. 'Mihat allowance, if any,
should be made for multiple or continuous exposure?
Is each successive year at risk of equal significance?
(c) Co,tstitutional factors. What is the nature of theirradiated population with respect to age, general health,genetic constitution, etc. ?
(d) Dose-effect curve. I s there a threshold? I s theeffect a linear or some other function of dose? Can afactor be determined that will relate hTxto D ?

Leukemia in vron
27. Demographic data relating the incidence of leukemia to radiation exposure come from four populationgroups whose exposures were either a hazard of war or
profession, or were incurred during diagnostic andtherapeutic medical procedures.
Atont borttb survizvors itr Hiroshima
28. The most recent information on the incidence of
leulcemia in the Japanese survivors of the 1945 atomic
bomb is given in a report which is reproduced in paragraph 33 below. From the condensed summary in table
VI of the Hiroshima data, it is seen that the incidenceof leukemia in the population exposed at 0-1,499 metresfrom the hypocentre has been twenty times greater thanin the population exposed a t 1500 metres and beyond.
Thus a t the end of 1957, N (0-1,499 m.) = 5570;
N ( > 1,499 m.) = 280. N is the total number of cases
per million persons present at the time of the explosion.
Taking the cases at 1.500 metres and beyond as a crude
estimate of the natural incidence of leukemia, the nurnber of cases N , due to radiation may be estimated as
5,570 - 280 = 5,290, or in round numbers 5,300 per
million.

TABLE
VI. LEUKEIIIAIN SIJRITVORS AT HIROSHIMA,
1948-1957'

1.500 and

Period of oascl

25. Constitutional factors are l a o w n to influence theproduction of cancer in man. These include race, age,sex, nutrition and other environmental and genetic influences. All of these factors have to be taken into
account in discussing the production of cancer in man
through exposure to ionizing radiation, especially whencomparing the effects in one group with those in another.
26. The tot21 of all human data that can be used forthe quantitative analysis of cancer-induction by radiation is meagre. For esample. only sixty-eight cases ofleukemia are involved in the Hiroshima data of table
VII. It is im~ortantthat full use be made of suchdata while at the same time recognizing and giving due
weight to their limitations. In the, case of the calculations. extrapolations and applications that follow, thereader is urged to note the simplifying assumptions that
may have entered into the analyses, especially in regard
to the follo\vmg items :(a) Absorbed dose. In what organ is the absorbed
dose to be determined? If the dose is not uniform
throughout the organ, ho\v shall it be averaged or other-R (average of cases per year per 106).

Tofol

. 84

&1,399beyond557

28

Data from reference 13. The full report from which theseand the data of table VII were taken is s v e n below.
b 10,051 persons were esposed at 0-1,499 metres; 85,768 were
esposed at 1.500 metres and beyond.

29. The data in table VI indicate that t l e biennial rateof leukemia in the heavily esposed population reached
its ma.imum in 19j0-1951 and has been declinillg siilce
then. If this tendency continues. practically all cases ofha\.e occurredradiation-induced leukemia
bv 1960, within fifteen years of exposure, so that at
1Gase ~ 0 ' ~ cente r of them may be said to have occurredalready, within ten years of exposure. In these circurnstances. the annual rate of leukemia taken by itself is notTABLE
VII. LEUKEVL~INCIDENCE FOR 1950-5;
Duiance from

%?

zonc

A

under 1,000
1,000-1,699
1,500-1,999
2,000-2,999
over 3,000

B
C
D
E

L
(Cores of

Nb

Dose
(red

Persons
ez$osed2cuRc11:su)s/t(tofal rases
per I@)

1,300
500
500
2
0

1,241
8,810
20,11332,69232,963

15
33
8
3
9

3.9
5.7
2.8
1.7
3.0

12,087 f 3,143
3,746=t 647
398 f 139
92 f 52
273 f 91

Based on data in reference 13. Prior to 1950 the number ofcases m a y be understated rather seriously.
b

AFTER E-XPOSURE AT HIROSHIJLL~

The standard error is taken as N (V La).

a good index o i the total radiation efiect ; it is the total
number of case N , that should be employed as such ameasure.
30.
thethe -pased population
segment thatthe hypocentre has had thegreater incidence of leukemia. However, the quantitative
relation between leuketrtia hcidence i?z Hirosliima andradiatiotr dose is not yet known. Before such a relation
can be formulated it will be necessary to have better
estimates of the absorbed dose in rev&than have been
available hitherto. The estimates must be made both forthe various dose zones in which the ~ 0 ~ u l a t i owas
n distributed, and, also, for every individ&dAcaseof leukemia,
taking into account both its position within the zone andthe shielding immediately around it. Such work is underway.
31. None the less, using such data as were available,
estimates have been made of the ~ o t e n c vof this bombradiation in causing leukemia.li ~ g exp&edepopulationsof Hiroshima and Nagasaki were considered to have been=posed in a 'lumber 'Ones forof which a mean
The extra probabilify of leukemia
dose wasoccurring in an =posed Person Per rem and Per Yearafter exposure was thenfor the population of each zone :''average estra number of new cases per year
(1948-1955)-

