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11:25 11.4 116
MICROCOPY RESOLUTION TEST CHART
wowo STANDARDS 1963
CFSTI PRICES
Conf-660314-1
H.C. $ 3.00 ;MN .50
COMPARATIVE OBSERVATIONS ON RADIATION CARCINOGENESIS IN MAN AND ANIMALS*
i
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i..
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"MASTKY
Arthur C. Upton
Biology Division,

Oak Ridge National Laboratory
RELEASED FOR ANNOUNCEMENT
Oak Ridge, Tennessee
IN NUCLEAR SCIENCE ABSTRICTS
INTRODUCTION
More than half a century has elapsed since the carcinogenic action of
ionizing radiation was first recognized, and radiation carcinogenesis has
since been studied extensively in humans and experimental animals (see
ren
ta
Furth and Lorenz, 1954; Glucksman, Lamerton, and Mayneord, 1957). Interest
in the subject has been intensified in the past decade because of expandir-
HUS
use of radiological apparatus and isotopes and because of fallout from
atomic weapons tests. Hence, although large radiation doses have long
been acknowledged to exert carcinogenic effects, there is now mounting
concern that small increases in the environmental radiation level may
.
augment the risk of cancer (UNSCEAR, 1964).
Epidemiological studies in man are currently reshaping our attitudes
1
toward dose-effect relationships, and experimental studies in animals
are disclosing mechanisms of radiation carcinogenesis hitherto unsuspected.
These developments will be surveyed in the following.
..
-
-
-
.
c.
*Research sponsored by the U. S. Atomic Energy Commission under contract
with the Union Carbide Corporation.
Paper to be presented at the Twentieth Annual Symposium on Fundamental Cancer
Research, March 7-9, 1966, Houston, Texas.
LEGAL NOTICE
This report was prepared as an account of Governaent sponsored work. Neither the United
States, nor the Commission, nor any person acting on behalf of the Commission:
das Makes any warranty or representation, expressed or implied, with respect to the accu-
racy, completeness, or usefulness of the information contained in this report, or that the use
of any information, apparatus, method, or proceso disclosd in this report may not Infringe
privatoly owned rights; or
B. Assumes any liabilities with respect to the use of, or for damages resulting from the
080 of any information, apparatus, method, or process disclosed in his report.
Ao used in the above, "person acting on behalf of the Commission" includes any em-
ployoe or contractor of the Commission, or employee of such contractor, to the extent that
such employee or contractor of the Commission, or employee of such contractor prepares,
disseminates, or provides access to any information pursuant to his employment or contract
with the Commission, or his employment with such contractor,
-20
EPIDEMIOLOGICAL STUDIES IN HUMAN POPULATIONS
Leukemia
Postnatal Irradiation
All types of leukemia, with the exception of the chronic lymphocytic
type, appear to be increased in prevalence among irradiated populations (see
UNSCEAR, 1964); however, the relation between the incidence of any given
hematologic type and the dose of radiation is not known precisely. Nor do
we know the duration of the period during which the incidence is increased;
i.e., although a latency of 4-5 years appears to intervene before the incidence
of any type rises to peak values, we cannot state unreservedly when, if
ever, the incidence returns to normal. In patients treated with X ray
therapy to the spine for rheumatoid spondylitis the incidence appears no
longer to be elevated 15-20 years after irradiation (Court Brown and Doll,
1965), but in Japanese A-bomb survivors it continues now to be elevated 20
IS
LIT
years after exposure (UNSCEAR, 1964; R. W. Miller, 1966). Whether this.
difference between the two populations is attributable to differences
rence
en
ences
in predominant types of leukemia, in average doses of radiation, or in
other variables, remains to be determined.
Also poorly known is the influence of age on susceptibility to
radiation leukemogenesis. Existing data suggest, however, that irradiation
OC
increases principally those types of leukemia that are most likely to
occur naturally in the age group at risk. Moreover, the increase
corresponds more closely in magnitude to a constant multiplication of the
U
rease
natural age-incidence than to the induction of a given number of cases
per unit dose (Fig. 2).
In view of these age-dependent variations in the incidence and types
(F-1)
of induced leukemia, it is difficult to interpret effects of radiation on
-3-
the combined incidence of the different types averaged over all ages.
Nevertheless, it is noteworthy that the available evidence generally
supports Lewis's (1957) suggestion (Table 1) that the overall
Ove
(T-i)
incidence of leukemia in populations irradiated under widely differing
conditions of exposure approximates 1-2 cases per 10° person-years
at risk per rad during the first 15 years after irradiation (see UNSCEAR,
1964). The similarity in the dose-incidence relation among the exposed
populations is remarkable in view of the differences among them in the
distribution of the radiation in space and time.
It is not clear, however,
that small doses of radiation to the whole hody or large doses to a small
part of the body are leukemogenic. 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 consistent with
a linear dose-incidence relationship for spinal and whole-body irradiation
(Fig.
2), but do not exclude the existence of a threshold at low doses,
(F- 2 )
as
as stressed earlier (Brues, 1959). The lack of evidence of leukemia
essa
induction in patients treated with radiotherapy for carcinoma of the
cervix (Simon et al., 1960) and in individuals with large body burdens
of radium (UNSCEAR, 1964) suggests that irradiation may be only weakly,
if at all, leukemogenic when the fraction of the total hemopoietic marrow
exposed is small. The reported association between diagnostic irradiation
of the trunk and the subsequent development of leukemia remains to
be verified (see UNSCEAR, 1964).
Prenatal Irradiation
Evidence further implying the existence of leukemogenic effects of
radiation at low dose levels is the association between prenatal
diagnostic irradiation and leukemia in childhood (see MacMahon and
Hutchinson, 1964). This association has not been proven to be one of
Ven
cause and effect, but another explanation for it has yet to be
established. Hence, it suggests that prenatal whole-body irradiation at
dose levels of 5 rads or less increases by about 40 per cent the probability
that the expused child will develop leukemia, implying that any threshold
for leukemogenesis must be considerably lower than 5 rads, at least in the
fetus.
It also suggests that susceptibility to radiation leukemogenesis
is several times higher before birth than after birth.
The latency of the
leukemias in the prenatally exposed also appears different from that in the
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
(Grahum, et al., 1966 ) but remains to be confirmed.
-
-
-
• ••.
•
• •
•
• •
•
•
L
-
-5-
Neoplasms of Bone
In several dozen patients, osteosarcomas have been observed to
асс
develop within 3-30 years after therapeutic external irradiation, in
most instances arising at the site oi a pre-existing benign tumor or
chronic inflammation (see Bloch, 1962). Although grossly detectable
radiation damage to the affected bone has not always been evident in
advance of such neoplasms, the doses involved have been high, i.e., 3000
rads is the lowest dose associated with tumor formation in the absence
o other factors known to predispose to neoplasia (see Jones, 1953).
Smaller doses, however, (i.e., 60-600 rads) have been associated with the
formation of osteochondromas in infants and young children irradiated
therapeutically over the chest (Pifer et al., 1963; UNSCEAR, 1964).
The latter cases suggest that susceptibility to induction of bone tumors
may be higher in children than adults, but quantitative data on the dose-
incidence relationship from tumorigenesis after external irradiation
are not available for any age group.
Semi quantitative dose-incidence data have been obtained from populations
re
containing high body burdens of radium, the incidence of osteosarcomas (Table 2) (T-2)
in such groups appearing to vary approximately as the square of the
terminal concentration of radium in the skeleton (see Marinelli, 1958;
Burch, 1960). Expression of this dose-incidence relation in rads, however,
is complicated by the inhomogeneity of the radiation dose in space and
time; i.e., radium varies greatly in concentration throughout bone, tending
to localize in hotspots where the dose may be an order of magnitude higher
than elsewhere. Furthermore, the radium present when the tumors have been
detected generally has constituted only a small and unknown percentage
of the amount of radium present earlier when the tumors were initiated.
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Nevertheless, attempts have been made to analyze the dose-incidence
relationship in rads, the cells lining bone surfaces being assumed to be
the source of the tumors in question, the probability of neoplasia being
assi
assumed to vary as a function of the mean dose to such cells, and the
associated body burden being assumed to have diminished with time
according to a given pattern of excretion and decay.
The resulting
16
estimates, although crude, give an induced incidence of 4 cases per
200 person-years at risk per rad (UNSCEAR, 1964), a rate remarkably
similar to that for leukemia cited earlier.
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-7-
Thyroid Tumors
rs
An association between therapeutic external irradiation of the thyroid
gland in childhood and the subsequent development of thyroid tumors,
reported first by Duffy and Fitzgerald in 1950, has since been amply
confirmed (UNSCEAR, 1964). The latent period between irradiation and the
een
appearance of such tumors averages 10-15 years (UNSCEAR, 1964; Lindsay and
Chaikoff, 1964).
In addition to: carcinomas, the growths include adenomas
and hyperplastic nodules.
Although no single survey contains a large enough number of cases
to provide quantitative data on the dose-incidence relation, it has been
(F-3)
as 6
ars
estimated from pooled statistics (Fig. 3) that the incidence of thyroid car.cer
is approximately 1 case per 100 person-years at risk per rad during the
first 15 years after exposure (Beach and Dolphin, 1962; UNSCEAR, 1964).
As in the case of bone tumors, this rate appears remarkably similar to that
for induced leukemias cited earlier.
The above estimate is based on the response of the child's thyroid to
high-dose ( >100 rads) high-intensity irradiation. Hence, it may not apply to
the response of the adult's thyroid or to the response of the child's thyroid
to low-dose rate i rradiation such as from internally deposited iodine-131.
