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MICROCOPY RESOLUTION TEST CHART
NATIONAL BUREAU OF STANDARDS -1963
ORXL-Do 3130
670709-1
JUN 2 7 1967
stP
MASTER
For proceedings of the Symposium
on Peaceful Uses of Atomic Radiation,
(Rio de Janeiro, July 9-15, 1967).
CFSTI RRICES
Radiation and Carcinogenesis
H.C. $(3.00: MN_65
Arthur C. Upton
Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee
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LEGAL NOTICE
This report was proparod u an account of Govoramont sponsored work. Noither the United
States, nor the Commission, nor any porson acting on behalf of the Commiaslon:
A. Makes any warranty or representation, expressed or implied, with respect to the accu-
racy, wompleteness, or usefulness of the information contained in this report, or that the use
of any information, apparatus, method, or process disclosed in this roport may not infringe
privately owed rights; or.
B. Asmumos hay liabilities with respect to the use of, or for damages resulting from the
use of any information, apparatus, method, or procube disclosed in this report.
As used in the above, "person acting on behalf of the Commission" includes any om-
ployee or contractor of the Commission, or employs of ruch contractor, to the extent that
such employee or contractor of the Commission, or employee of such contractor proparos,
dienominatos, or provides accous to, any information pursuant to his employment or contract
with the Commission, or his employment with such contractor.
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DISTRIBUTION OE THIS DOCUMENT IS UNLIMITED
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Running head: RADIATION AND CARCINOGENESIS
Send proof to: Dr. Arthur C. Upton
Biology Division
Oak Ridge National Laboratory
P. 0. Box Y
Oak Ridge, Tennessee 37830 .
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INTRODUCTION
The carcinogenic action of ionizing radiation was first recognized
more than half a century ago and has since been studied extensively in
human and animal populations (see Furth and Lorenz, 1954; Glucksman,
Lamerton, and Mayneord, 1957). Although radiation in large doses has
long been acknowledged to exert carcinogenic effects, concern now exists
that a small increase in environmental radiation may magnify the risk
of cancer (United Nations, 1964). This concern is intensified by the expand-
ing use of radiological apparatus and isotopes in modern society and by
worldwide fallout from atomic weapons tests.
of the various agents known to cause cancer, ionizing radiation has
probably been the most thoroughly investigated. Clinical and experimental
observations have indicated that it may cause nearly any form of cancer.
if administered under appropriate conditions to susceptible subjects.
However, because cancer may arise spontaneously, a causal connection
between irradiation and cancer can be inferred only from a statistical
correlation between increased cancer incidence and radiation dose. At
low dose levels, such a correlation is not obvious and the carcinogenic
action of radiation is problematic. Furthermore, attempts to predict the
effects of small amounts of radiation by extrapolation from the high-
dose range are hampered by the lack of precise knowledge about the
.
relation between cancer incidence and dose, the radiobiologic
mechanisms of cancer-induction, and the influence of radiologic and
physiologic variables that may affect cancer development.
. In the following, salient information about radiation-induced
cancer is surveyed briefly. Although the mechanisms of the carcinogeneic effects
of radiation remain largely unknown, facts which throw new light on
I
1. the role of radiation in carcinogenesis are reviewed.
Probability of Cancer in Relation to Low-I.evel
Irradiation: Extrapolation
From High Dose Levels
A variety of cancers have been reported in heavily irradiated
individuals, but there are relatively few growths in animals or man for
which quantitative dose-incidence data are available.
Furthermore, the data for these few are largely restricted to a dose
range hundreds or thousands of times higher than the natural background
radiation in the environment. (see below).
To put these dose considerations into perspective, the principal
sources and the average levels of environmental radiation are
summarized in Table 1. Although natural radiation has always existed
in man's environment, it differs widely from one geographic region to
another, depending on the concentration of radium and other radioactive
elements in the earth and on the intensity of cosmic radiation from
space, which varies inversely in relation to elevation.
Man-made radiations are of recent origin but are gradually increasing
throughout the world, depending primarily on the local use of diagnostic
radiology (Table 1). Attempts to limit radiation exposure from medical (T-1)
(Chamberlain, 1965) and other man-made (International Comm. on Rad. Protect.,
1966) sources are now being intensified, in part because of the desire
to minimize any possible carcinogenic risks involved.
RADIATION AND THE INCIDENCE OF SPECIFIC NEOPLASMS
Leukemia
Human Data
Postnatal Irradiation All types of leukemia, with the exception
of the chronic lymphocytic typer; have been increased in frequency
anong irradiated populations (see United Nations, 1964); however, the
dose-incidence relation for any given hematologic type is not well
known. Nor is the durat:ion of the period during which the incidence
is increased known precisely; i.e,, although a latency of 4-5 years
intervenes before the incidence of any type rises to peak values, the
time when, if ever, the incidence returns to normal is not known. In
patients treated with X-ray therapy to the spine for ankylosing
spondylitis the incidence is apparently no longer elevated 15-20 years
after irradiation (Court Brown and Doll, 1965), but in Japanese A-bomo
survivors it continues to be elevated more than 20 years after exposure
(United Nations ,1964; R. W. Miller, 1965). Whether this difference
between the two populations is attributable to differences in types of
leukemia, or other variables, remains to be determined.
Poorly known also is the influence of age on susceptibility to
radiation leukemogenesis. Evidence suggests that irradiation increases
principally those types of leukemia most likely to occur naturally in
the age group at risk and that the increase more nearly approximates a
constant multiplication of the natural age-incidence than a given
number of cases per unit dose irrespective of age (Figure 1).
(F-1)
Because of these age-dependent variations in the incidence and
types of induced leukemia, the effects of radiation on the combined
incidence of the different types averaged over all ages may vary,
depending on age at exposure. Nevertheless, the available evidence
generally supports Lewis's (1957) suggestion (Table 2) that the overall (T-2)
incidence of leukemia in populations irradiated under widely differing
conditions approximates 1-2 cases per 100 person-years at risk per rad
during the first 15 years after irradiation (see United Nations, 1964).
The similarity in the dose-incidence relation among the exposed populations
18 remarkable in view of the differences among them in the distribution
of the radiation in space and time. The most extensive dose-effect
data, which come from the follow-up studies of the Japanese A-bomb
survivors and of patients given X-ray therapy for spondylitis, are con- .
sistent with a linear dose-incidence relation for spinal and whole-
body irradiation (Figure 2), but do not exclude the existence of a thřes- (F-2)
hold at low doses, as stressed earlier (Brues, 1959).