number of persons exposed X dose (rem)I n zones A (1,300 rern), B (500 rem), and C (50 rem),the values of PLwere calculated to be 0.9,0.7, and 0.7 X
l W , respectively. This finding was taken to support thesuggestion that the extra leukemia incidence is directly
proportional to radiation dose, and conversely, to argue
against the existence of a threshold for leukemia
induction.
32. PL might be used in estimating N,, the total number of extra cases of leukemia that follow a dose ofradiation. The average value of P, in paragraph 31 is
0.8 X 10-8 based on statistics for the years in which theleukemia rate is considered to be maximal. Taking 15
years to be the entire period of leukemia production(period at risk), the total number of cases (per individual exposed per rem) = 15 X 0.8 X lo4 = 12 X
lVa, O n this basis if each of a million persons receives
1 rem, a total of 12 extra cases of leukemia will eventually develop.
33. I t is of interest to apply the above method to thelatest data on leukemia incidence in Hiroshima, using
the same zoning system and estimates of dose (table

S.

(Radiationind-d casts*I@)

11,814
3,473
125
-181
ControlPL-vJrcm(-\-Jl@/ytar/,tm)

9.1
6.9
2.5
-90

1.14 x 104
0.86 X 104
0.31 X 104-11 X 104--

It has been noted ' 5 . l6 that almost all cases of leubmia inthis zone occurred in patients who had severe radiation cornplaints, indicating thar their doses were greater than 50 rem.

VII). Contrary to previous findings, the present findings
indicate that PL decreases marltedly as the dose falls,
that therefore leukemia incidence is not a linear function of dose, and that a threshold for leukemia inductioi
might occur. In fact, according to bble VII a dore of
2 rem is associateda decreased leukemia rate. I t is
to be emphasized again, however, that the estimates ofdose employed in the present and previous analyses aremuch too uncertain to permit drawing conclusions relative to the vital points in question. The calculations are
made only to illustrate how variable the results may belvhen inadequate data are utilized.
LEUKEXIAIN HIROSHIJIACITYAMXIC BOMBSURVIVORS*byNIEL ~ V A L D ~Atotraic Bomb Casualty Co~tt~tiissiotl
Hiroshima, Japan

It has become generallythat an increased
incidence of leukemia follows the acute or chronic aposure of various experimental animals and of man toionizing radiation.l Recently an a n a p t has been madeto establish a
between the probability of radiation-induced leukemia and the unit-dose ofradiation received. on the basis of data from studies ofvarious groups of'radiation-exposed human beings.?
The survivors of the atomic bombings in Hiroshima
and Napsaki, Japan, comprise two such groups. Reports
concerning the occurrence of leukemia in these populations over a period through June 1956 have been published at intervals by various staff members3 of the
I n addition. an
Atomic Bomb casual^ Commi~sion.~
unpublished compilation of certain specific detailed information requested by the British Medical ResearchCouncil was prepared in September 1955.JAn analysisof these data appeared in a publication of the Medical
Research Council6 and a portion was also published in areport of the National Research Council.'
Since that time a review has been made of all theleukemia cases known to the Atomic Bomb Casualty
Commission, and a master list has been compiled. Someof the cases on the September 1955 listing have been
dropped for various reasons, and many cases have been
added. No detailed official report has been publishedrecently in the hope that more adequate dosimetry data
might become available. This wish is nearing fulfilmentof
because of the joint initiation of a large- programme~*Science In, 699-700,19% for table 1 and bibliography referred to in this article, see immediately following the article.
t. Present address :University of Pittsburgh, Graduate Schoolo i Publ~cHealth. Pittsburgh, Pa.

dosimetry studies in 1955 by the Atomic Bomb Casualty
Commission and a group of interested organizations
including the Atomic Energy Commission's Division of
Biology and Medicine, the National Academy of
Sciences - h'ational Research Council, the U.S. Air
Force School of Aviation Medicine, Los Alamos Scientific Laboratory, and Oak Ridge National Laboratory.
The programme is designed to make possible the assignment of a specific neutron or gamma ray dose or bothin rads to the record of each survivor in the Atomic
Bomb Casualty Commission's files for whom sufficientpertinent information is available.
A detailed interim report on leukemia in the Hiroshima atomic bomb survivors is presently being prepared by various staff members of the Atomic Bomb
Casualty Commission and the National ResearchCouncil. I t will include the best currently available dosimetry information resulting from the &fore-mentioned
collaborative effort, However, because of the presentinterest in data pertinent to radiation leukemogenesis andthe desirability of making available current irlformation
obtained by the Atomic Bomb Casualty Commission,table I, summarizing results of the leukemia survey inHiroshima as of December 1957, is presented at thistime.
Certain limitations of these data should be pointed
out. The programme was initiated in 1917 but the present level of intensity of effort was not achieved until
about 1950. Therefore, while it may be assumed thatthe numbers of cases shown for the years 1950 through1956 are fairly accurate, the numbers that arose in thepreceding years may be understated rather seriously.
With respect to 1957, it is probable that additional cases
remain to be discovered with onset in that year.
The denominators of the incidence rates are estimates,
subject to errors of presently unknown magnitude. The