Preliminary data suggest, in fact, that the child's thryoid exceeds the
adult's in susceptibility to radiation carcinogenesis (UNSCEAR, 1964).
Evidence that iodine-131 is not without carcinogenic activity is available
from animalsexperiments (see below) and 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 the latter,
thyroid nodules have occurred in nearly half of those exposed under 10
years of age, whereas none have occurred among the non-exposed controls
-8-
(Conard and Hicking, 1965; Conard, personal communication). The
radiation doses to the thyroid glands of such children are difficul:
1400 rads, including radiation from external gamma rays as well as from
Amma
OS
the internally deposited radioiodine.
-9-
Carcinoma of the Respiratory Tract
Although carcinoma of the lung has been known to be endemic in ore
miners of Saxony and Bohemia for centuries (see Weller, 1956), only
within the past decade has radiation come to be accepted as the principal
cause of this disease. (see UNSCEAR, 1964). Uranium miners in the U. S.
show a similarly elevated incidence of pulmonary carcinoma, the rate
increasing with the duration of exposure (Fig. 4 ), even after
correction for such variables as age, cigarette consumption, "heredity,
vre
(F- 4 )
urbanization, self-selection, diagnostic accuracy, prior 'hard-rock
mining, or nonradioactive-ore constituents including silica dust"
(Wagoner, et al., 1965). Anatomical features of the sease in the
uranium miners which further implicate radiation in its etiology are the u:-
usual distribution and histologic character of the cancers; i.e., they
ve
sure
are predominantly undifferentiated small-cell carcinomas occurring in the
hilar region (Wagoner et al., 1965).
Calculation of the relationship between the cancer incidence and the
radiation dose is complicated by many uncertainties, owing to the
conditions of irradiation (see UNSCEAR, 1964; Altshuler et al., 1964;
Jacobi, 1964; Wagoner et al., 1965). The average duration of exposure
among the affected miners is 15-20 years, but it is not clear what
fraction of the total cumulative exposure is responsible for the
carcinogenic effects in question. Moreover, estimates of the radiation
dose to the bronchial epithelium associated with such exposure vary from
about i rad per 40-hour week to values 1-2 orders of magnitude lower (see
UNSCEAR, 1964; Altshuler et al., 1964; Jacobi, 1964).
The above doses far exceed the "minimum dose" of 1 rad per year
estimated to be delivered to the bronchial epithelium from polonium-210
1 ASS
UTE
-10-
in cigarette smoke (Little et al., 1965). Hence, the extent to which the
latter radiation may contribute to the increased incidence of bronchial
carcinoma in cigarette smokers reniains to be determined.
-ll-
Skin Cancer
The first tumor attributed to irradiation was an epidermoid carcinoma
arising in an area of radiation dermatitis on the hand of an X ray tube
maker (Frieben, 1902). Within the following decade more than 90
similar cases were reported among physicians and others exposed occupationally
to ionizing radiation (Hesse, 1911). In nearly all such cases, the onset
of cancer was preceded by a long latent period and by chronic radiation
dermatitis (Fig. 5. ). Squamous cell carcinomas and basal cell
(F-5 )
carcinomas have predominated among these neoplasms, but fibrosarcomas
have also been reported (see Traenkle, 1963).
The dose-incidence relation for induction of cutaneous cancer is
Se
not known. It is generally postulated, however, that the probability
of the disease varies with the severity of radiodermatitis, being low
in the absence of gross skin damage (see Hempelmann and Hoffman, 1953;
Traenkle, 1963).
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-12-
Other Neoplasms
Among the Japanese A-bomb survivors (Harada and Ishida, 1960:
Jablon et al., 1965), patients treated with radiation for rheumatoid
spondylitis (Court Brown and Doll, 1965), children exposed to diagnostic
irradiation prenatally (see MacMahon, 1962), and U. S. radiologists
(Seltser and Sartwell, 1965), cancers other than those mentioned in the
foregoing appear to be increased in frequency. From the evidence to
date, the increase does not appear to affect all types of neoplasms, but i'i.
is too early to generalize as the magnitude and scope of the overall
effects. Likewise, quantitative dose-incidence data are not yet
out iü
.
available.
A wide variety of tumors have been observed to result from localized
irradiation. These include carcinomas of the paranasal sinuses in radium
poisoning (see Hasterlik et al., 1964; UNSCEAR, 1964), cholangiomas and
hemangio-endotheliomas of the liver in thorotrast poisoning (see Dahlgren,
1961; Blomberg, 1963; UNSCEAR, 1964), and miscellaneous sarcomas and
.
.
carcinomas at sites of intensive accidental or therapeutic exposure (see
Lacassagne, 1945; Jones, 1953; Furth and Lorenz, 1954; Cade, 1957;
Goolden, 1957; UNSCEAR, 1964). The diversity of neoplasms points to the
general susceptibility of the various tissues of the body to radiation
carcinogenesis, but the data on any single type of tumor are too
fragmentary to provide quantitative information about mechanisms or
.
.
.
.
.
. .
.
.
.
dose-effect relationships. .
.
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-13-
EXPERIMENTAL CARCINOGENESIS IN ANIMALS
Leukemia
The induction of leukemia by radiation was first demonstrated experi-
mentally by Krebs, Wagner and Rask-Nielsen (1930), in the mouse, and
confirmed soon afterward in the same species by Furth and Furth (1936).
Thymic Lymphosarcoma
The most widely studied experimental radiogenic leukemia arises in
the mouse thymus as a lymphosarcoma. This neoplasm may be induced in
many 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 tissue; 1.e., by shielding spleen or
marrow from radiation or by infusion of nonirradiated hemopoietic cells
after whole-body irradiation (see Odell, Cosgrove and Upton, 1960).
Moreover, it has been shown that nonirradiated thymic tissue may be
rendered neoplastic by implantation into an irradiated recipient, thus
conclusively demonstrating the role of host injury in the prthogenesis 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 as
well as on the total dose. In general, a given dose of X rays or gamma
een
ease
rays becomes less leukemogenic as the duration of irradiation is prolonged
(Mole, 1958a); whereas the effectiveness of neutrons is less, if at all,
dose rate-dependent (Fig. 6 ). X rays may, however, be more leukemogenic
re
eness
(F-6)
if given in several properly timed fractions than if given in a single
exposure (Kaplan and Brown, 1952; Upton, 1959). At a given dose rate,
-14-
the dose-incidence relation appears to be curvilinear rather than linear,
Sms are
suggesting that the incidence varies as a power function of the dose,
at least over the range 25-150 r (see Upton, 1961a).
The duration of the induction period is inversely related to dose
(see Upton, Kimball, et al., 1960). Relatively few neoplasms are evident
clinically within 100 days after irradiation, and few appear late in life,
the peak mortality from the disease occurring 150-400 days after exposure
(Upton, Kimball, et al., 1960; Upton et al., 1963).
Susceptibility to induction of the lymphoma varies with strain, sex,
and age (see Upton and Furth, 1957; Upton, 1959). Females are generally
more susceptible than males, and this difference is lessened DV,
gonadectomy (see Kirschbaum, 1957). With involution of the thymus in
adult life, susceptibility diminishes in both sexes (Upton, Odell, and Sniffen,
1960).
Irradiation does not increase the incidence or reduce the induction
period in mice of high-lymphoma strains (see Upton, 1962).
It is still too early to define the mechanism of leukemogenesis, but
there is growing evidence implicating viral factors, since 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; and others).
If the induction of this neoplasm does, in fact, depend 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 physiologic and genetic variables remain to be elucidated.
The production of an irreversible "initiating" or "priming" effect
(Kaplan, 1960) by irradiation, which may be associated with the appearance
As
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.
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-15-
of leukemogenic "initiating" activity in tissues other than the thymus
.
(Eerenbluni and Trainin, 1961), the promotion of radiation leukemogenesis
by various agents, including estrogen (see Kaplan, Nagareda, and Brown, 1954),
cortisone (Upton and Furth, 1951), urethan (Berenblum and Trainin, 1960), and
myleran (Upton, Wolff, and Sniffen, 1961), and the inhibition of leukemo-
genesis by administration of testosterone and corticoids after irradiation
(see 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 autonomy in such growths, as judged on serial biopsy
and transplantation (Kaplan and Hirsch, 1956).
The action of radiation may,
therefore, include "initiating" and "promoting" effects, depending on tre
::
and conditions of exposure.
Kaplan (1964) nas postulated radiation to act in the following three
ways:
(1) to liberate, or activate in some unknown way, a latent virus
leukemogenic to the thymus;
(2) to cause atrophy of the thymus, thereby stimulating regenerative
proliferation of the surviving thymocytoblasts, which are
postulated to be the target cells of the virus and more
susceptible when mitotically active than when in a 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) damage to the bone marrow, which impairs regeneration of the
thymus, thus prolonging the period during which thymocytoblasts
are in a state of heightened susceptibility.
qoo...
.
.
.
..
-16-
The role of the marrow in the third mechanism is not established,
but existing data suggest that it serves as a source of stem cells which
are capable of repopulating the thymus and thus facilitating its
regenration (sce Loutit, 1964).