It is not clear whether irradiation of a small part of
the body is leukemogenic. The lack of evidence of leukemia induction
in patients treated with radiotherapy for carcinoma of the cervix (Simon
Brucer, und Hayes, 1960) and in individuals with large body burdens of
radium (United Nations, 1964) suggests that irradiation may be only
slightly, if at all, leukemogenic when but a small fraction of the
total hemopoietic marrow exposed. Although an association between 1 :
diagnostic irradiation of the trunk and the subsequent development of
leukemia has been reported, it remains to be verified (see United Nations,
1964).
Prenatal Irradiation. Evidence further implying leukemogenic
effects of radiation at low dose levels is the existence of an
association between prenatal diagnostic irradiation and leukemia in
childhood (see MacMahon and Hutchinson, 1964). This association may not
be one of cause and effect, but another explanation for it remains to
be found. Hence, it suggests that prenatal whole-body irradiation
at dose levels of 5 rads or less increases by nearly 50 per cent the
risk that the exposed child will develop leukemia. This implies that if
a threshold for leukemogenesis exists it must be considerably lower than
5 rads, at least in the fetus. It also implies that susceptibility to
radiation leukemogenesis is several times higher before birth than
.
after birth.
The latency of leukemia in prenatally exposed individuals differs
from that in postnatally exposed, the excess incidence in the former
apparently persisting no longer than 10 years after exposure (MacMahon,
1962).
An association between preconceptual irradiation of the mother
and leukemia in her subsequently conceived children has been reported
(Graham et al., 1966) but remains to be verified.
Animal Data
Mice
Thymic Lymphosarcoma. The commonest radiation-induced leukemia of
the mouse arises in the thymus as a lymphosarcoma. This neoplasm may
be induced in most strains of mice by a variety of agents (see Kirschbaum,
1951; Furth and Baldini, 1959; Law, 1960). Its induction by irradiation
is inhibited in the presence of intact hemopoietic cells; i.e., shielding
spleen or marrow from radiation or infusion of nonirradiated hemopoietic
cells after whole-body. irradiation inhibits induction of the disease
(see Odell, Cosgrove, and Upton, 1960). Nonirradiated thymic tissue
may, furthermore, be rendered neoplastic on implantation into an
irradiated recipient, thus conclusively demonstrating the role of
radiation injury to tissues other than the thymus in the pathogenesis
of this disease (see Kaplan, 1959; Upton, 1961a).
The relation between the incidence of the disease and the dose of
radiation is .complex, depending on time-intensity and quality factors
of irradiation as well as on the total dose.
In general, a given dose
of X-rays or gamma rays decreases in leukemogenic potency as the duration
of irradiation is prolonged (Mole, 1958a); whereas the effectiveness
of neutrons is affected less, if at all, by thë dose rate (Figure 3).
X rays may, however, be even more leukemogenic when given in
several properly timed fractions, than when given in a
a single exposure (Kaplan and Brown, 1952; Upton, 1959). At a given dose
(F-3)
rate, the incidence typically varies as a power function of the dose
over the range 25-150 r rather than as a simple linear function (see
Upton, 1961a).
The latency is inversely related to dose (see Upton, Kimball, et al.,
1960). The peak mortality from the disease occurs 150-400 days after
exposure, relatively few neoplasms appearing clinically within 100 days.
after irradiation and few appearing late ir life (Upton, Kimball, et al.,
1960; Upton, Kastenbáum, and Conklin, 1963).
Susceptibility to induction of lymphomas varies with strain, sex, and
age (see Upton and Furth, 1957; Upton, 1959). Females are characteristically
more susceptible than males, this difference being lessened by gonadectomy
(see Kirschbaum, 1957). After involution of the thymus, susceptibility
diminishes in both sexes (Upton, Odell, and Sniffen, 1960). Irradiation
has little effect on the incidence, although it may shorten the induction
period slightly, in mice of high-lymphoma strains (see Upton, 1963; Duplan,
1965).
spice
It is too early to specify the mechanism of leukemogenesis, but
filterable leukemogenic agents have been repeatedly extracted from thymic
tumors in irradiated mice (Gross, 1958, 1959; Lieberman and Kaplan,
1959; Latarjet and Duplan, 1962; Hiraki et al., 1962; Libansky et al.,
1963; Holmberg et al, 1967; and others). If the induction of this
neoplasm depends on some form of radiation-induced activation of a
latent leukemia virus, the nature of this effect, its relation to the
dosage of radiation, and the mode of action of conditioning factors
remain to be elucidated.
The production of an irreversible "priming" effect (Kaplan, 1960)
by irradiation, which may be associated with the appearance of leukemogenic
"initiating" activity in tissues other than the thymus (Berenblum and
Trainin, 1961), the promotion of radiation leukemogenesis by estrogen
(see Kapları, Nagareda, and Brown, 1954), cortisone (Upton and Furth,
1954), urethane (Berenblum and Trainin, 1960), and myleran (Upton,
Wolff, and Sniffen, 1961), and the inhibition of leukemogenesis by
administration of testosterone and corticoids after irradiation (Ree
Kaplan et al., 1954) suggest that the evolution of neoplasia in the
thymus is a multistage process. This inference is supported by the
stepwise progression of malignancy in such growths (Kaplan and Hirsch,
1956). The action of radiation may, therefore, include •both "initiating"
and "promoting" effects, depending on the dose and conditions of exposure.
Kaplan (1964) has postulated radiation to act in the following three
Ways in inducing thymic lymphomas:
1) to liberate, or activate in some way, a latent leukemogenic
virus;
2) to cause atrophy of the thyr B, thereby stimulating regenerative
· proliferation of surviving thymocytoblasts; the latter are
postulated to be the target cells of the virus and to be
more susceptible when mitotically active than when in a
10
resting condition atrophy of the thymus induced by other means
also acts in the same way; hence, irradiation of the thymus
itself is not necessary to this mechanism); and
3). to damage the bone marrow, which impairs regenerations of the
thymus, thus prolonging the period during which thymocytoblasts
are in a state of heightened susceptibility to viral transformation.
The role of the marrow in the latter mechanism is not established,
but existing data suggest that the marrow supplies stem cells which
repopulate the thymus and thus facilitate its regeneration (see Loutit,
1964).
The mechanism by which radiation"activatest the leukemogenic virus,
likewise, remains to be determined. Leukemogenic virus may, however,
be recoverable from exposed mice within only a few days after irradiation
(Haran-Ghera, 1966), and there is evidence implying that virus may be
activated, at least partially, even in nonnemopoietic tissues within
minutes after irradiation in vitro (see Berenblum and Trainin, 1963).
That the virus may be "activated" in situ and need not enter the body
from outside is suggested by studies with germ-free mice, which develop
radiation-induced leukemia and contain leukemia-virus-like particles,
in their tissues, in the absence of other detectable viruses or
microorganisma (Polard and Matsuzawa, 1964; Walburg et al, 1965).
These studies are thus consistent with Gross's hypothesis that the
leukemia virus is transmitted vertically from mother to young, either
across the placenta or via the zygote (see Gross, 1961).