3 June 1953 Residential Census of Hiroshima was conducted by the Hiroshima Census Bureau and was presumably of a reasonable degree of accuracy. The categorizatton by distance from the hypocentre was madeon the - basis of Atomic Bomb Casualty Commission
investigations of 50.8 per cent of the males and 44.6
per cent of the females who reported themselves exposedto the bomb. However, it was found that 3.1 per cent of
those reportedly exposed were in fact not in the city atthe exact time of the bombing.
Apart from the uncertainties regarding the population
on 3 June 1953, it may be incorrect to assume that
migration in and out of the city during the period from1950 to the present was the same for persons exposedin different distance categories. However, despite thecurrent lack of pertinent information, the simple expedient of multiplying the June 1953 population values by
eight to obtain estimates of person-years at risk has been
adopted since the census date is roughly near the midpoint of the interval under study. This procedure seems
reasonable at present, although the magnitude of any
resultant error is hard to estimate.

In addition to the above-mentioned points, which hare
to do with the intrinsic accuracy of the data presented,
a further caution should be strongly emphasized. The
uncertainties involved in inferring radiation dose fromdistance alone are too large to support conclusions
beyond the previously reported qualitative one that thosesurvivors who received large doses of radiation-that is,
who were within 1,500 metres of the hypocentre, had asignificantly higher incidence of leukemia than thosebeyond that distance, who recei\-ed relatively little ornone.s The relationship of incidence to distance as presented in table I cannot be given a more quantitativeinterpretation because there are too many variables, as
yet unresolved, which cannot be ignored.

TABLE
I.
Of preceding paper by Niel Weld
LEUKE~IIA
LV HIROSHIMAATOMIC BOMB SURVIVORS ~ ' H OWERERESIDENTS OF HIROSHIBIACITYAT THE TIME OF DIAGNOSIS(DIAGYOSESVERIFIED BY THE ATOMICBOMBCASUALTY
CO~IIIISSION)
Year of On+&

Total

1945 .......................
1946
1947. ......................
1948 .......................
1949. ......................
1950 .......................
1951 .......................
1952... ....................
1953. ......................
1954 .......................
1955 .......................
1956
1957 .......................

Under
1.000

1.0001.499

1.5W

2.000-

1

2
1
1

1999

2999

Om
31UX)

.........a+............

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

TOTAL

3
7
5
9
11
11
12
6
8
6
5
83

....... 95,819
Estimated
Number of cases uith onset in
1950-1957 ................
68
Estimated person-years at risk. 766,552
Annual incidence of leukemia
per100,OOO...............
8.9

1

9

7

1
3
1
10

1,241

4
1
5
7
5
6
2
4
1
3
39
8,810

20,11332,63232,963

15
9,928

33
70,4808
160,904

3
261,536

9
263,i04

151.1

46.8

5.0

1.1

3.4

2
1
3
3
3
2
2
1
1
18

1
1
2
1
2
1

1
1

1

1
1

2
1

Based on Hiroshima Census Bureau's Daytime Population Census of Hiroshima City,

S , June 1953.

166

For example, the presently available estimates of the
air dose in Hiroshima have a large uncertainty, themagnitude of which is itself not yet definite. Also, experimental dosimetry studies at Oak Ridge National
Laboratory emphasize the need for detailed information, such as is being collected by the Atomic Bomb
Casualty Commission, concerning the shielding situationof any particular survivor at any distance. I t is conceivable that the radiation received within a light framehouse (the most common shielding situation) may varyfrom an amount almost equalling the outside air dose to
one equal to the outside air dose attenuated by perhaps
a factor of 'nvo, depending on the position of the personin the house.
I n determining the relationship of radiation exposure
to the incidence of leukemia, such detailed data must be
examined not only for each leukemic survivor, but also
for enough of the population at risk to permit calculation of statistically significant incidence rates. Until thisinformation becomes available from the dosimetry programme, it is premature to attempt precise quantitatio?
of dose-effect relationships in radiation leuliemogenesls
on the basis of the Hiroshima and Nagasaki radiationpop~lations.~
BIBLIOGRAPHYFOR PRECEDING PAPER BY NIEL WALD