The mechanism by which radiation "activates" the virus, likewise,
remains to be determined. There are inuications that leukemogenic virus
may be recoverable from exposed mice within a few days after irradiation
(Haran-Ghera, 1966) and that virus may be activated, at least partially,
even in non-hemopoeitic tissues of the body within minutes after irradiation
in vitio (see Berenblum and Trainin, 1963). The presence of the virus
elsewhere in the body than merely in the thymus and other nemic tissues
is further suggested by the appearance of virus-induced antigens in the
skin of mice during the induction period preceding the onset of viral
leukemia (Breyere and Williams, 1964). That the virus need not enter
the body from outside but may be "activated" in situ is suggested by
studies with germ-free mice, which disclose that such animals develop
radiation-induced leukemia and contain leukemia-virus-like particles in
their tissues, in the absence of other detectable viruses or micro-
organisms (Pollard and Matsuzawa, 1964; Walburg et al., 1965). These
LWS
studies are, thus, consistent with Gross's hypothesis that the leukemia
virus may be transmitted vertically from mother to young across the
placenta or via the zygote (see Gross, 1961).
The nature of the virus-host cell interaction and the resulting
leukemic transformation is obscure. Several theoretical models have been
postulated (Kaplan, 1962; Dulbecco, 1963), but these remain as yet
hypothetical.
The origin of the neoplasm from a single transformed cell
is implied by cytogenetic studies. These suggest that the lymphoma in
-17-
most instances comprises a clone of cells having a particular chromosomal
abnormality, which appear in the thymus during the preneoplastic period
(see Loutit, 1964; Joneja and Stich, 1965).
Granulocytic Leukemia
The induction of myeloid leukemia by ionizing radiation has received
less study than the induction of thymic lymphomas, probably because myeloid
leukemia is rare by comparison in most strains of mice. In the RF mouse,
however, its incidence is increased tenfold by 150 r whole-body x radiation;
i.e. , to about 30%, as compared with the natural incidence of 2-3% in this
strain (Upton et al., 1958).
Increase in the incidence of the disease
has also been noted in irradiated mice of other strains (see Upton, Kimball,
et al., 1960, Cottier, 1961) but in numbers too small to provide quantitative
data.
As in the genesis of thymic lymphoma, the induction of myeloid leukemia
is conditioned by physiologic variables (i.e., age, sex, hormonal activity,
and other factors) and appears to be inhibited, at least partially, by
shielding of part of the body (Upton, 1959, 1962; Upton et al., 1966). It
is also associated with the appearance of a filterable leukemogenic
agent in the leukemic tissues, suggesting the role of a viral mechanism in
its pathogenesis (see Upton, 1959; Parsons et al.,1962; Jenkins and Upton, 1963).
The failure of radiation 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) under-
scores the importance of physiologic factors in leukemogenesis. The
action of these factórs on the host-virus relationship and on granulocyte
population kinetics deserves further study. It has been proposed elsewhere
eive
**::
**..19.
Wer
-18-
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 leukemia and the
UTA
radiation dose in RF mice depends markedly on the conditions of exposure
(Fig. 7). The shape of the curve below 150 r is uncertain but appears
curvilinear within the limits of experimental error. The decline of the
(1-7
)
ON
curve above 300 rads cannot be explained but is a feature characteristic
· of many other neoplasms (see Upton, 1961a). It may conceivably reflect
extensive injury to hemopoietic organs and to the host at high radiation
dose levels, in keepirig with certain theoretical expectations (Reif, 1961).
The diminished induction of leukemias by gamma rays at low dose rates is
consistent with observations on the dose-rate dependency for induction
of lymphomas, as noted above, and of certain other neoplasms (see Mole,
1959; Upton, 1961a; Aleksandrov and Galkovskaya, 1963).
-19-
Other Leukemias
In mice of many strains, lymphomas and reticulum cell sarcomas of
extra-thymic origin are relatively common late in life. The incidence
of such neoplasms is not characteristically increased by irradiation
(see Upton, Kimball et al., 1960), except in CBA mice (Mole, 1958a). A
similar increase has been noted, however, in C57BL (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 induction of lymphatic
leukemia in chronically irradiated guinea pigs has been reported by
Lorenz and Congdon (1955). In rats exposed to supralethal X irradiation
under the life-saving influence of an intact parabiotic partner (Binhammer et al.,
1957), or fractionation (Hunstein et al, 1962), lymphocytic neoplasms developed.
Also, a heightened frequency of plasma cell neoplasms has been reported in
Tevey
rats following whole-body X irradiation (Maisin et al., 1957); however, the
rat would appear less susceptible to radiogenic leukemia, in general, than
the mouse. Preliminary data on the effects of strontium-90 in dogs and swine
se
suggest an increased frequency of leukemias in these species as result of
internal irradiation, but quantitative information on the response of these
animals is not available (see Andersen and Goldman, 1962; McClellan and
Bustad, 1964; Andersen and McKelvie, 1964; and Biskis et al., 1964).
.'
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-20-
Osteosarcoma
OL
A variety of malignant bone tumors have been induced in experimental
animals by external irradiation (see Cater, Baserga, and Lisco, 1959; Law,
1960) and by bone-seeking radionuclides (see Furth and Tullis, 1956; Odell
and Upton, 1961). Most of the available data come from experiments with
internally deposited isotopes, and in such experiments, evaluation of
dose-effect relations and mechanisms of tumorigenesis is complicated by
complexities in the distribution of the radiation within space and time
(see Lamerton, 1960).
These uncertainties result from several variables :
(1) nonuniformity in the deposition of radioisotopes within the skeleton,
to the extent that the dose in "hot spots" may be higher than that in
surrounding bone by a factor of 10 or more; (2) changes with time in the
distribution and concentration of radioactivity in bone, owing to the
metabolic turnover and excretion of the radioelement and its decay
daughters; and (3) progressive diminution in the dose rate of the emitted
radiation as the emitter decays physically. Although the latter source
of variation is predictable, since it depends solely on the physical
half-life of the radionuclide in question, the rate at which an element
is excreted from the body, or its "biological half-life," may depend
on the influence of metabolic, nutritional, anu physiologic factors
(Wasserman, 1960).
The comparative tumorigenic activity of a variety of bone-seeking
radionuclides, as observed in CF, mice, is suminaried in Fig. 8. The
.
(F-8)
differences among radionuclides in tumorigenic potency reflect differences
in quality of emitted radiation (1.e., energy, and charge) as well as in
uptake, distribution, and retention within the skeleton. Although
..
..
-...
,
....
.
*
'
'
'
:7*!!,
.
.
-21-
comparable effects have been observed in other strains of mice, and in rats,
rabbits, and dogs (see Odell and Upton, 1961), strain difíerences in
susceptibility have been noted among mice, and limited data suggest that the
rat miy be appreciably more susceptible than the mouse (see Law, 1960).
Furthermore, because of differences in the geometry of the radiation
between the mouse and larger animals, making for less escape of penetrating
el
nouse
Ses
radiation from larger bones and hence less "wastage" of the total emission,
it is not surprising that the dog is several times more responsive than
90
the mouse to the same injected dose of Srº (Finkel, 1958). Strain and
species differences in the sites of neoplasia within the skeleton, a.
variable influenced within a particular strain or species by the radionuclide
administered and the age at exposure (see Bensted, Blackett, and Lamerton,
1960), remain to be fully characterized and explained. The enhancing
effects of certain hormones on the development, of bone tumors (Cater et al.,
1959) implicate additional physiclogin factors deserving further study.
The length of the average induction period is inversely related to
dose (Fig. 9), but it may also vary among strains of mice at the same level (T-91
of dose and incidence (Finkel, Bergstrand, and Biskis, 1961). That there is
not a simple relation between induction period (or tumor incidence) and
total accumulated dose is indicated by the complexity of results obtained
when the administration of a radionuclide has been varied with respect to
number of injections and interval between injections (Finkel, 1958; Blackett,
1959; Lamerton, 1960; Bensted et al., 1961). It is also noteworthy that
the incidence of osteosarcomas induced by X irradiation of the mouse leg
is appreciably higher than that expected from the same dose delivered by
internally deposited isotopes and appears from preliminary data to
approximate a linear function of the X ray dose (Finkel, 1964).
-22-
Indications that the minimal induction period may approach 150 days
independently of dose in mice and rabbits have been cited (Finkel, 1958).
In larger animals, however, such as the dog, the minimal latent period
appears to be several times longer (Finkel, 1958). The causal importance,
if any, of the pathologic changes occurring during the latent period is not
known. Although gross bone injury and reparative proliferation have been
observed :: Precede the development of skeletal tumors in most instances,
there is no convincing evidence that such a sequence is required to indice
neoplasia (see Finkel, 1958; Bensted et al., 1961; Lamerton, 1960; Nilsson,
1962). The transmissability of some such neoplasms by cell-free extracts
(Finkel et al, 1966) casts doubt on the hypothesis that gross damage is
VI
required for oncogenesis.
leon
.....
.....
.
.si nove
romans pots.gporr....
.
.....
...........
.
.
.
:
';. ....
-23-
Breast Tumors
The induction of mammary tumors by irradiation has been observed
repeatedly in mice (see Furth, 1959; Law, 1960; Upton, 1961a; Cottier, 1961)
and rats (see Shellabarger et al., 1957; Law, 1960). Changes in the
incidence of neoplasia vary, however, with the type of tumor in question
and with host factors; i.e., in certain strains of mice, a dose-dependent
decrease in the incidence of sarcomas has been noted (see Upton, 1961a).
In Sprague-Dawley female rats, the over-all incidence of mammary tumors
appearing within the first year 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 appear to be considerably more tumorigenic than X rays or gamma
rays (jaran-Ghera et al., 1959; Upton, Kimball, et al., 1960).