Although the nature of the virus-induced leukemic transformatioa
is obscure, several, theoretical models have been postulated (Kaplan,
1962; Dulbecco, 1963). The origin of the neoplasm from a single
kathy
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transformed cell is implied by cytogenetic studies indicating the
lymphoma in most instances to be a clone of cells having a particular
chromosomal abnormality, which becomes detectable in the thymus during
· the "preneoplastic" period (see Loutit, 1964; Joneja and Stich, 1965).
Granulocytic Leukemia. The experimental induction of myeloid leuke-
mia by ionizing radiation has received less study than the induction of
thymic lymphoma, presumably because myeloid leukemia is ráre in
tenfold by 150 r whole-body X-irradiation; i.e., to about 30%, as
compared with the natural incidence of 2-3% in this strain (Upton et al.,
1958). An increase in the incidence of the disease has also been
noted in irradiated mice of other strains (see Upton et al., 1960;
Cottier, 1961), but the numbers of affected animals have been too small
to provide quantitative data.
As in the pathogenesis of thymic lymphoma, the induction of myeloid
leukemia is conditioned by physiologic variables, such as age, sex,
hormonal activity, and other factors (Upton, 1959, 1963, Upton et al.,
1966). It is also associated with the appearance of a filterable
leukemogenic agent in the leukemic tissues, suggesting that a virus,
is also involved in its pathogenesis (see Upton, 1969; Parsons et al.,
1962; Jenkins and Upton, 1963).
Radiation has failed to induce this disease in RF mice exposed
in the neonatal period or in the germ-free state, or to induce any
form of leukemia in RF mice exposed. prenatally (see Upton et al., 1966),
which underscores the importance of physiologic factors in leukemogenesis. :
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T
12
The action of these factors on the host-virus relationship and on the
dynamics of granulocyte turnover deserves further study. It has been
proposed that the same virus may cause granulocytic leukemia, thymic
lymphoma, and other leukemias, depending on the constitution of the
host (see Gross, 1961; Upton, 1964; Upton et al., 1966).
The relation between the incidence of myeloid jeukemia and radiation
dose in RF mice depends markedly on the conditions of exposure (Figure 4). (F-4)
The curve below 150 r appears curvilinear, and it declines at high doses,
& feature characteristic of many other neoplasms (see Upton, 1961a).
The decline may conceivably reflect excessive cytotoxicity at high dose
levels, in keeping with certain theoretical expectations (Reif, 1961;
Gray 1965). Gamma rays are relatively ineffective at low dose rates,
which is consistent with the dose-rate dependency for induction of
lymphomas, noted above, and of certain other neoplasms (see Mole, 1959;
Upton, 1961a; Aleksandrov and Galkovskaya, 1963).
Preliminary cytogenetic studies suggest that the marrow cells in a
considerable proportion of granulocytic leukemias are characterized
by a consistent chromosomal abnormality (Wald et al., 1964). In view .
of the evidence for a viral etiology of the leukemias. in question, i
the clonal nature of the affected cells remains to be established.
Nevertheless, this observation points to a possible explanation of
the occurrence of the Philadelphia chromosome in successive generations
of a family, in association with chronic granulocytic leukemia in the
grandfather (Hirschborn, 1965).
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13
Other Leukemias. In mice of many strains, lymphomas and reticulum
cell sarcomas of extrathymic origin are common late in life. The incidence
of such neoplasms is not characteristically increased by irradiation
(see Upton, Kimball et al., 1960). A radiation-induced increase has
been noted, however, in CBA mice (Mole, 1958a) and in C57B1 (Kaplan,
Hirsch, and Brown, 1956) and RF (Upton et al., 1958) mice after removal
of the thymus.
Species Other Than the Mouse
By comparison with the extensive data on radiation leukemogenesis
in the mouse, information on other species is meager.
The effects of radiation on the development of leukemia in the rat
are less clear-cut than in the mouse. In many studies, irradiation.
has been observed to be followed by an increased overall incidence of
reticular neoplasms (Metcalf and Ida, 1954; Kuzma and Zander, 1957;
Zipf, 1959; Sipila, 1960; Berdjis, 1963; Hunstein et al., 1964; Moloney,
et al., 1965). On the other hand, irradiation has been followed by no
. increase in the incidence of reticular tumors in some experiments
(Koletsky End Gustafson, 1955; Maisin et al., 1957; Lamson et al., 1958)
and by a decreased incidence in others (Brown and Thorson, 1956). The
basis for the inconsistent effects of radiation on leukemia incidence
in the rat remains to be determined. In no strain of rats has
radiation been observed to increase the incidence as markedly as in
susceptible strains of mice.
In dogs, reticular tissue neoplasms are apparently increased in
frequency by internally deposited Sr%°The cases reported include
24
one lymphosarcoma and one reticulum cell sarcoma (Andersen and McKelvie,
1964), one myeloid leukemia and one acute reticulosis (Biskis et al, 1964),
and one lymphoma (Dougherty, 1962). These cases far exceed the incidence
observed to date in the respective nonirradiated control populations and,
therefore, have been viewed as tentative evidence of leukemia induction
by Srsº (McClellan, 1966). Protracted x-ray exposure has, likewise,
been reported to induce leukemia in the dog, four cases (acute and
subacute myeloid leukemia and blast cell leukemia) having been described
by Lapteva-Popova (1958).
Minature swine surviving internal irradiation by Srº also have been
reported to develop lymphosarcoma and myeloid leukemia in increased
frequency (McClellan 1966).
In primates, isolated cases have been described after irradiation
by internal isotopes (Petroff et al., 1959; Tuttle, 1966) and whole-
body external irradiation (Yakovleva, 1964; Zalusky et al., 1965;
Dzhikidze and Yakovleva, 1965). The neoplasms have varied in morphology,
and it remains to be determined whether they denote leukemia induction
in this species.
In guinea pigs, Congdon and Lorenz (1954) have noted chronic
lymphatic leukemia more often in irradiated animals than in controls.
In Chinese hamsters,Kohn and Guttman (1964) have noted three lymphoid
tumors in 195 irradiated animals, as opposed to one in 112 controls.
15
Neoplasms of Bone
Human Data
Osteosarcomas have been observed in several dozen patients within
• 3-30 years after therapeutic external irradiation, in most instances
arising at the site of a preexisting lesion or chronic inflammation
(see Bloch, 1962). Grossly detectable radiation damage to the affected
bone has not always been evident in advance of such neoplasins, but the
doses involved have been high, 3000 rads being the lowest dose associated
with tumor formation in the absence of other factors known to predispose
to neoplasia (see Jones, 1953).
Smaller doses (60-600 rads) have been associated with the formation
of osteochondromas in infants and young children irradiated therapeutically
over the chest (Pifer, Toyooka, and Murray, 1963; United Nations, 1964).