1. J. Furth and E. Lorenz. Radiatio~z Biology (McGraw-Hill, New York. 1951), vol. 1,pt. 2.
2. E. B. Lewis. Scietzce 123, 965 (1957).
3. J. H. Folley, W. Borges, T. Yama~vaki,Am. J. Med.
13. 311 (1952) : R. D. Lange. W. C. Moloney,
T. k'arnawaki, Blood 9, 574 (1954) ; W. C. Moloney,
and M. A. Kastenbaurn, Science 121, 308 (1955) ;N. Wald, Acta Haematol. Jap. 20, 152 (1957) ;N. W-ald et al., "Proc. Intern. Soc. Hematol., 6thIntern. Congr. Boston, 1956" (Grune and Stratton,
New York, in press).
4. The Atomic Bomb Casualty Commission is a fieldagency of the National Academy of Sciences National Research Council, operated with funds supplied by the U.S. atomic Energy Commission.
5. "Listing of Leukaemia Cases in Hiroshima andNagasaki" (Atomic Bomb Casualty Commission,
Hiroshima. Japan, Sept. 1955).
6. "The Hazards to Man of Nuclear and Allied Radiations" (~Vled.Research Cozcrzcil (Brit.)Cntd. 9780)( H . M . Stationery Office, London, 1956). appendix A.
7. "Report of the Committee on Pathologic Effects ofAtomic Radiation'' Natl. Acad. Sci.-Natl. ResearchCozmcil, Publ. N o . 452 (Washington, D.C., 1956).
appendix I.
8. Grateful acknowledgement is made for the biostatistical assistance of Mr. Seymour Jablon. National
Research Council, and also for the aid of Dr. Lowell
Woodbuq. head of the Biostatistics Department of
the Atomic Bomb Casualty Commission, and his staff.
-4ppreciation is also expressed for the help of
Dr. Robert ill. Heyssel. who provided the hernatological data for 1957, and for the co-operation of thephysicians of both the Atomic Bomb Casualty Commission and the city of Hiroshima, who make thelong-term Hiroshima leukaemia study possible.

L e t ~ k e ~ t zitr
i a radiologists
34. The most recent estimate of the leukemia death
rate for United States radiologists (ages 35 to 74 years)

is based on the data of 1938-1952. inclusive.14 During
this period there were 17 deaths, corresponding to an
average annual rate of 610 per million. The rate observedin the population at large (corrected for age distribution) was 121 per million.
3j. Two reports have associated leukemia in children
with previous X-ray exposure during infancy or the
prenatal period. I n the first,'' a study was made of 1,700
United States children treated during infancy for a condition known as enlargement of the thymus gland. The
untreated siblings of the irradiated children served ascontrols. There were 17 cases of cancer, including 7 ofleukemia in the irradiated group; there were 5 cases ofcancer, but none of leukemia in the control group(tables VIII and IX).

TABLE
VIII. EYPECTED
m OBSERVEDU T E S FOR CA-YCER8

All cancers.. ...........
Leukemia.
Thyroid cancer. ........

2.6
.6
.08

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

a17 (119)
7 (? 8)

6.

2.7
.6
.08

5
0
0

Data from reference 17.

TABLE
IX. DISTRIBUTIONOF NEOPWSL~ACCORDING TO m O U N T OF R ~ D I A T I O N ~--Number treated. ............ 604
Cases of leukemia.. ..........
2
Other cancers. ...............
0
Carcinoma of thyroid. ........
0
Adenoma of thyroid.. ........
0

801
5
4

313
(?I)
0

6
6

0
3

Data from reference 17.

36. In a British studyls of the history of 547 mothers
whose children had died before the age of ten fromleukemia and other cancers, it was found that 85 of themothers (15.5 per cent) reported that they had had
diagnostic abdominal radiography involving the foetus
during the relevant pregnancy. In a comparison series of
547 mothers with healthy and living children only 45(8.3 per cent) reported radiologic exposure during therelevant pregnancy (table X)

.

TABLE
X. LEuKEJ~L~
Ah3 CANCER INCIDENCE
OFFSPRING RELATED TO X-RAY EX-4lffNATIONS I N
THEIR MOTHERS DUREYG THE RELEVANT PREGN-ZNCP~
hrzmbn of molhcrs andfoetuses cx&+osrd lo
Tybe of c a w in child

Numberof cases.......... 269
Controls (living). ... 269
2. Other cancers.. ....... 278
Controls (living). ... 278
3. Total cancer.. ........ 547
Total control. ........ 547
1. Leukemia..

aAbdominal
Examinolion o f
c ~ m i n a i w n other Bar& of body

42
24
43
21
85
45

25
23
33
32
58
55

Data from reference 18.

37. The suggestion has been made that a proportionof the leulcemias and cancers in the first group, namely

7.2 per cent, may have been caused by the exposure
during intrauterine life of the patients in question.
However, radiological examination of other parts of the
body was not correlated with increased cancer incidence.
38. The data indicate a correlation between leukemia
and other cancers in childhood and irradiation of the
foetus, although alternative possibilities cannot be excluded. It is possible that some mothers who give birth
to leukemic children might be in greater need for diagnostic X-ray sen6ce during pregnancy and that in thepresent cases leukemia or cancer may have resulted independently of exposure sustained during intrauterine life.
39. In any event, the clinical indications for the X-ray-aminations of the mothers of these particular children
are not known, nor is information available on the typesof examinations performed and on the actual doses of
X-ray received by the mothers and the foetuses. Additional data and final evaluations of their significance are
known to be in course of publication (British Medical
Journal).