The influence of hormona). factors in the pathogenesis of radiation-
induced mammary tumors is well established. Thus, females are more
susceptible than males, and their greater susceptibility is dependent
Ors
ar
on ovarian function (Cronkite et al., 1960). In addition, however, there
are indications that pituitary mammatropic activity may also enhance the
induction of mammary tumors (Yokoro, Furth, and Haran-Ghera, 1961).
The induction of these growths invol.ves, therefore, indirect as well
as direct factors. Nevertheless, localized irradiation is tumorigenic only
to mammary tissue directly exposed (Bond et al., 1960b). Efforts to
implicate viruses in the pathogenesis of these tumors have been
unsuccessful as yet though limited (see Upton, Kimball, et al., 1960).
Tumorigenic effects of internally deposited Atat have been reported in
rats (see Durbin et al., 1958), but the relative importance of localized
mam
ve
irradiation of the breast in their pathogenesis is complicated by the
frequent occurrence of pituitary and adenocortical adenomas in the same animals.
SOMA
-24-
Pituitary Tumors
The induction of pituitary tumors by irradiation has been noted in rats
and mice (see Yokoro et al., 1961). The thyrotropic tumors induced in mice
by 1+3+ are now attributed chiefly to the effects of thyroid injury rather
than to irradiation of the pituitary itself (see Furth, 1959). On the
other hand, external irradiation of the whole body, or merely of the head
and neck, has been implicated in the pathogenesis of mammotropic and
adrenotropic pituitary tumors (see Furth, 1959; Upton, Kimball, et al.,
1960; Yokoro et al., 1961). That such growths may be induced by effects
of radiation on the pituitary alone is suggested by the development of such
tumors in rats after deuteron irradiation localized to the hypophysis
(Van Dyke et al., 1959). The conditioning role of hormonal factors in
their pathogenesis, however, is 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).
......
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,
r
pe...
.
. .
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: ; .
:
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.
-25-
10
Thyroid Tumors
A number of investigators have reported induction of thyroid tumors by
internal and external radiation 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 induced 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
(F- 10)
in frequency (Fig. 10).
In the induction of thyroid neoplasms, the existence of an optimal
radiation dose-range is strikingly evident (Fig. 10).
Thus, investigators
lors
have on occasion failed to induce such tumors (Field et al, 1959) by
administering too much 1134, thereby essentially destroying the gland.
Based on the amount of radioiodine needed to "initiate" thyroid neoplasia
in rats treated with methylthiouracil, Doniach (1957) has estimated that
30 uc of Its corresponds to 1100 rads of X rays applied externally to the
gland. A high carcinogenic effectiveness of fast neutrons relative to X
rays and gamma rays is suggested by the work of Hara-Ghera et al. (1959)
and Upton, Kimball et al. (1960).
.
-26-
Adrenal Tumors
The frequency of cortical adenomas and medullary chromaffine tumors
is increased in mice of certain strains by exposure to whol.e-body external
radiation early in adult life (see Upton, Kimball, et al., 1960; Cottier, 1961).
The induction of such 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., 1.960).
In rats, cortical adenomas have been reported after injection of At211
(Durbin et al., 1958), and medullary tumors after injection of Po210
(Casarett, 1952).
Ovarian Tumors
nous
The high susceptibility of the female mouse to induction of ovarian
tumors by irradiation is a characteristic apparently peculiar to this species
and to certain strains within the species.
The neoplasms induced are complex
and may comprise virtually any or all histological 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 predominant cellular morphology and hormonal activity
even on serial transplantation (Bali and Furth, 1949). Hence these neoplasms
resemble those induced by transplantation of the intact ovary into the spleen,
and their pathogenesis is apparently dependent on the stimulatory action of
pituitary gonadotropin.
Tumorigenesis will not occur if ovarian function is preserved by shielding
one ovary or if estrogen replacement therapy is given (see Kirschbaum, 1957;
*Clifton, 1959). Irradiation, therefore, may exert its tumorigenic effects
merely by causing premature menopause through the killing of oocytes, since
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n
rie
im
..
.
po
..
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!...
.
...
.
.
.
i!ig!!,
,
-27-
mice of strains in which menopause occurs spontaneously at an early age
develop a high incidence of ovarian tumors without irradiation or other
treatment (Thung, 1959).
The radiosensitivity of mouse oocytes is such that ovarian tumori-
genesis is readily induced by 50 r of x rays or gamma rays (Fig. 11 ),
mma
(F-11)
although the effectiveness of the radiation is dependent on the dose rate
(Fig. 11).
The induced tumors develop slowly, appearing only after a
latent period of many months (Upton, Kimball, et al., 1960), despite the
fact that sterilization and luteinization of the cvary ere evident within
a few weeks after irradiation.
-28-
Skin Tumors
Cutaneous carcinogenesis by ionizing radiation was noted experimentally
more than half a century ago and has since been confirmed repeatedly (see
Glücksmann, 1958; Law, 1960; Hulse, 1962).
In comparison with chemically
induced tumors of the skin, those caused by radiation require longer for their
induction. Their histological character varies with host factors and with
the conditions of irradiation. To induce a high incidence of neoplasia,
it is generally necessary to administer ulcerating doses of radiation,
under which conditions healing is impaired by residual vascular changes and
scurring. The ensuing neoplasms appear to arise from transformation of
marginal proliferating epidermal cells or fibroblasts (Glücksmann, 1958).
Non-ulcerating doses also have been found carcinogenic, in the absence of
obvious radioderuatitis; e.g., sublethal whole-body X and gamma irradiation
(see Law, 1960; Hulse, 1962).
As yet, it is not possible to define the relation among the factors
eva
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
et al., 1961) and that the effects of radiation may be enhanced by croton
oil (Shubik et al., 1953), chemical carcinogens (Cloudman et al., 1955), and
conceivably by irradiation of distant parts of the body (Bock and Moore, 1959).
*
-29-
Liver Tumors
The production of hepatomas in rats by thorot rast (Guimaraes, Lamerton,
and Christensen, 1955) and in mice (Upton, Furth, and Burnett, 1956) and
rats (Harel et al., 1956) by colloidal radioactive gold is well documented.
Hepatic' neoplasms in experimental animals following irradiation from other
sources, internal and external, have also been reported (see Guimaraes
et al., 1955).
The induction of hepatic tumors by intravenously injected radioactive
MOU
colloids is attributable to the high selective concentration of the radio-
active material in Kupffer cells, and the resulting intensive irradiation
of neighboring liver parenchyma. It is surprising that neoplasia of
reticuloendothelial elements has not been equally prominent under these
circumstances.
The hepatomas observed have been found to be associated
with regenrative hyperplasia incident to gross liver injury. Hence, it
may be inferred that relatively large doses of radiation were involved in
their pathogenesis. Precise estimates of dose, however, are complicated by
the nonuniformity of the radiation.
That sublethal amounts of whole-body gamma radiation may also increase
the incidence of hepatomas in mice has been suggested (Lorenz et al., 1954;
Upton, Kimvall, et al., 1960).
..
.
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.
.
...
4."10
;
-30-
Kidney Tumors
An increased incidence of renal adenomas and carcinomas has been noted
in whole-body irradiated mice (Hollcroft et al., 1957; Upton, Kimball, et
al., 1960) and rats (Koletsky and Gustafson, 1955; Rosen et al., 1961). The
pathogenesis of these growths remains to be defined.
Their high frequency
contrasts with the paucity of other radiation effects on the kidney at the
radiation dose levels involved (Rosen et al., 1961). No data are available
as yet, however, to define the shape of the dose-incidence curve or to reveal
whether effects of extra-renal tissues contribute indirectly to the
development of such tumors.
As in the induction of other neoplasms, neutrons appear more effective
than X or gamma rays (Upton, Kimball, et al., 1960; Rosen et al., 1962).
Gastrointestinal Tumors
Omas
mas
Induction of adenomas and carcinomas of the stomach, small intestine,
and colon by external and internal irradiation has been reported in rats ana
- -
-
-
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 body, except in the case of fast neutrons, which
apparently have a high relative tumorigenic effectivensss for the gastro-
intestinal mucosa.
Lung Tumors
Sms
Alveolar and bronchial neoplasms have been reported in rats and mice
following local deposition of a variety of radioactive substances (see Bair,
1960). They also have been observed in increased frequency among rats
injected intravenously with thorotrast (Guimaraes et al., 1955) and mice
..
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.
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"
:
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1.
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o
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a web
-31-
injected intravenously with colloidal radiogold (Upton et al., 1956).
In
all of these instances, radioactivity was concentrated within the thorax
nonuniformly, tending to produce "hot spots" of relatively high radiation dosage
to adjacent lung and bronchus. Hence, the radiation dose responsible for
neoplasia under these circumstances cannot 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
W2S
ure
Kre:
WS
was given in a single exposure early in life (Nowell and Cole, 1959; Upton
et al., 1960) but increased when the radiation was administered 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, amons
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,
1962). Hence, mice subjected to irradiation early in life probably will
die prematurely, before the induction of lung tumors has time to take place.
With irradiation localized to the lung, on the other hand, pulmonary
carcinogenesis by urethane is inhibiteå through mechanisms other than
life-shortening (Foley and Cole, 1964).
Other Neoplasms
In addition to the tumors already mentioned, a wide variety of other
neoplasms has been reported in irradiated animals. Hence, it may be
inferred that radiation is potentially carcinogenic to nearly all tissues
under the proper conditions of dosage and host responsiveness (Furth and
Lorenz, 1954; Furth and Tullis, 1956; Law, 1960; Uptozi, Kimball, et al., 1960;
Odell and Upton, 1961; Upton, 1961a; Casarett, 1965).