The latter cases suggest that susceptibility to induction of bone
tumors may be higher in children than adults, but quantitative dose- .
.
incidence data are not available for any age group.
Semiquantitative dose-incidence data have been obtained from :
populations with high body burdens of radium, in which the incidence of
osteosarcomas (Table 3) varies approximately as the square of the terminal (T-3)
concentration of radium in the skeleton (see Marinelli,.1958; Burch, 1960).
Expression of this dose-incidence relation in rads is complicated
by the inliomogeneity of the radiation dose in space and time. Radium
varies greatly in its concentration throughout bone, tending to localize
in hotspots where the dose may be an order of magnitude higher than else-
where. Furthermore, the radium present at the time the tumors have been
detected generally has constituted only a small percentage of the amount
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16
present earlier. Despite these sources of uncertainty, attempts have been
made to analyze the dose-incidence relationship in rads, resulting in
a crude estimate of an induced incidence of four cases of osteosarcoma
per 10° person-years at risk per rad (United Nations, 1964), a rate
remarkably similar to that for leukemia in human populations cited
earlier.
Animal Data
Bone tumors have been induced in experimental animals by external
irradiation (see Cater, Baserga, and Lisco, 1959; Law, 1960), as well as
by bone-seeking radionuclides (see Furth and Tullis, 1956; Odell and
Upton, 1961). Most of the data, however, come from experiments with
internally deposited isotopes, and in such experiments, evaluation of
the dose-effect relation is hampered by complexities in the distribution
of the radiation in space and time (see Lamerton, 1960). These complexities
result from (1) nonuniformity in the deposition of radioisotopes within
the skeleton, resulting in hotspots, where the dose exceeds that in
surrounding bone by a factor of up to 10 or more, (2) changes with time
in the distribution and concentration of radioactivity in bone, owing to
the metabolic turnover and excretion of isotopes and their decay daughters,
.and (3) progressive diminution in the dose rate of the emitted radiation
through physical decay of the emitter. The latter source of variation
is predictable, since it depends solely on the physical half-life of
the radionuclide in question.On the other hand, the rate at which an
elezaent is excreted from the body, or its "biological half-life," depends
on the influence of metabolic, nutritional, and physiologic factors
(Wasserman, 1960). Tumorigenic activity varies considerably among bone-
seeking radionuclides (Figure 5). The variation results from differences (F-5)
is.
17
in the quality of emitted radiations (1.e., energy and charge) as well as
in the uptake, distribution, and retention of the isotopes within the
skeleton. Species and strain differences in susceptibility to a given
isotope have also been noted, limited data suggesting that the rat may
be appreciably more susceptible than the mouse (see Law, 1960). Further-
more, because of differences in the geometry of the radiation between
the mouse and larger animals, making for less escape of penetrating
radiation from larger bones and hence less "wastage" of the total
emission, the dog is several times more responsive than the mouse to
the same injected dose of Sr90 (Finkel, 1958). There are also strain
and species differences in the sites of neoplasia within the skeleton,
depending in part on the radionuclide administered and the age at
exposure (see Bensted, Blackett, and Lamerton, 1961). Certain hormones
enhance the development of bone tumors (Cater et al., 1959).
Although, in general, the length of the average induction period is
inversely related to dose, the relation between the induction period
(or tumor incidence) and the total accumulated dose varies, depending
on the number of injections of isotope and the interval between injec-
tions (Finkel, 1958;. Blackett, 1959; Lamerton, 1960; Bensted et al.,
1961). The incidence of osteosarcomas induced in the leg of the mouse
by x-irradiation is appreciably higher than that obtained from the
same radiation dose delivered by internally deposited isotopes. Moreover,
preliminary data suggest that the incidence approximates a linear
function of the x-ray dose (Finkel, Jinkins, and Biskis, 1964).


18
Although gross bone injury and reparative proliferation have been
observed to precede radiation-induced skeletal tumors in most instances,
there is no evidence that such changes are required to induce neoplasia
(see Finkel, 1958; Bensted et al., 1961; Lamerton, 1960; Nilsson, 1962).
Some bone neoplasms are transmissable by cell-free extracts (Binkel,
Biskis, und Jinjins, 1966), and the development of skeletal tumors in
Sr®°-injected mice is suppressed by nonspecific imunol.ogical stimula-
tion (Nilsson, Revesz, and Stjernsward, 1965). The latter observations
imply that the tumors, like certain murine leukemias, may be virus-
induced and characterized by antigenic specificity, possibly viral in
nature.
Thyroid Tumors
Human Data
An association between x-irradiation of the thyroid gland in child-
hood and the later development of thyroid tumors, reported first by
Duffy and Fitzgerald in 1950, has since been confirmed (United Nations,
1964). The latent period between irradiation and the appearance of
such tumors averages 10-15 years (United Nations, 1964; Lindsay and
Chaikoff, 1964). The growths include adenomas and hyperplastic nodules,
in addition to carcinomas.
Although no one survey contains enough cases to define the dose-
• incidence relation, it has been estimated from pooled statistics
(F-6)
(Figure 6) that the incidence of thyroid cancer is approximately one
case per 100 person-years at risk per rad during the first 15 years
after exposure (Beach and Dolphin, 1962; (United Nations, 1964). As
in the case of bone tumors, this rate appears similar to that for
induced leukemias, cited earlier.
19
The above estimate, based on the response of the child's thyroid
to high-dose (> 100 rads) high-intensity irradiation, may not apply to
the response of the adult's thyroid or to the response of the child's
thyroid to low-dose rate irradiation. Preliminary data suggest, in fact,
that the child's thyroid exceeds the adults in susceptibility to radiation
carcinogenesis (United Nations, 1964).
Evidence that iodine-131 may have oncogenic activity comes from the
high incidence of thyroid nodules among children ingesting large amounts
of I-131 through accidental exposure to nuclear fallout in the Marshall
Islands. Among these children, thyroid nodules have occurred in nearly
half of those exposed under 10 years of age, whereas none have occurred
among the nonexposed control.s (Conard and Hicking, 1965; Federal
Radiation Council, 1966). The radiation doses to the thyroid glands of
such children are difficult to estimate but are considered to range
from 700 to 1400 rads, including radiation from external gamma rays
as well as from internally deposited radioiodine.
Animal Data
Thyroid tumors induced by internal and external radiation have been
reported in rats (see Doniach, 1957; Potter, Lindsay, and Chaikoff,
1960), mice (see Upton, Kimball, et al., 1960), and sheep (see Thompson
et al., 1958). The neoplasms in rats resemble the papillary and
follicular growths resulting from prolonged administration of goitrogens
or from iodine-deficient diets. In contrast, alveolar carcinomas, which
are relatively common in aging Long-Evans rats, have not been increased
in frequency by irradiation.