Leukemia after X-ray therapy f or anky1osi)tg spoidylitis
40. A dependence of the incidence of leukemia onradiation exposure has been demonstrated in a study of
13,352 cases of ankylosing spondylitis treated during
1935-1954 at 82 radiotherapy centres in Great Britain.l0
I n this series. 28 patients were certified to have died ofleukemia and 12 of aplastic anemia, as of 31 December
1955. The numbers of expected deaths were 2.9 forleukemia and 0 3 for aplastic anemia. (The over-all
death rate per million persons for leukemia in Englandand Wales has been as follows: 21 in 1935, 34 in 1945,
49 in 1954). A thorough study of the series led to thef o l l o ~ ~ ~tabulat~oning
of cases with blood disease :
,Woks

Group

Leukemia (A). ...................... 35
Probable leukemia (B). ............... 5
Aplastic anemia.. ....................
42
Undecided ..........................

F c d s

1
0

0
2

.

41. T o study the distribution of cytological types, allavailable cases of leukemia in patients with ankylosing
spondylitis, both treated and untreated were tabulated :X-ray hcokd series
prr

Lymphatic leukem'ia.. ... 3 (8)M yeloid leukemia. ...... 31 (78)
Monocytic leukemia.. ... 6 (15)Type unspecified.. ...... 9

ment, but some ( 1,119) received as many as four courses
over a period of years. Preparatory to examining therelation between leukemia incidence and radiation doseelaborate studies were made so that for each course oftreatment in each case there could be determined :(a) T h e spinal dose: the mean dose to the spinal marrow, based on the average of 3 points (upper sacral, middorsal, mid-cervical).
(b) T h e integral dose: the integral dose to the wholebody.
The distribution of doses in the entire population of
11,287 men mas estimated from the doses of a randomly drawn sample of 1,878 men. The dose of eachleukemia case was determined individually. F o r multiple
courses of treatment due allowance was made for theyears at risk a t each dose level. Dose-classes were thenrem), andestablished (e.g., 2 5 M 9 9 rem, 500-749
the crude incidence of leukemia determined in each class.
In addition, the standardized incidence of leukemia wasdetermined, i.e., the incidence standardized for age.
44. I n studying the dose-effect relationship, the following assumptions were made :(a) The significant parameter of dose is the meandose to the spinal marrow. (The spinal marrow was
always irradiated : the amount of irradiated extra-spinal
marrow was variable.)(b) There is an absolute waiting period of one year
after exposure during which no cases occur. Thereafter,
each year at risk has equal weight. (The authors considered this to be an over-simplification, but used it as apractical method of dealing with the many cases that hadreceived multiple courses of treatment).
(c) Fractionation of dose did not diminish its
effectiveness.
(d) The probability of inducing leukemia is directly
proportional to the number of man-years at risk. The
number of man-years at risk equals the product of(number of individuals given a particular dose) X(mean years since exposure-1 )(e) constitutional- factors . may predetermine agreater radiosensitivity in this population, but no allowance can be made for it.
45. Results from these studies are summarized intable XI and figure 4. I t is clear that the incidence ofUntreakd wriw
9-3 (38).i (50)1 (13)
0

'

80a

C

There is a relative deficiency of the lymphatic type ofleukemia among the X-ray treated cases, and the differaence between the two series was found to be just significant (P = 0.05).
a5
42. Only male cases of leukemia and "probable leukemia" (groups A and B) were available in adequate% a%numbers for further statistical analysis. After a single
course of treatment, the evidence of 10 cases indicatedthat leukemia occurred within 5 years. When all cases
Q
20were cons-idered, i.e. those receiving multiple courses
over a period of years as well as those receiving a singlezcourse in a mo~?thprso, it was noted that leukemia wasdiagnosed wlth~n3 years of the last treatment in 35 of1OF
37 cases.
500. KlOO
IS00
2Ka
2500
n u n dco.suinat marrow (r.)
43. The radiological treatment of ankylosing sponFiglire 4. The incidence of leukemia, standardized ior age, in
dylitis usually consisted of irradiating the spine and therelation to the mean dose of radiation to the spinal marrow : alljoints.
cases other reregion of themale patients in the study series and 'A' and 'B'cases of leugions were also treated. Most (7,215) of the ~ztients kemia, =duding co-existent cases. (Figure 4 is Figure 1 in thein the present series received only one course or' treatoriginal reference 19.)

1=
.
1

I:

I

168

involves the precise relation between the total numberof radiation-induced cases N , and the radiation dose D,
throughout an extended range of dosage. At present,such a statement cannot be satisfactorily made for any
kind of human cancer. For certain purposes, however?
a very crude estimate may be better thm none at all andhvo methods have been proposed with this end in mind.

leukemia increases with radiation dose and that the relation between them is not linear. The curve through thepoints in figure 4 is drawn to reach the control rate atzero dose without indicating a threshold for the induction of leukemia. I t should be noted. however, that only
one case of leukemia received a dose of less than 400
rern and that this case had lymphatic leukemia and had
had large doses oi extra-spinal irradiation. Therefore
the course of the curve between this dose and zero must
be regarded as practically undetermined. The slope ofthe curve between 750 and 1.250 rern appears to be relatively constant and is equal to about 0.6 new cases per
year per 106 men per rern to spinal marrow.
46. The data for the limited group of patients thatreceived irradiation to the spinal axis only are given intable XII. In this group, 1s patients developed leukemia.
-4nalysis of these dataz0suggested a threshold of 51 rernby one method and of 130 rern by another. These estimates, however, are subject to great uncertainty owing
to the small number of cases in the series and the lack ofdata for the range in question. Statistical analysis indicated that the threshold might lie anywhere between
0 and 460 rem. The slope of the dose-effect curve wasabout the same as that given in paragraph 45.