-32-
DOSE-RESPONSE RELATION
Total Dose
It is evident that under certain conditions ionizing radiation can
increase the probability of neoplasia in many, if not all, organs, but
quantitative data concerning the relation between tumor incidence and
-
NA
S
a
radiation dose are scanty. The data are particularly meager on effects of
small amounts of radiation (i.e., less than 50 rads), which are of
primary concern in environmental carcinogenesis. Although systematic
efforts to relate the incidence or induction period of neoplasia to the
radiation dose have failed thus 'far to provide unequivocal examples of a
straight-line relation over a wide range of dose and dose rate, exidemologice
studies in human populations suggest an unexpectedly high similarity amone
leukemias, bone tumors, and thyroid neoplasms in the incidence per unit dose,
and the available data are consistent with a linear relation between
incidence and dose (UNSCEAR, 1964). Nevertheless, the bulk of available
evidence argues against the hypothesis that the neoplastic transformation
is a simple "one-hit" process and, therefore, 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; hence, since the induction period may
vary with dose, the tumorigenic effects of high radiation doses in such
analyses are exaggerated in relation to those of low doses. Unfortunately, .
a statistical correction for this cannot confidently be applied because of
uncertainties concerning the interrelation of dose, latency, and longevity.
It is clear, however, that effects of radiation on the incidence of any
neoplasm may be affected by changes in the incidence of other diseases
influencing physiology and survival. Attempts to cope with this problem
mathematically (Bryan and Shimkin, 1941; Wollman, 1955; Kimball, 1958;
-33-
Sachs, 1959; Kodlin, 1959) remain speculative.
A related problem hampering evaluation of dose-response data is the
occurrence of side-effects of radiation at high dose levels, which
specifically promote or inhibit tumorigenesis.
Thus, even if the
rye
"initiating" effect of irradiation were a linear function of dose, the
dose-incidence curve might depart from linearity owing to such side-effects.
This and other complications, including the problem of dosimetry in human
studies, have been reviewed elsewhere (Mole, 1958b; Upton, 1961a).
man
-34-
INFLUENCE OF RADIOLOGICAL VARIABLES
Time-intensity Factors
It is evident that the carcinogenic potency of a given dose of
radiation is influenced by the rate at which the dose is administered.
The precise role of the various time-intensity factors, is, however, still
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
S
ene
ma
radiations of low linear energy transfer (LET), such as X and gamma rays.
When fractionated into several exposures of intermediate size and periodicity,
however, a dose may be more tumorigenic than when given in a single brief
exposure. The interaction of time-intensity variables thus appears comple:
(see Mole, 1958b; Upton, 1961a). That such time-intensity variations are
not inconsistent with the somatic mutation hypothesis of radiation
carcinogenesis is indicated by the observation of similar complexities in
the dose-response relation for mutations in irradiated mammalian
spermatogonia and oocytes (Russell, Russell, and Kelly, 1960; Russell, 1965).
Radiation Quality
For carcinogenesis, as for many other effects on mammalian cells,
radiations of high LET (a particles, neutrons, protons), have been founä
generally more effective than those of low LET (X rays, gamma rays). The
relation between LET and relative biological effectiveness (RBE) is never
simple, however, and available data on carcinogenesis are limited to
fragmentary observations which fail to define the influence of ion density
in quantitative terms. The data suggest, nevertheless, that the carcinogenic
effectiveness of radiations of high ion density is less dependent on dose rate
than is that of radiations of low ion density. Hence, the difference in
n
effectiveness between the two types of radiation appears to increase with
-35-
decreasing dose rate (see Upton, 1961a). Under conditions of low-level
irradiation most pertinent to environmental carcinogenesis, therefore,
the oncogenic potency of high-LET radiations is generally assumed to be
relatively high; i.e., 10-20 times that of X and gamma rays (National Commitin
on Radiological Protection, 19544; ICRP Committee on RBE, 1963).
-36-
INFLUENCE OF HOST FACTORS
Species and Strain
lost data on radiation carcinogenesis come from studies on human
beings and rodents. Relatively little information is available on animals
of intermediate size and life span.
Insofar as comparisons are possible
with existing data, no fundamental qualitative species differences are
evident.
Thus, it would seem reasonable to suppose that ionizing radiations are
oncogenic to all mammals, although susceptibility to any one type of
neoplastic response varies under the influence of genetic factors (see
Upton and Furth, 1957). Since strain differences in spontaneous tumor
se
incidence formerly attributed solely to genetic variations are now
ascribed also in part to variations in tumor-virus distribution, differences
among strains and species in susceptibility to radiogenic neoplasia may,
likewise, depend to some extent on epidemiologic variations.
Comparison and extrapolation of radiogenic neoplasm data from one
species to another are further complicated by the foilowing questions:
(1) What is the significance of the induction period in neoplasia and
how is it related to the life span of the species, to the life expectancy
of the individual, and to the accumulated dose of radiation?
(2) How and why do species differ in the spontaneous incidence of a
neoplasm, and are such differences correlated with variations in susceptibility
to induction of the same neoplasm by radiation?
..? Since, as yet, satisfactory answers to these questions are lacking
(Brues, 1955), data on comparative carcinogenesis are largely empirical.
-37-
Age at Time of Irradiation
The influence of age on susceptibility to radiation carcinogenesis has
been studied relatively little (Doll, 1962). Although the young, growing
organism is radiosensitive as regards most types of radiation injury,
limited data suggest that mice are relatively insensitive to radiation
OS
re
carcinogenesis during the prenatal period, as mentioned above. Conversely,
epidemiologic data suggest that the human being may be unusually susceptible
to radiation carcinogenesis before birth. This disparity calls for further
study. Also deserving of special investigation is the suggestion that the
induced incidence of each of the various types of leukemia, and possibly
other neoplasms, varies as a multiple of the natural age-related incidenc:
rather than as a given number of excess cases per unit radiation dose.
Eine
implications of this hypothesis in relation to aging and age-related chances,
such as variations in immunity, warrant further investigation, as noted
Warr
elsewhere (Upton, 1964).
Hormonal Factors
on
1 SUN
Mamma
1&
The profound influence of gonadal hormones on susceptibility to radio-
genic mammary neoplasia and lymphomas is well established (see Kirschbaum,
1957; Furth, 1959; Clifton, 1959). The influence of hypophyseal hormones
has been demonstrated in the pathogenesis of tumors of endocrine-dependent
end
Drmones
target organs; e.&., ovary, breast, thyroid (see Furth, 1959; Haran-Ghera et al.,
1959). The extent to which humoral factors are involved in the genesis of
other types of neoplasia is not known, but their influence cannot be cate-
gorically excluded in any of the radiogenic neoplasia studied to date
(see Upton, 1961b).
SICOT
Another factor observed to enhance the development of radiation-induced
sarcomas, possibly through homeostatic humoral mechanisms, is local
inflammation (see Burrows and Clarkson, 1943). Since nearly any dose of
YOWS
ne
i. -38-
radiation is productive of some degree of inflammatory reaction and reparative
cellular proliferation, this factor may complicate the induction of any type
of neoplasm, although its relative importance is probably dose-dependent.
--39-
INFLUENCE OF COCARCINOGENIC AGENTS
The additive oncogenic effects of X rays and methylcholanthrene were
first reported by McEndy, Boon, and Furth (1942). Since then, additional
studies have extended their work.
Thus, combined application of radiation
and chemical carcinogens increases the incidence of skin tumors (cloudman
et al., 1955) and lymphomas (see Upton et al., 1961) above the level induced
by either agent alone.
It is evident, however, that the interaction of the
two agents is not simple, the doses and order in which they are administered
profoundly influencing the resulting oncogenic response (see Upton et al.,
1961). In fact, combined treatment may decrease, rather than increase, the
yield of neoplasms if the additive toxicity of the two agents outweighs
their oncogenic effects per se (Lisco, Ducoff, and Baserga, 1958; Lcassage
and Hurst, 1962).
The metabolic repair of radiation injury at various levels
of biologic organization within the cell makes it especially important to
analyze the combined carcinogenic effects of chemicals and radiation
administered in various time-dose schedules (see Upton, 1964).
There is, consequently, need for greater research into ühe addivity
of different oncogenic agents administered concomitantly, since from present
data no confident estimate can be made as to the combined effects of the
diverse oncogenic stimuli which may coexist in a modern, urban environment.
-40-
POSSIBLE MECHANISMS OF RADIATION CARCINOGENESIS
Somatic Mutation Theory
In view of the mutagenic potency of ionizing radiation, it is logical
to consider that radiation-induced somatic mutation may play an etiologic
role in radiogenic cancer. Furthermore, the discovery that the induction
and expresion 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. In other words, the existence
of time-intensity effects in the induction of radiogenic neoplasms do not
per se argue against the origin of such neoplasms from somatic mutations,
m
IS
nor does the dependence of the neoplasia on homonal stimulation or other
conditioning and promoting factors. At the same time, experimental evidence
that amny neoplasms evolve to autonomy through a stepwise succession of changes
(see Furth, 1953) argues against the idea that carcinogenesis is induced by
a single mutation, as do other arguments summarized elsewhere (Brues, 1958;
Burch, 1965).
Nevertheless, if cancer arises as the end result of successive alter-
ations, 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
the preliminary data on the age-specific incidence of malignant growths among
Japanese A-bomb survivors, in whom the numbers of. cancers induced by
lese
1
irradiation vary in relation to age at time of exposure (Harada and Ishida,
1960).