20
In the induction of thyroid neoplesms, there is an optimal radiation
dienas-panyse (Figure 70),, thereo muodh 3d casserttitally dilestreguing the gozand and
failing to induce such tumors (Field et al., 1959). From the amount of
radiolodine needed to "initiate" thyroid neoplasia in rats treated with
methylthiouracil, it has been estimated that 30 uc of Its corresponds
to 1100 rads of X rays applied externally to the .gland (Doniach, 1957).
Fast neutrons appear relatively more carcinogenic than X rays and
gamma rays (Haran-Ghera et al., 1959; Upton, Kimball et al., 1960).
Carcinoma of the Respiratory Tract
Human Data
Although carcinoma of the long has been known to be prevalent in
ore minors of Saxony and Bohemia for centuries (see Weller, 1956), only
recently has radiation been accepted as the principal cause of this
disease (see United Nations, 1964). Uranium miners in the U. S. show
a similarly elevated incidence of pulmonary carcinoma, the rate increasing
with the duration and intensity of exposure (Figure 8), even after (F-8)
correction for such variables as age, cigarette consumption, "heredity, .
urbanization, self-selection, diagnostic accuracy, prior hard-rock
mining, or nonradioactive-ore constituents including silica dust"
(Wagoner et al., 1965). Anatomical features of the disease in the
uranium miners which tend further to implicate radiation in its etiology
are the unusual distribution and histologic character of the cancers;
i.e., they are predominantly undifferentiated small-cell carcinomas
occurring in the hilar region (Wagoner et al., 1965).
21
Determination of the relationsh:.y between the cancer incidence pind
the radiation dose is comp...cated by many uncertainties, owing to the
conditions of irradiation see United Nations, 1964; Altshuler, Nelsyn,
end Kuschner, 1964; Jacob; 1964; Wagoner et al., 1965). Although the
. average duration of exposure among affected miners 18 15-20 years, 11
is not clear what fraction of the total cumulative exposure is respossible
for the carcinogenic effects in question. Moreover, estimates of thi
radiation dose to the ortachial epithelium from such exposure vary from
about 1 rad per 40-hour week to values 1-2 orders of magnitude lower
(see United Nations, 1982. Altshuler et al., 1964; Jacobi, 1964).
Animal Data
Alveolar and bronchli neoplasms have been reported in animals
following local deposition of a variety of radicactive substances (see
Bair, 1960; Cember, 1962They also have been pbserved in increase
frequency among rats inje:fed intravenously with Thorotrast (Guimaraf's
et al., 1955) and mice injected intravenously with colloidal radiogola
(Upton et al., 1956). In all of these instances, radioactivity was
concentrated nonuny.formly within the thorax, tending to produce hotspots
of relatively high radiation dosage to adjacent Lung and bronchus.
Hence the radiatior. dose responsible for neoplasia under these
circumstances canngt be readily estimated.
The incidence of pulmonary adenomas in LAF, mice exposed to sublethal
levels of whole-body radiation has been found decreased when the radiation
was given in a single exposure early in life (Nowell and Cole, 1959;
Upton et al., 1960) but increased when the radiation was administered
OS
22
in daily exposures for the duration of life (Lorenz et al., 1954, 1955).
The basis for these differences remains to be explained but probably
involves, among other factors, a failure of whole-body radiation to
advance the age-distribution of pulmonary tumors enough to offset
life-shortening from other causes (see Lindop and Rotblat, 1961; Upton,
Kastenbaum, and Conklin, 1963). Hence, mice subjected to irradiation
early in life may die prematurely, before the induction of
lung tumors has time to take place. Even, however, with irradiation
localized to the lång, pulmonary carcinogenesis by urethane is
inhibited through mechanisms other than life-shortening (Gritsyute,
1961; Foley and Cole, 1964).
Skin Cancer
Skin Cancer
Human Data
The first neoplasnı attributed to irradiation was an epidermoid
carcinoma arising in an area of radiation dermatitis on the hand of an
X-l'ay tube maker (Frieben, 1902). More than 90 similar cases were
reported within the following decade among physicians and radiation
workers (Hesse, 1911). Squamous cell carcinomas and basal cell carcinomas
here predominated among these neoplasms, although fibrosarcomas have also
been reported (see Traenkle, 1963). .
The dose-incidence relation for induction of cutaneous cancer is
not known (UNSCEAR, 1964). It is generally postulated, however, that the
risk of the disease varies with the severity of radiodermatitis, being
low in the absence of gross skin camage (see Hempelmann and Hoffman, 1953;
Traenkle, 1963).
Never
23
Animal Data
Cutaneous carcinogenesis by ionizing radiation, noted experimentally
more than half a century ago, has since been confirmed repeatedly (see
Glucksmann, 1958; Law, 1960; Hulse, 1962). In comparison with chemically
induced tumors, those caused by radiation require longer for their
induction. Their histological character varies with host factors and
with the conditions or irradiation. To induce a high incidence of
neoplasia, it is generally necessary to deliver ulcerating doses of .
radiation. Under these conditions the hair folicies are destroyed
(Albert et al., 1967) and healing is impaired by residual vascular
changes and scarring. The ensuing neoplasms appear to arise from
transformation of marginal proliferating epidermal cells or fibroblasts
(Glucksmann, 1958). Nonulcerating doses also, however, have been found
carcinogenic, in the absence of obvious radiodermatitis (see Law, 1960;
Hulse, 1962).
As yet, it is not possible to define precisely the relation among
--
-
-
. ". -
'.
...
-
the factors influencing the development of cutaneous neoplasia; i.e.,
-
-
.
.
.
. --
total radiation dose, dose rate, area and depth (number of epidermal
and dermal cells ) irradiated, and physiologic condition of the host.
It would appear, however, that radiation is optimally effective at
intermediate dose levels (Albert, Newman, and Altshuler, 1961) and that
the effects of radiation may be enhanced by other agents, such as:
croton oil (Shubik et al., 1953) and chemical carcinogens (Cloudman
.
. .-
.
-
-
..
.
...
...
..
-
-
'
..
..
et al., 1955), and conceivably by irradiation of distent parts of
the body (Bock and Moore, 1959). .
.
.....
....
.
.
..
25
.
:
n
;-...---
.
..
Animal Data
Breast Tumors. The induction of mammary tumors by irradiation has
been observed in mice (see Furth, 1959; Law, 1960; Upton, 1961a; Cottier,
1961) and rats (see Shellabarger et al., 1957; Durbin et al, 1958; Law,
1960). The effects of radiation on the incidence of neoplasia
vary, however, with the type of tumor in question and with host factors.