48. The first method assumes (1) that all cancer iscaused by ionizing radiation and (2) that the annual
cancer rate is directly proportional to the annual radiation dose. The total cancer incidence rate R in the UnitedStates, for instance, is now about 2,800 cases per annum
per million population. The annual background radiationdose rate is about 0.1 rem, and the dose rate from othersources is perhaps another 0.1 rern. The average annual
dose rate per individual is thus about 0.2 rem. The
potency factor k is, therefore,i.e., 1 rern will produce a total of 14.000new cancer cases
when a population of one million has been exposed.
Such a figure appears to be absurdly large. It has beensuggested that such a calculation applies only to certain
kinds of cancer but not to others. There appears to be
no scientific basis for such a selection, however.

TIteoretical consideratiotls fur estiinatiotz of radiatioia
hazards
47. The quantitative statement of a radiation hazard

THENU?rIBERS O F PATIENTS WHO DEVELOPED LEUI(EMI.4, AND T H E CRUDE -4YD STAhmARDIZEDINCIDENCE R4TES: AFTER DIFFERENT MEAN DOSES OF THEIWPEUTIC RADIATION TO THE SPINAL hLZRROW:hLXE 'Af Ah?) 'B' CASES, EICLUDIKG CO-EXISTENT CASES

TABLE
XI.'

Atcan dose to spinal marrow (r.)-?io. of men dmebping leukemia'A' cases. ....................... 'A' and 'B' cases.. ............... Crride incidence per 10,000 men per year
'A' and 'B' u s e s . ................ 0 4 9Standardized incidence per 10,000nren
per year'A' and 'B' cases. ................ 0 -49
a

1
1

2
3

6
6

3
4

7
8

2
3

3
3

1
1

2
2

3
4

1
1

1
1

3
3

2
7

2 - 16

4 -59

6.99

12.18

63 -65

5.98

1 -98

4 -66

7.21

14-44

72.16

5 -98

the same period, calculated from the mortality from leukemia
experienced by the whole male population of Britain.

This table was table 19 in the original reference.19

b The rate given for 'zero' therapeutic dose is the corresponding

rate among men of the same age-distribution and observed over

THEINCIDENCE O F LEURE&fIAAFTER DIFFERENT bfEXN DOSES O F THER4PEUTIC RADIATION TO T H E
SPLUAL >lr\mOTF: b L a E 'A) -4ND 'B' CASES GIVEN ONLY SPINAL IRR.IDIATION, EXCLUDING CO-EXISTENT CASES

TABLE
XII.'

Mean dose lo spinal t n o n m (r.)
Less

No. of man-years a t risk following exposure t o dose

250499than250

1.2501.499

1,5001.749

1.7501.999-

5,404 7,673 6,553 8,262 7,111 2,782

897

566

679 40,247

2
2

1
1

1

5 W
749

7509991.0001.249

2.000

0

or

AIL
dosrc

No. of men developing k~tkonia'A' cases. ................................
'A'and 'B' cases. ......................... Crude incidence per 10,000 men per year
'A'and'B'cases .......................... 0.49
Standardized incidence per 10,000 nren per year
'A'and'B'cases .......................... 0.49
a

0
0

2

2

3
3

4
5

0
0

1

17
18

1 -53

4.72

6-75'

8.12d

4 -47

1-44

1-83

6-82.:

8-70d

4 -47

This table was table 20 in the original reference.19

b Average dose, 2,290r.

For the group receiving 1,000-1,499r. the crude incidence
is74 91 ;standardized incidence 5 -06.
For the group"receiving 1,000-1,749 r. the crude incidence-

44

is 6.31:standardized incidence 6.82.
d For the group receiving 1,500r. or more the crude incidence
is 18-68;standardized incidence 19.86.
For the group receiving 1,750 r. or more the-crude incidence
is 16-07;standardized incidence 16.82.