Also in support of the somatic mutation hypothesis is the occurrence of
specific cytogenetic abnormalities in patients with leukemia; i.e., the
-41-
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). In this connection it is
OUT
noteworthy that chromosomal aberrations have been observ:d to be increased
ur
man
in frequency even at occupational radiation exposure levels (Norman et al.
1964; Court Brown et al., 1965) and to persist for years after
irradiation (Bender and Gooch, 1962; Buckton, et al., 1962).
A class of radiogenic neoplasms that cannot, however, even tentatively
be ascribed 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 this case were 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 torough viruses or mechanisms as
yet unknown.
Virus Theory
The indirect induction of lymphosarcoma in unirradiated thymic tissue
by the implantation of such tissue into an irradiated recipient mouse has
TCOIN
been tentatively ascribed to the activation of a leukemogenic virus (see
Gross, 1961). It would appear that the induction of myeloid leukemia, and
possibly osteosarcoma, also involves similar viral mechanisms in the
mouse (see above). Whether other radiogenic neoplasms will ultimately prove
to be viral in pathogenesis cannot be decided at present, but this possibility
demands careful consideration in view of the growing spectrum of oncogenic
viruses and virus tumors now recognized.
The mechanism by which radiation
may cause virus activation is yet to be defined, but this question clearly
calls for intensified research into the effects of radiation on mammalian
-42-
viruses and the virus-host cell interrelation, a subject relatively
little studied to date (see Levine, 1963).
-43-
SUMMARY
An association between irradiation and the incidence of neoplasia nas
been detected in human populations at lower levels of radiation exposure and
involving a greater variety of neoplasms than hitherto suspected. The
relation between incidence and radiation dose cannot be specified precisely
for any neoplasm, but the limited quantitative data that are available
for several widely different neoplasms suggest a remarkable similarity among
ce
these growths in dose-incidence relationships. The effects of radiation on the
development of any particular neoplasm, however, appear to be influenced
greatly by the age of the population at the time of exposure, and certain
neoplasms have not been detectably induced by irradiation in human
populations. The significance of the dose-incidence correlations observed
to date is, therefore, uncertain.
Although studies on experimental animals provide a number of hypothetical
models for explaining the observed effects of radiation in man, the
carcinogenic effects of radiation in animals are not able for their
diversity and complexity.
The degree to which the process of carcinogenesis
involves indirect effects on the host, as well as direct effects on the
tumor-forming cells themselves, cannot yet be specified in most instances.
In a growing number of instances, however, neoplasia appears to involve
interactions among the effects of radiation, viruses, chemicals, and
various host factors. In no case has the mechanism of the neoplastic
transformation been defined fully enough to enable confident interpretation
of radiation carcinogenesis in animal or human populations.
-44-
BIBLIOGRAPHY
Albert, R. E., W. Newman and B. Altshuler. 1961.
The Dose-Response
Relationships of Beta-Ray-Induced Skin Tumors in the Rat. Radiation
coses
Sure
Research 15:410-430.
Aleksandrov, s. N. and K. F. Galkovskaya. 1963. Rate of Induction of
Leucoses by Single and Fractionated Exposure to Radiation. Dokl.-Biol.
Sci. Sect. (English Translation) 149:325-327.
Altshuler, B., N. Nelson, and M. Kuschner. 1964. Estimation of Lung
Tissue Dose from Inhalation of Radon and Daughters. Health Physics 10:
1137-llól.
Andersen, A. C. and M. Goldman.
1962. "Pathological Sequalae in Bearing
Following Continuous Feeding of Sr-90 at a Toxic Level," Some Aspects o
Internal Irradiation, T. F. Dougherty, W. S. S. Jee, C. W. Mays,
and B. J. Sover, Eds. Oxford, England, Pergamon Press, Pp. 319-328.
Andersen, A. C. and D. H. McKelvie. 1964. Pathology Report. 7th Annual
Progress Report--The Effects of Sr-90 and Ra-226 on the Beagle.
Radiobiology Project, School of Veterinary Medicine, University of
California, Davis. UCD 472–110. Pp. 132-146.
Bair, W. J. 1960. "Radioisot npe Toxicity: From Pulmonary Absorption,:
A Sympo ium on Radioisotopes in the Biosphere, R. S. Caldecott and
L. A. Snyder, Eds. Minneapolis, Minnesota, University of Minnesota, .
Pp. 431-438.
Bali, T. and J. Furth. 1949. Morphological and Biological Characteristics
of X-ray Induced Transplantable Ovarian Tumors. Cancer Research 9:
449-472.
Beach, S. A. and G. W. Dolphin. 1962. A Study of the Relationship between
X-ray Dose Delivered to the Thyroids of Children and the Subsequent
cen
Development of Malignant Tumors. Physics in Medicine and Biology 6
(No. 1): 583-598.
e
.
...
.... .
.
-15-
omosom
Bender, M. A. and P. C. Gooch. 1962. Persistent Chromosome Aberrations in
Irradiated Human Subjects. Radiation Research ló: 41–53.
Bensted, J. P. M., N. M. Blackett, and L. F. Lamerto". 1961. Histological
and Dosimetric Considerations of Bone Iwnour Production with Radioactive
OYUS.
Phospnorus. The British Journal of Radiology 39 : 160-175.
Berenblum, I. and N. Trainin. 1960. Possible 2-Stage Mechanism in
Experimental Leukemogenesis. Science 132: 40-41.
Berenblum, I. and N. Trainin. 1961. Leukemogenesis by Urethane in C57B1 Mice
ves
Bearing Isologous Tissues from X-irradiated Mice. Science 134:2045-20147.
Bloch, Claude. 1962. Postradiation Osteogenic Sarcoma. The American Journal
COM.
of Roentgenology, Radium Therapy and Nuclear Medicine 87: 1157-1162.
Berenblum, I. and N. Trainin. 1963. "New Evidence on the echanism of
Radiation Leukaemogenesis," Cellular Basis and Aetiology of Late Somatic
Effects of Ionizing Radiation, R. J. C. Harris, Ed. London, England,
Academic Press, Pp. 41-56.
Binhammer, R. T., J. C. Finerty, M. Schneider, and A. W. B. Cunningham. 1957.
Tumor Induction in Rats by Single Toal-Body X Irration. Radiation
Research 6: 339-348.
Biskis, B. 0., M. P. Finkel, and I. L. Greco. 1964. Myelogenous Leukemia.
and Acute Reticulosis in Beagles after Sr-90 Administration. Radiatioli
Research 22: 169.
Blackett, N. M. 1959. An Effect of Dose Fractionation on the Incidence of
Bone Tumours using Radioactive Phosphorus. Nature 184 (Suppl. 8): 565-566.
Blomberg, R., L. E. Larsson, B. Lindell, et al. 1963. Late Effects of
Thorotrast in Cerebral Angiography. Acta Radiologica 1: 996-1006.
Bock, F. G. and G. E. Moore. 1959. Carcinogenic Activity of Cigarette-smoke
Condensate. I. Effect of Trauma and Remote X Irradiation.
Journal of the
National Cancer Institute 22: 401-411.
-46-
Bond, V. P., E. P. Cronkite, S. W. Lippincoti, and C. J. Shellabarger. 1960a.
Studies on Radiation-Induced Mammary Gland Neoplasia in the Rat. III.
Relation of the Neoplastic Response to Dose of Total-Body Radiation.
Radiation Research 12: 276-285.
Bond, V. P., C. J. Shellabarger, E. P. Cronkite, and T. M. Fliedner. 1960h.
Studies on Radiation-Induced Mammary Gland Neoplasia in the Rat. V.
Induction by wcalized Radiation. Radiation Research 13: 318-328.
Breyere, E. J. and L. B. Williams. 1964. Antigens Associated with a Tumor
Virus : Rejection of Isogenic Skin Grafts from Leukemic Mice. Science 1.46
(3647): 1055-1056.
Brill, A. Bertrand, Masanobu Tomonaga, and Robert M. Heyssel. 1962.
Leukemia in Man Following Exposure to Ionizing Radiation: A Surinary
ny
of the Finding in Hiroshima and Nagasaki, and A Comparison with Other
Human Experience. Annals of Internal Medicine, Vol. 56, No. 4, 590-609.
Brues, A. M. 1969. Biological Hazards and Toxicity of Radioactive Isotopes.
Journal of Clinical Investigation 28: 1286-1296.
Brues, A. M. 1955. Radiation as a Carcinogenic Agent. Radiation Research 3:
272-280.
Brues, A. M. 1958. Critique of the Linear Theory of Carcinogenesis. Science 128:
693-699.
Brues, A. M. 1959. "Somatic Effects." Low Level Irradiation, A. M. Brues, Ed.
Washington, D. C., Association for the- Advancement of Science. PP. 73-86.
Bryan, W. R. and M. B. Shimkin. 1941. Quantitative Analysis of Dose-Response
• Data Obtained with Carcinogenic Hydrocarbons. Journal of National
Cancer Institute 1: 807-833.
nse

-17-
suckton, ř., P. Jacobs, W. M. Court Brown, and R. Doli. 1962. A Study on
the Chromosome Damage Persisting after X-ray Therapy for Ankylosing
Spondylitis. Lancet 2: 676-682.
Burcia, P. R. J. 1960.