In certain strains of mice, a dose-dependent decrease in the incidence i
of sarcomas has been noted (see Upton, 1961a). In Sprague-Dawley
female rats, the overall incidence of mammary tumors appearing within
the first year apparently varies as a linear function of X-ray dose
over the range 25-400 r (Bond et al., 1960a). For a given radiation
dose, neutrons are more tumorigenic than X rays or gamma rays (Haran-
Ghera et al.., 1959; Upton, Kimball, et al., 1960.
Hormonal factors have a profound effect on the pathogenesis of
radiation-induced mammary tumors, females being more susceptible than
males and their greater susceptibility depending on ovarian function
(Cronkite et al., 1960). In addition, there are indications that
- aniami
pituitary mammatropic activity may enhance the induction of mammary
tumors (Yokoro, Furth, and Haran-Ghera, 1961).
Although the induction of these growths involves, therefore,
!
..
...
..
27
.
indirect as well as direct factors, localized irradiation is tumorigenic
only to the mammary tissue directly exposed (Bond et al., 1960b).
Limited efforts to implicate viruses in the pathogenesis of these
tumors have been unsuccessful (see Upton, Kimball, et al., 1960).
.-
--
.
.
-.
-
26
Pituitary Tumors. Pituitary tumors are induced by irradiation in
rats and mice (see Yokoro et al., 1961). Thyrotropic tumors induced in
mice by Its are attributed chiefly to the effects of thyroid injury
rather than to irradiation of the pituitary itself (see Furth, 1959).
On the other hand, direct irradiation has been implicated in the
pathogenesis of mammotropic and adrenotropic pituitary tumors (see Furth,
* 1959; Van Dyke et al, 1959; Upton, Kimball, et al., 1960; Yokoro et al., .
1960; Yokoro et al, 1961). Hormonal factors influence their pathogenesis,
. as indicated by the inhibitory influence of ovariectomy (Furth et al.,
1959). Neutrons are more effective in pituitary tumorigenesis than
X rays (Haran-Ghera et al., 1959).
Adrenal Thumors. Cortical adenomas and medullary chromaffine tumors
are induced in mice of certain strains by exposure to whole-body external
radiation early in adult life (see Upton, Kimball et al., 1960; Cottier,
1961). The induction of these growths is enhanced by ovariectomy, and .
their incidence is higher after fast neutron irradiation than after
similar doses of X rays and gamma rays (Haran-Ghera et al., 1959; Upton,
Kimball et al., 1960). In rats, cortical adenomas have been reported
after injection of At211 (Durbin et al., 1958), and medullary tumors after
injection of P.210 (Casarett, 1952).
Ovarian Tumors. The female mouse is unusually susceptible to
induction of ovarian tumors by irradiation. The neoplasms induced
are complex and may comprise virtually any or all of the histologic
elements remaining in the ovary after depletion of the oocytes; i.e.,
granulosa cells, lutein cells, mesothelial cells, thecal cells,
...
endothelial cells, etc. Furthermore, these growths retain their
27.
morphology and hormonal activity on serial transplantation (Bali and
Furth,
Like the similar neoplasms induced by transplantation of the
intact ovary into the spleen, pathogenesis of these tumors is apparently
dependent on stimulation by pituitary gonadotropin. Tumorigenesis is
inhibited if ovarian function is preserved by shielding one ovary or
if estrogen is injected (see Kirschbaum, 1957; Clifton, 1959). Hence,
irradiation may exert its tumorigenic effects by causing premature
menopause through the killing of oocytes, mice of strains prone to
early menopause developing a liigh incidence of ovarian tumors without
irradiation or other treatment. (Thung, 1959).
Because of the high radiosensitivity of mouse oocytes, 50 rads of
X rays or gamma rays induce ovarian tumors in mice; however, the
effectiveness of the radiation is dependent on the dose rate (Upton,
1961b). The induced tumors develop only after a latent period of many
months (Upton, Kimball et al., 1960), although sterilization and
luteinization of the ovary are evident within weeks after irradiation.
ors
C
Pancreastic Tumors. islet-cell tumors of the pancreas are induced
by irradiation in intact (Rosen, Castenera, Jones, and Kimeldorf, 1961a)
and parabiotic (Warren et al., 1964) rats.
Kidney Tumors. An increased incidence of renal adenomas and
carcinomas has been noted in irradiated mice (Hollcroft et al, 1957;
Upton, Kimball et al, 1960) and rats (Koletsky and Gustafson, 1955;
Rosen et al., 1961b). No data are available, however, as to the
shape of the dose-incidence curve. As in the induction of other
neoplasms, neutrons appear more tumorigenic to the kidney than are
X-' or gamma-rays (Upton, Kimball et al., 1960; Rosen et al., 1961b).
Gastrointestinal Tumors. Induction of adenomas and carcinomas
of the stomach, small intestine, and colon has been reported in
irradiated rats and mice (see Nowell and Cole, 1959; Upton, Kimball,
et al., 1960). In general, such growths have been numerous only
after doses that would be supralethal if applied to the whole bodys
except in the case of fast neutrons, which apparently have a high
relative tumorigenic effectiveness for these tissues.
Liver Tumors. Hepatomas are produced in rats by Thorotrast
-
-
i
..
....
- (Guimaraes, Lamerton, and Christensen, 1955) and in mice (Upton,
Furth, and Burnett, 1956) and rats (Harel et al., 1956) by colloidal
radioactive gold. Hepatic neoplasms may also follow irradiation from
other sources, internal and external, (see Guimaraes et al., 1955;
Upton, Kimball, et al, 1960). :
...
-
-
-
.
..
-
...
-
----
..
.
INFLUENCE OF RADIOLOGICAL VARIABLES
Total Dose
Quantitative data on the relation between tumor incidence and radia-
tion dose are scanty, especially as regards the effects of small amounts
of radiation (1.e., less than 50 rads), which are of primary concern in
environmental carcinogenesis. Although efforts have failed thus far
to provide unequivocal examples of a straight-line relation over a wide
range of dose and dose rate, epidemiological studies in human populations
suggest that leukemias, bone tumors, and thyroid neoplasms are unexpectedly.
similar in incidence per unit dose, the available data also being consistent
with a linear relation between incidence, and dose (United Nations, 1964).
This is verplexing, since the bulk of available evidence argues against
the hypothesis that the neoplastic transformation is a simple "one-hit"
process' and should, therefore, be a linear function of dose (see Brues,
1958, 1959; Burch, 1965). Interpretation of the data is further
complicated by the fact that the incidence values are based on interim
analyses and not on final incidence levels.
Time-Intensity Factors
Although it is evident that the carcinogenic potency of a given
dose of radiation is influenced by tħe rate at which the dose is
administered, the precise role of the various time-intensity factors
is poorly understood. In general, irradiation at a high dose rate is
more effective than irradiation at a low dose rate, at least in the
case of radiations of low linear energy transfer (LET), such as X and
--
..