49. The second nlethod uses the results of the British
study of leukemia incidence in a radiation-treated population, discussed above. (The data for Hiroshima haveriot been used owing to the uncertain dosimetry.) To
compensate for the paucity of data, a number of assumptions are made in the following analysis :( a ) The significant parameter of dose is the meandose to the entire red marrow. I n uniform whole-body
expowre, the doses to the entire red marrow and thespinal marrow are the same. When only the spinal marrow is irradiated, the mean dose to the entire red marrowis probably about 40 per cent of the spinal dose.
( b ) The total number of years at risk is 15, and eachyear has equal weight. This assumption was arrived atfrom the following considerations. The mean period of
observation in the British study was 5 years ; this would
set a lower limit for all types of cases. Those 10 cases ofleukemia that received only one course of treatment all
occurred within 5 years of that treatment. For the population exposed at Hiroshima the cancer rate began falling
after 8 years. and a complete period at risk of 15 years
has been suggested. The maximum duration of theperiod at risk cannot be greater than the duration of life
after exposure. In the case of a population of children,
this could be 65 years, in the case of the usual mixed
population, the average would be about 35 years.
(c) Fractionation or protraction of dose does not dirninish its effectiveness.
(d) Constitutional factors may be neglected.
( e ) b ~ c e productionr
is a linear function of radiation dose. Linearity has been assumed primarily for purposes of simplicity. In the case of the British data fordoses below 1,300 rem, a linear relation provides a fairly
accurate fit.
( f ) There may or may not be a threshold dose. The
two possibilities of thrcshold and no-threshold have beenretained because of the very great differences they engender.
50. The potency factor k, equal to N J D , can now be
calculated. For a single exposure of the entire red marrow to 1 rem, the average annual leukemia rate is estimated to be 1.5 cases per million persons exposed. If thetotal number of ears at risk is assumed to be 15, k isequal to 1.5 X 1 , or approximately 20 cases per million
exposed per rem. 'These calculations are based on observations following single large exposures. However,under conditions of prolonged exposure at lower dose
rates, the period of risk may be longer. I n the calculations of chapters V and VII where a maximunt estimate
is wanted, the period at risk is assumed to equal theaverage remaining life-time of the exposed population(35 years). The value of k has therefore been taken as
52 cases er million per rem in the calculations in paragraph 12 of annex D and in paragraph 61 of chapter Vof this report.
51. The use of k to predict the number of cases ofleuliemia depends on the magnitude of the threshold.
If there is no threshold. N, is equal to the product of k,D, and the number of persons exposed. If a thresholdis assumed. there will be no cases in persons who havereceived less than that dose.
52. Besides the alternative possibilities of a linear relation with or without a threshold, it is possible that a
non-linear relationship may exist, as has been found,for example, in the case of many chromosonie abnormalities.?l As noted in paragraph 35 and illustrated infigure 4, the incidence oi le-A-eniia i : ~tile British study

2'

C

170

was a curvilinear function of dose. not a linear one.
A curve providing a good fit to these data is obtained
when leukemia incidence is considered to be proportional to the square of the radiation dose. In general,
curves of this type predict a finite incidence of leukemia
at small doses. However, this incidence may be verymuch lower than that predicted by a linear function
based on all of the same data.
33. The methods used above to estimate the risk ofleukemia after radiation exposure are of general use.
They may be applied both to other cancers and also to
non-cancerous lesions such as occur in the eye (cataract). the skin and in the bones. Their use is contingent
upon the availability of adequate statistical estimates of
the incidence of the disease in question related to theradiation doses received by the population at risk. I t may
be noted that such methods do not depend on detailed
knowledge of how tile radiation induces the lesion within
the cell, e.g. by somatic mutation or some other allegedor hypothetical mechanism. At present, adequate statistical data are not available for bone tumours or fortumours of other organs to make such estimates of risk.
However, it is known that pertinent studies are under
way for bone tumours in man that are caused by radioactive substances.
REFERENCES
1. Bond, V., and J. S. Robertson, Annual Review of
Nuclear Science 7,135-162,1957.
2. Knowlton, N. P., and L. H. Hempelmann, Journalof Cellular and Comparative Physiology 33, 73,
1949.
3. Conard, R. A., Radiation Research 5. 167-188, 1956.
De Brupn, P. P. H., and 11. M. Tornova-Svehlik,
Radiation Research 6, 573-584, 1957.
Kallman, R. F., and H. I. Kohn, Radiation Research
3, 77-87, 1955.
Kohn, H. I., and R F. Kallman, British Journal ofRadiology 27, 586-591, 1954.
Patt, H. M., hf. E. Blackford, and R. L. Straube,
Proceedings of the Society for Experimental Biology and Medicine 80, 92-97, 1952.
Oakberg, E. F., Radiation Research 3, 369-391,
1955.
Trowell, 0. A., Journal of Pathology and Bacteriology 64,687-704,1952.
Schrek, R., Radiology 46,395-410, 1946.
Storer, J. B., P. S. Harris. J. E. Furchner, andW. H. Langham, Radiation Research 6, 188-285,
1957.
Patt, H. hii., Annals of the New York Academy of
Sciences 59, Art. 4, 649-664, 1955.
4. Kolln. H. 1. and R. F. Kallman, radiation Resear&
7,85-97, 1957.
5. Blair, H. A., Collected data pertaining to shorteningof life span by ionizing radiation, available as University of Rochester Report U R 4 2 , 1956. See
also: Blair, H. A.. Proc. Internat. Coni. PeacefulUses of Atomic Energy 11, 118-120.United Nations
1956.
6. Communicated by R. F. Kallrnan and H. I. Kohn,
1958.
7. Mole, R. IX.U N document A/AC.82/G/R.115.
Also published in Nature 180,45640, 1957.
8. Carlson. L. D.. W. J. Scheyer. and B. H. Jackson,
Radiation Research 7, 190-197, 1957.