Radiation Carcinogenesis: A ilew liypothesis. Nature .285:
135-112.
surch, P. R. J. 1965. Natural and Radiation Carcinogenesis in Man. I. Theory
of Initiation Phase. II. latural Leukemogenesis: Initiation. III Radiation
DC
Carcinogenesis. Proceedings of Royal Society (London), Ser. B, 162: 223-
287.
row
Burrows, H. and J. R. Clarkson. 1943. The Role of Inflammation in the
Induction of Cancer by X Ray's. British Journal of Radiolory 1.5: 331-37.
U
Cade, Stanford. 1957. Radiation Induced Cancer in Man. British Journa.
Radiolory 30: 393-402.
Casarett, G. W. 1952. listopathology of Alpha Radiation from Internally
Administered Polonium. USAEC Unclassified Report UR-201, Part II.
PP. 409-504.
Casarett, G. W. 1965. Experimental Radiation Carcinogenesis.
Progress in
101
sel
Experimental Tumor Research, Vol. 7, pp. 49-82.
Cater, D. 3., R. Baserga, and H. Lisco. 1959. Studies on the Induction of
Zone and Soft Tissue Tumours in Rats by Garoma Irradiation and the
mmoUYS
Unma
Effect of Growth Hormone and Thyroxine. British Journal of Cancer 13:
214-227.
Clifton, ä. II. 1959. Problems in Experimental Tumorigenesis of the Pituitary
Gland, Gonads, Adrenal Cortices, and Mammary Glands: A Review.
Cancer Research 19: 2-22.
les.
Cloudman, A. M. K. A. Himilton, R. S. Clayton, and A. M. Brues. 1955. Effects
of Combined Local Treatments with Radioactive and Chemical Carcinogens.
Journal of National Cancer Institute 14: 1077-1084.
-48-
Conard, Robert A. and Arobati Hicking. 1965. Medical Findings in Marshallese
People Exposed to Fallout Radiation. Results from a Ten-Year Study.
JAJA 192 (6): 457-159.
Cottier, llans. 1961. Strahlenbedingte Lebensverkürzung. Springer-Verlag,
Berlin.
Court Brown, W. M., Karin E. Buckton, and A. S. McLean. 1965. Quantitative
Studies of Chromosome Aberrations in Man Following Acute and Chronic
Exposure to X Rays and Gamma Rays. The Lancet, Vol. 1, No. 7398, pp. 1239-
1241.
Court Brown, W. M. and R. Doll. 1957. Leukaemia and Aplastic Anemia in Patients
Irradiated for Ankylosing Spondylitis. Medical Research Council Special
Report. No. 295, London, England, H. M. Stationery Office.
Court Brown, W. M. and Richard Doll. 1965. Mortality from Cancer and Other
Causes after Radiotherapy for Ankylosing Spondylitis. British Medical
Journal, Vol. 2. PP. 1327-1332.
Cronkite, E. P., C. J. Shellabarger, V. P. Bonci and S. W. Lippincott. 1960.
Studies on Radiation-Induced Mammary Gland Neoplasia in the Rat. I.
The
Role of the Orary in the Neoplastic Response of Breast Tissue to Total-
or Partial Body X-irradiation. Radiation Research 12: 81-93.
Dahlgren, Sven. 1961. Thorotrast Tumours. A Review of the Literature and
Report of Two Cases. Acta Pathologica et Microbiologica Scandinavica 53
(Fasc. 2): 147-161.
Doll, Richard. 1962. The Age Factor in the Susceptibility of Man and Animals
to Radiation.
II. Age Differences in Susceptibility to Carcinogenesis
in Man. The British Journal of Radiology, Vol. 35, No. 109, pp. 31–36.
-
19-
Doniach, I. 1957. Comparison of the Carcinogenic Effect of X-irradiation
with Radioactive Iodine on the Rat's Thyroid. British Journal of Cancer ?1:
67-76.
Dulbecco, R. 1963.
Transformation of Cells in Vitro by Viruses. Science 1:42:
es
ince
932-936.
Duffy, B. J., Jr. and P. J. Fitzgerald. 1950. Thyroid Cancer in Childhood
and Adolescence: A Report on 28 Cases. Cancer 3: 1018–1032.
Durbin, Patricia W., C. Willet Asling, Muriel E. Johnston, Marshall W. Parrott,
Nylan Jeung, harilyn H. Williams, and Joseph G. Hanilton. 1958. The
Induction of Tumors in the Rat by Astatine-221. Radiation Research 9:
378-397.
Feygin, S.,1914. Du Cancer Radiologique.
These Fac. med. Paris.
Field, John B., Charles J. McCammon, Rodney J. Valentine, Sol Bernick,
Charles Orr, and Paul Starr. 1959. Failure of Radioiodine to Induce
Thyroid Cancer in the Rat. Cancer Research 19: 870-873.
Finkel, M. P. 1958. Mice, Men, and Fallout. Science 128: 637-641.
Finkel, M. 1959. "Induction of Tumors with Internally Administered Isotopes,"
Radiation Biology and Cancer, Austin, Texas, University of Texas Press,
Pp. 322-335.
Finkel, Miriam P., Patricia B. Jinkins, and Birute 0. Biskis. 1964. "Parameters
Icer
of Radiation Dosage that Influence Production of Osteogenic Sarcomas in
Nice." Control of Cell Division and the Induction of Cancer. Monograph 14,
National Cancer Institute, Bethesda, Maryland. Pp. 243-263.
Finkel, M. P., Patricia J. Bergstrand, and Birute 0. Biskis. 1961. The
Latent Period, Incidence, and Growth of Srº-induced Osteosarcombas in
crl and CBA Mice. Radiology, Vol. 77, No. 2, pp. 269-281.
Finkel, M. P., B3.0. Biskis, P. B. Jinkins. 1966. Virus Induction of
S2
Osteosarcomas in Mice. Science, Vol. 151, No. 3711, pp. 698-701.
.
-50-
Foley, William A. and Leonard J. Cole. 1964. Interaction of Urethan and
Fractionated or Regional X-Radiation in Mice: Lung Tumor and Leukemia
Incidence. Cancer Research, Vol. 24, No. 11, pp. 1910-1917.
Freiben, A . 1.902. Demonstration eines Cancroids des rechten Handrückens, das
sich nach langdaurn der Einwirking von Röntgenstrehlen entwickelt hatte.
Fortschr. Gebiete Röntgenstrahlen 6: 106.
Furth, J. 1953. Conditioned and Autonomous Neoplasms: A Review. Cancer
Research 13: 477-92.
Furth, J. 1959. "Radiation Neoplasia and Endocrine Systems."_Radiation Biology
and Cancer. Austin, Texas, University of Texas Press. Pp. 7-25..
Furth, J. and Mario Baldini. 1953. "Physiopathology of Leukemia." The
Physiopatholory of Cancer, Second Edition, Freddy Homburger, 2a.
New York, New York, Paul B. Hoeber, Inc. Pp. 364-468.
Furth, J. and 0. B. Furth. 1936. Neoplastic Diseases Produced in Mice by
General Irradiation with X Rays. I. Incidence and Types of Neoplasms.
American Journal of Cancer 28: 54-65.
Furth, J. and E. Lorenz. 1954. "Carcinogenesis by Ionizing Radiations."
Radiation Biology, A. Hollaender, Ed. New York, N. Y. McGraw-Hill Book
.
.
Company, Inc. Pp. 1145-1201.
Furth, J. and J. L. Tullis. 1956. Carcinogenesis by Radioactive Substances.
Cancer Research 16: 5-21.
Furth, J., N. Haran-Ghera, H. J. Curtis and R. F. Buffett.
1959. Studies
on the Pathogenesis of Neoplasms by Ionizing Radiation. I. Pituitary
Tumors. Cancer Research 19: 550-556.
Glücksmann, A. 1958. Carcinogenesis of Skin Tumors Induced by Radiation.
British Medical Bulletin 14: 178-180.
-51
Glücksmann, A., L. F. Lamerton, and W. V. Mayneord. 1957. "Carcinogenic
acer
Cnce
Effects of Radiation. Cancer, vol. 1, R. W. Raven, Ed. London, England.
Butterworth and Company, Ltd. PP. 497-539.
Goolden, A. W. G. 1957. Radiation Cancer. A Review with Special
Reference to Radiation Tumours in the Pharynx, Larynx and Thyroid!
British Journal Radiology 30: 626-610.
Graham, S., m. L. Levin, A. M. Lillienfeld, L. M. Schuman, R. Gibson,
J. E. Dowd, and L. Hempelman. (In Press) "Preconception, Intrauterine
and Postnatal Radiation as. Related to Leukemia." JNCI Monograph No. 19.
Gross, L. 1958. Attempt to Recover Filterable Agent from X-ray-induced
SS
Se
Leukemia. Acta fiaematol. 19: 353–361.
Gross, L. 1959. Serial Cell-free Passage of a Radiation-Activated Mouse
Leukemia Agent. Proceedings Society Experimental Biology and Medicine 2.00:
102-105.
Gross, L.,,1961. Oncogenic Viruses. Pergamon Press, New York.
Guimaraes, J. P., L. F. Lamerton and W. R. Christensen. 1955.
The Late
UTI
Effects of Thorotrast Administration. A Review and an Experimental
Study. The British Journal of Cancer 11: 253-267.
Gunz, Frederick W. and P. H. Fitzgerald. 1964. Chromosomes and Leukemia.
Blood 23: 394-400.
Harada, T. and M. Ishida. 1960. Neoplasms Among A-bomb Survivors in Hiroshima :
First Report of the Research Committee on Tumor Statistics, Hiroshima,
Japan. Journal of National Cancer Institute 25: 1253–1264.