*
30
gamma rays. However, a dose fractionated into several exposures of
intermediate size and frequency, may be even more tumorigenic than
when given in a single brief exposure (see Mole, 1958b; Upton, 1961a).
...
r
Radiation Quality :
For carcinogenesis, as for many other radiobiological effects,
radiations of high LET (a particles, neutrons, protons) are apparently
more effective than those of low LET (X rays, gamma rays). The relation
between LET and relative biological effectiveness (RBE) is not simple,
however, and available data on carcinogenesis fail to define it
:
.::
.
. .
quantitatively.
The carcinogenic ::.
.
.
.
effectiveness of high-LET radiations is less dependent on dose rate
.
.
.
.
than is that of low-LET radiations, the difference in effectiveness
:-
between the two types of radiation increasing with decreasing dose
rate (see Upton, 1961a). Under conditions of low-level irradiation, the
oncogenic potency of high-LET radiations is generally assumed to be
10-20 times that of X and gamma rays (National Committee on Radiological
Protection, 1954; International Commission on Radiological Protection
Committee on RBE, 1963).
...
.
........
.
.
.
...
INFLUENCE OF PHYSIOLOGICAL FACTORS
Species and Strain
...
. ...
.
..
.
....
- .
- -
- --
Data on radiation carcinogenesis pertain largely to human beings and
rodents, relatively little information being available on animals of
intermediate size and life-span. Insofar as comparisons are possible
from existing data, no qualitative species differences are apparent.
From this, it would seem reasonable to infer that ionizing radiations
are oncogenic to all mammals, although susceptibility to any one type
of neoplastic response varies with genetic background (see Upton and
------
-
-
-
-
- -
IC
im
.......
-
-
--
-
Furth, 1957). In addition, however, since strain differences in
spontaneous tumor incidence formerly attributed solely to genetic
:: variations are now ascribable also in part to variations in the dis-
tribution of oncogenic viruses, diferences among strains and species
in susceptibility to radiogenic neoplasia may depend to some extent
on epidemiologic variations.
Comparison and extrapolation of data on radiation carcinogenesis
from one species to another are further complicated by the following
questions; answers to which cannot yet be given (Brues, 1955):
(1) What is the significance of the induction period in neoplasia,
and how is it related to the life-span of the species and to the dose
of radiation? (2) Why do species differ in the spontaneous incidence
of a given neoplasm, and are such differences correlated with variations
in susceptibility to induction of the same neoplasm by radiation?
Age at Time of Irradiation
The influence of age on susceptibility to radiation carcinogenesis
.
has received little study (Doll, 1962). Although epidemiologic data
suggest that the human being may be unusually susceptible to radiation
carcinogenesis before birth (MacMahon, 1962), the incidence of each
of the various types of leukemia, and possibly other neoplasms,
induced by irradiation after birth apparently varies as a multiple of
the natural age-related incidence rather than as a given number of
excess cases per unit radiation dose. The implications of this
hypothesis in relation to the mechanisms of carcinogenesis and aging
and in relation to the possible role of age-related changes, such as
:
32
variations in immunity (see Makinodan and Peterson, 1964; Caso, 1965) in
carcinogenesis, warrant further investigation (see Upton, 1964).
Hormonal Factors
.
The influence of gonadal hormones on susceptibility to radiation-
induced.. mammary neoplasia and lymphomas (see Kirschbaum, 1957; Furth,
1959; Clifton, 1959) and the influence of hypophyseal hormones on the
induction of tumors of endocrine-dependent target organs; e..., ovary,
breast, and thyroid (see Furth, 1959; Haran-Ghera et al., 1959) 18
well documented. The extent to which hormonal factors may be involved
in other types of neoplasia is not known, but their influence cannot
be excluded in any of the radiation-induced growths studied to date
(see Upton, 1961b).
Another factor observed to enhance the development of certain
radiation-induced sarcomas, possibly through homeostatic humoral
mechanisms, is local inflammation (see Burrows and Clarkson, 1943).
Since radiation is generally productive of some degree of inflammatory
reaction and reparative cellular proliferation, this factor may be
involved in the induction of any type of neoplasm, although its
relative importance is probably dose-dependent.
-
-
-
-
-
-
.
..
-
... -
- -
-
-
-
...
- -
-
-
.. -
33
.
EFFECTS OF COCARCINOGENIC AGENTS
Additivity of the oncogenic effects of X rays and methylcholanthrene
was first reported by McEndy, Boon, and Furth (1942). Combined administra-
tion of radiation and other chemical carcinogens, likewise, increases
the incidence of skin tumors (Clouaman et al., 1955) and lymphomas (see
Upton et al., 1961) above the level induced by either agent alone.
The interaction of the two agents is not simple, however, the doses
and order in which they are administered influencing the oncogenic
additivity (see Upton et al., 1961). In fact, combined treatment
may decrease, rather than increase, the yield of
neoplasms if the combined toxicity of the two agents outweighs their
oncogenic effects per se (Lisco, Ducoff, and Basexga, 1958; Lacassagne
and Hurst, 1962). In part, this may result from effects of the chemical
agent on the metabolic repair of radiation injury at various levels of
biologic organization within the cell, depending on the time-dose
schedule (see Upton, 1964).
POSSIBLE MECHANISMS OF RADIATION CARCINOGENESIS
Somatic Mutation Theory
my
The mutagenic potency of ionizing radiation makes it logical to
-
-
-
consider that radiation-induced somatic mutation may play an etiologic
-
-
role in radiation-induced cancer. The discovery that the induction and
expression of point mutations in animal germ cells do not necessarily
follow one-hit kinetics (see Russell et al., 1960; Russell, 1965)
serves to reconcile observations on radiation carcinogenesis heretofore
considered contradictory with the mutation hypothesis. At the same
time, experimental evidence that many neoplasms evolve to autonomy
through a stepwise succession of changes (see Furth, 1953; Brues,
1958; Burch, 1965) argues against the idea that carcinogenesis is
induced by a single mutaion. Nevertheless, if cancer arises as the
result of successive alterations in a cell or tissue, some of which
may be mutations, it is conceivable that a single radiation-induced
somatic mutation might complete the neoplastic transformation in a
suitably conditioned individual. Consistent with this possibility are
preliminary data on the age -specific incidence of malignant growths
among Japanese A-bomb survivors, in whom the prevalence of cancer
induced by irradiation varies in relation to age at time of
exposure (Harada and Ishida, 1960). Also in support of the somatic
mutation hypothesis is the regular occurrence of specific cytogenetic
abnormalities in patients with leukemia; i.e., the Philadelphia
chromosome in chronic granulocytic leukemia; and trisomy for
chromosome 21 in Down's Syndrome, with its predilection toward
leukemia (see Gunz and Fitzgerald, 1964; Miller, 1964).