9. Dublin, L. I., and M. Spiegelman, Journal of theAmerican hledical Association 137, 1519-1524,
1948.
10. Communicated by G. A. Sacher, 1957.
11. Seltser, R, and P. E. Sartwell, Journal of the American Medical Association 166. 585-587, 1958.
12. Warren, S., Journal of the American Medical Association 162, 464-468, 1956.
13. Wald, N., Science 127,699-700, 1958.
14. Lewis? E. B., Science 125,965-972, 1957.
15. Hempelmann, L. H.. in Hearings before the special
subcommittee on radiation of the joint committee on
atomic energy, Congress of the United States, Part
1;989,1957. U N document A/AC.82/G/R.130.
16. Pathologic Effects of Atomic Radiation. Report of
the Committee of the National Academy of Sciences

National Research Council, Washington, D. C.,
1956. Appendix I, pp. 1-13. Un document A/AC.82/G/R. 11.
17. simpson, C. L., and L. H. Hempelrnann, Cancer 10,
42-56,1957.
18. Stewart, A., J. Webb, D. Gies and D. Hewitt,
Lancet ii, 447, 1956.
19. Court-Brown, W. M., and R. Doll, Leukaemia andaplastic anaemia in patients irradiated for anh710sing spondylitis, Medical Research Council, Special
Report Series No. 295. London, H.M.S.O., 1957,
See also UN document A/AC.82/G/R.loj.
20. Court-Brown, W. M., and R. Doll, Lancet 4, Jan.
1958.
21. Lea, D. E., Actions of radiations on living cells,
Cambridge University Press, 1946.

Appendix

LIST O F SCIENTIFIC EXPERTS
The scientific experts who have taken part in the preparation of the report while attending Committee sessions
as members of national delegations are listed below. The Committee must also express its appreciation to the many
individual scientists not directly connected with national delegations whose voluntary co-operation and good willcontributed in no small measure to the preparation of the report.
ARGENTINA:
Dr. C. Nuiiez (Representative)
Dr. D. J . Beninson
Professor E. Favret
Dr. N. Nussis
Dr. J. A. Olarte
AUSTRALIA:
Dr. C. F. Eddy (Representative-first
Mr. D. J . Stevens (Representative)
Dr. A. R W. Wilson

Dr. A. Halawani (Representative)
Dr. H. T. Daw

session)BELGIUM:
Professor Z. Bacq (Representative)
Mr. R. Boulenger
Dr. M. Errera
Professor F. Twisselman
BRAZIL:
Professor C. Chagas (Repesetrtative)
Dr. B. Gross
Professor N. Libanio
Professor C. Pavan
Father F. X. Roser, S.J.
CANADA:
Dr. E. A, Watkinson (Representative)
Dr. R. K . Appleyard
Dr. P. M. Bird
Dr. W. E. Gnunmitt
Dr. Colin Hunter
Dr. G. H. Josie
Dr. C. A. Mawson
Dr. H. B. Newcombe
Dr. F. D. Sowby
CZECHOSLOVAKIA:
Professor F. Hertik (Representative)
Professor F. BEhounek
Dr. M. HaSek
Dr. L. Novik
Professor V. Sobek
Dr. I. Ulehla
Dr. V. Zelenf

Professor L. Bugnard (Representative)
Dr. A. Allisy
Dr. J. Coursaget
Dr. H. Jammet
Dr. J. Labeyrie
Dr. J. Lejeune

INDIA:
Dr. V. R. Khanolkar (Representative)
Dr. A. R. Gopal-Ayengar
Dr. A. S. Rao
JAPAN :

Dr. M. Tsuzuki (Representative)
Dr. Y. Hiyama
Dr. D. Moriwaki
Dr. K. Murati
Dr. M. Nakaidzumi
Mr. S. Ohta
Dr. N. Saito
Dr. E. Tajima
MEXICO:
Dr. M. Martinez Baez (Representative)
Dr. F. A. Andrade
Dr. H. Zalce

Professor R. M. Sievert (Representative)
Dr. B. A. A. Aler
Dr. R. G. Bjarnerstedt
Professor G. Bonnier
Professor T. 0. Caspersson
Professor C. A. T. Gustafsson
Dr. A. G. A. Nelson* Now in the United Arab Republic.

UNIONOF SOVIETSOCIALISTREPUBLICS:
Professor A. V. Lebedinsky (Representative)
Professor K. K. Aglintsev
Professor B. M. Isaev
Professor P. M. Kireev
Professor A. N. KraevsLy
Professor A. bZ. Kuzin

UNITEDKXNGDOM
OF GREATBRITAINAND
NORTHERNIRELAND
Professor W. V. Mayneord (Represetltativefirst session)
Dr. E. E. Pochin (Represelztative)
Dr. T. C . Carter
Mr. A. C. Chamberlain
Dr. W. G. Marley
Mr. N. G. Stewart

Dr. Shields Warren (Represe~rtative)
Professor G. W. Beadle
Dr. A. M. Brues
Professor J. Crow
Professor Th. Dobzhansky
Dr. C. L. Dunham
Mr. Merril Eisenbud
Professor Sterling Emerson
Professor G. Failla
Dr. J. H. Harley
Dr. J. S. Laughlin
Professor J. V. Nee1
Dr. M. Zelle