A class of radiation-induced neoplasms that cannot, however, be
ascribed even teatatively to the direct mutagenic action of radiation
are the growths induced indirectly by irradiation of other parts of
the body (see Kaplan, 1959; Upton, 1961b). Since the tumor-forming
cells in growths of this type are not themselves irradiated, mutagenesis
cannot explain their pathogenesis, unless they result from spontaneous
neoplastic mutations selected as a result of distant irradiation or
induced indirectly through viruses or mechanisms as yet unknown
(Waid et al., 1964; Hirschborn, 1965).
Virus Theory
The indirect induction of lymphosarcomas in unirradiated thymic
grafts implantated into irradiated recipient mice has been tentatively
ascribed to the action of a leukemogenic virus (see Gross, 1961;
Kaplan, 1964.
It would appear that the induction of myeloid leukemia,
91
and possibly osteosarcoma, also involves similar viral mechanisms in
the mouse (see above). Whether other radiation-induced neoplasms
are viral in pathogenesis remains to be determined, but this possiblity
demands careful consideration in view of the growing variety of
oncogenic viruses and virus tumors now recognized. The mechanism üby
which radiation may cause virus activation is yet to be defined,
although possible mechanisms of viral oncogenesis have been conceived
(see Kaplan, 1962; Dulbecco, 1963; Temin, 1966). This question calls
for intensified research into the effects of radiation on mammalian
viruses and on the virus cell interrelation, a subject relatively
little studied to date (see Levine, 1963).
SUMMARY
An association between irradiation and neoplasir, has been
detected in human populations at lower levels of radiation exposure
and in a greater variety of neoplasms than hitherto suspected. The
dose-incidence relation cannot, however, be specified precisely for
any neoplasm. Furthermore, the oncogenic effects of radiation appear
to depend on the age of the population at the time of exposure.
. The carcinogenic: effects of radiation in animals appear diverse :
and complex. The degree to which the process of carcinogenesis may
involve indirect effects on the host, as well as direct effects on
the tumor-forming cells themselves, cannot be specified. In many
Instances, neoplasia apparently involves interactions among the effects
of radiation, viruses, chemicals, and various host factors.
--
-
---
37
ACKNOWLEDGMENT
Research sponsored by the U. S. Atomic Energy Commission under contract
with the Union Carbide Corporation.'
- ...
-
- - ..
-.-.
Li....nimene.
-
-
-
-
-
.
Table 1
Estimated Average Annual Radiation
Dose to the General Population*
Source of radiation
Dose
(millirem)
External sources
32-73
Cosmic rays
Gamma rays from earth's crust
25-75
Internal sources
Potassium-40
19
Carbon-14
1.6
-
-
-
.
-
Radium-226
Subtotal
80-170
Man-made
Medical (exposure of patients)
Diagnostic (x rays)
40-240
Therapeutic
Internal (radionuclides)
Occupational (radiation workers)
Environs
Other (luminous dials, TV, etc.)
Fallout from nuclear weapons tests
Subtotal
80-280
Total
160-450
*Modified from Federal Radiation Council Report No. 1 (1960).
TABLE 2
Lewis's Estimates of the Probability of Radiation-Induced Leukemia
in Various Populations
POPULATION
EXPOSED
TYPE OF
RADIATION
REGION
IRRADIATED
PROBABILITY
OF LEUKEMIA
(per million) **
A-bomb survivors
Gamma rays,
neutrons
:
Whole body
--- ... -------
-
Patients with
ankylosing spondylitis
X rays
Spine
-
-,.-.
.
.
.
.
Children irradiated for
thymic enlargement
X rays
Chest
.
.
. .
.
. .
.
Radiologists
X rays,
radium, etc.
Partial to
whole body
.
.
......
..
.....
*From Lewis (1957)
**Probability of induced leukemia per million person-years at risk per.
year per rem to region irradiated.
TABLE 3
Incidence of Bone Cancer in Relation to Skeletal Radiation Dose
NO. OF
SKELETAL
DOSE*
PERSONS
MALE
FEMALE
10.8
1900
5.2
1336
3.0
1.77
.
0.26
2.2 X 10-3
1.0 x 10-2
9 X 10-4
- -
-
4. X 100
3.5 x 100
1.91
1.977
1.62
1.596
.....
* From Marinelli (1958).
Skeletal dose in units equivalent to 1 uc of Ra“co + 0.3 uc daughters permanently
fixed in skeleton.
*Data for population of Chicago 1940-1950 (excluding cancer of jaw).
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LEGENDS FOR FIGURES
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FIGURE 1. Incidence of leukemia in relation to age. A Acute and chronic
laukomia in irradiated spondylitics, in relation to oge at first exposure (Dell, 1962)
A Acute and chronic leukemia, chronic lymphatic type excluded, in England and
Wales, in relation to age (Doll, 1962). O Acute granulocytic leukemia in survivors
exposed within to A-bomb radiation within 1500 meters at Hiroshima and Nagasaki,
in relation to age at exposure (Brill, Tomonagct, and Hayssel, 1962). Acute
granulocytic leukemia in Japan, Kinki district, in relation to age (Wakisaka, 1958).
.
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FIGURE 2. Annual incidence of leukemia, all types, in relation to radiation dose.
... Nagasaki A-bomb survivors (Brill et al, 1962). Hiroshima A-bomb survivors
(Brill et al., 1962), with revision of dose estimates as per J. A. Auxier, personal
communication). A Irradiated spondylitics, radiation exposurs' expressed in mean
dose (R) to spinal marrow (Court Brown and Doll, 1957),
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Fig. 3. Incidence of thymic lymphomas in relation to dose and dose rate of *- and
y-irradiation. Shaded symbols, C57BL mice (Kaplan and Brown, 1952); open
symbols, RF mice (Upton et al., 1966).
Osingle, brief irradiation, 7 to 25 r./min.
Wfour exposures at 1-day intervals
Afour exposures at 8-day intervals ,
Oten exposures at 30-day intervals :
Osemicontinuous exposure at 0.5 mr./min.
· FIGURE 4. Dose-incidence relation for granulocytic leukemia in whole-body-irradiated.
RF male mico, as influenced by protraction or irradiation. (All mice were 8-10 works
old at start of irradiation:) O. Single, acute exposure to X rays at 50-100 rads/min.
..a Daily expuwura to Co® gamma rays at 0.0006 rads/min. A Daily exposure to ..,
fast noutrons at 0.0006-0.006 rads/min. (A.C. Upton, J. W. Conklin, und
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with various doses of 251 (from Mole, 19586, after Lindsay, Potter, and
Chaikoff, 1957, and Potter et al., 1960). O Foliicular adenoma.
Alevolar carcinoma. · A Papillary and follicular carcinoma.
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