Haran-Ghera, Nechama. 1966. Leukemogenic Activity of Centrifugates from
rrow.
UNT
Irrediated Mouse Thymus and Bone Marrow. International Journal of
Cancer, Vol. 1, No. 1, pp. 81-87.
-52--
llaran-Ghera, N., J. Furth, R. F. Buffett, and K. Yokoro. 1959. Studies
on the Pathogenesis of Neoplasms by Ionizing Radiation. II. Neoplasms
of Endocrine Organs. Cancer Research 19: 1181-87.
iiarel, J., M. Gaurin, M. Tubiana, and J. Abbatucci. Production de Tumeurs
eurs
Malignes (hepatomes et autres) per Injections Intraperitoneales d'or
OC
CHS
ce
Radioactif chez le Rat Blanc. Bulletin du Cancer 43: 423-444.
Hasterlik, R. J. A. J. Finkel, C. E. Miller. 1964. "The Cancer Hazards
of Industrial and Accidental Exposure to Radioactive Isotopes."
Unusual Forms and Aspects of Cancer in Man. H. E. Whipple and N. H.
Moss, Eds. New York, N. Y. Annals New York Academy Science Vol. 114.
Hempelmann, L. H. and J. G. Hoffman. 1953. Practical Aspects of Radiation
Injury. Annual Review Nuclear Science 3: 369-392.
llesse, 0. 1911. Symptomatologie, Pathogenese and Therapie des Rontgenkarzinoms.
J. A. Barth, Leipzig.
Hiraki, Kiyoshi, Shozo Irino, Susunu Sota, and Koji Ikejiri. 1962.
wnu
Leukemogenic Activity of Cell-free Filtrates from Radiation-induced
Leukemia of RF Mice. Acta Haematologica Japonica 25: 816-821.
Hollcroft, J., E. Lorenz, E. Miller, C. C. Congdon, R. Schweisthal, and D.
Uphoff. 1957. Delayed Effects in Mice Following Acute Total-body
Ours
X Irradiation: Modification by Experimental Treatment. Journal
National Cancer Institute 18: 615-640.
Hlulse, E. V. 1962. Tumours of the skin and Other Delayed Effects of
External Beta Irradiation of Mice Using 90sr and 32p. The British
Journal of Cancer 16: 72-86.
Hunstein, W., E. Stutz, and V. Reincke. 1962. X-ray Induced Leukemias in
Wistar-rats After Fractionated Whole-Body Radiation. Freiburg. Med. Res. 1:
226-227.
-53-
International Commissions on Radiological Protection and on Radiological
Units and Measurements. 1963. Report of the RBE Committee to the
International Commissions on Radiological Protection and on Radiological
Units and Measurements. Health Physics 9: 357–386.
Jablon, Seymour, Morihiro Ishida, and Mitsuru Yamasaki. 1965. Studies
of the mortality of A-oomb Survivors 3. Description of the Sample and
Mortality, 1950-1960. Radiation Research 25: 25-52.
Jacobi, W. 1964. Dose to Human Respiratory Tract by Inhalation of
Short-lived 222 Rn- and 22° Rn-decay Products. Health Physics 10:
1163-1175.
Jenkins, V. K., and A. C. Upton. 1963. Cell-free Transmission of Radioseni:
omosomes
Myeloid Leukemia in the Mouse. Cancer Research 23: 1718-1755.
Joneja, lú. G. and II. F. Stich. 1965. Chromosomes of Tumor cells. IV. Cell
Population Changes in Thymus, Spleen, and Bone Marrow during X-ray-induced
Leukemocenesis in C57BL/6J Mice. JNCI, Vo... 35, No. 3, pp. 421-434.
Jones, A., Irradiation Sarcoma. British Journal Radiology 26: 273-284.
Kaplan, H. S. 1959. Some Implications of Indirect Induction Mechanisms
in Carcinogenesis: A Review. Cancer Research 19: 791-803.
Kaplan, H. S. 1960.
A "Priming" Effect of Shielded Irradiation on Lymphoià
Tumor Induction in Irradiated C57BL Mice. Proceedings American Association
Cancer Research 3: 123.
Kaplan, H. S. 1962. Possible Mechanisms of Virus Carcinogenesis. Federation
Proceedings 21: 1-4.
Kaplan, H. S. 1964. "The Role of Radiation on Experimental Leukemogenesis!
International Symposium on the Control of Cell Division and the Induction
of Cancer, C. C. Congdon and P. Mori-Chavez, Eds. National Cancer Institute
Monograp: 14.
-54-.
Kaplan, H. S. and M. B. Brown. 1952. A Quantitative Dose-response Study
of Lymphoid Tumor Development in Irradiated C57 Mice. Journal National
Cancer Institute 13: 185-208.
Kaplan, H. S. and B. B. Hirsch. 1956. Evolution of Autonomy of Lymphomas
Arising in Non-irradiated Thymic Grafts in Thymectomized, Irradiated
C57BL Mice. Proceedings American Association Cancer Research 2: 123.
Kaplan, H. S., B. B. Hirsch, and M. B. Brown. 1956. Indirect Induction of
Lymphomas in Irradiated Mice. IV. Genetic Evidence of the Origin of the
Tumor Cells from the Grafts. Cancer Research 16: 434-436.
Kaplan, II. S., C. S. Nagareda, and M. B. Brown. 1954. "Endocrine Factors
and Raciation-Radiation-Induced Lymphoid Tumors of Mice. Recent Progress
in Hormone Research, Vol. 10, G. Pincus, Ed. New York, N. Y., Academic
Press. Pp. 293-338.
Kimball, A. W. 1958. Disease Incidence Estimation in Populations Subject
SS
. to Multiple Causes of Death. Bulletin International Statistics Institute 36:
193-204.
Kirschbaum, A. 1952. Rodent Leukemia: Recent Biological Studies; A Review.
Cancer Research 11: 741-752.
Kirschbaum, A. 1957. The Role of Hormones in Cancer: Laboratory Animals.
Cancer Research 17: 432-453.
Kodlin, D. 1959. On the Analysis of Tumor Induction Experiments. Cancer
Research 19: 694-699.
icer
Koletsky, S. and G. E. Gustafson. 1955. Whole-body Radiation as a Carcinogenic
Agent. Cancer Research 15: 100-104.
Krebs, Carl, Aage Wagner, and H. C. Rask-Nielsen. 1930. The Origin of
Lymphosarcomatosis and Its Relation to Other forms of Leucosis in White
Mice. Acta Radiol., suppl. 10, pp 1-53.
-55-
Lacassagne, Antonie. 1945a. Les Cancers Produits par les Rayonnements
Corpusculaires; Mécanisme Frēsumable de la Cancerisation par les Rayons.
Actualités Scientifiques et Industrielles, No. 981, Hermann & Cie,
Paris.
Lacassagne, Antonie and Lucienne Hurst. 1962. Effects of the Combined Action
of Roentgen Rays and a Chemical Carcinogen (DAB) on the Rat's Liver.
The American Journal of Roentgenology, Radium Therapy, and Nuclear
Medicine 87 (HO. 3): 536-542.
Lamerton, L. F. 1960. "Radioisctopes in the Skeleton: Consideration of
Padiation Damage in Relation to Bone Damage. Radioisotopes in the
Biosphere. Richard S. Caldecott and Leon A. Snyder, Eds. Minneapolis,
Minnesota, University of Minnesota. Pp. 382-400.
Latarjet, R. and J-F Duplan. 1962. Experiment and Discussion on Leukaemogenesis
by Cell-free Extracts of Radiation-Induced Leukemia in Mice. International
Journal Radiation Biology, Vol. 5, No. 4, 339-344.
Law, L. W. 1960. Radiation Carcinógenesis. Advances in Biology. Medical
Physics 7: 295-342.
Lerine, S. 1963. Effects of X-irradiation on the Response of Animal Cells
to Virus. Progress Medical Virology 5: 127-168.
Lewis, E. B. 1957. Leukemia and Ionizing Radiation. Science 125: 965-972.
Libansky, J., M. Lamicka, J. Jirasek, and J. Libanska. 1963. Transmission
of X-ray Induced LA VUFB Leukemia by a Cell-free Filtrate. Neoplasma 10,
No. 5, pp. 487-504.
Lieberman, M. and H. S. Kaplan. 1959. Leukemogenic Activity of Filtrates from
Radiation-Induced Lymphoid Tumors of Mice. Science 130: 387.
Lindop, Patricia J. and J. Rotblat. 1961. Long-term Effects of a Single Whole-
Body Exposure of Mice to Ionizing Radiations. II.
Causes of Death.
Proceedings of the Royal Society, B, 154: 350-368.
-56-
Lindsay, S. and I. I. Chaikoff. 1964. The Effects of Irradiation on the Thyroid
Gland with Particular Reference to the Induction of Thyroid Neoplasms: A
Sms
Review. Cancer Research 24: 1099-1107.
Lindsay, S., G. D. Potter, and I. L. Chaikoff. 1957. Thyroid Neoplasms in
the Rat: A Comparison of Naturally Occurring and 1131-induced Tumors.
Cancer Research 17: 183-189.
Lisco, Hermann, Howard S. Ducoff, and Renato Baserga. 1958. The Influence
C
ence
of Total Body X irradiation on the Response of Mice to Methylcholanthrene.
Johns Hopkins Hospital Bulletin 103: 101-113.
Little, John B., Edward P. Radford, Jr., H. Louis McCombs, and Vilma R. Hunt.
1965. Distribution of Polonium-210 in Pulmonary Tissues of Cigarette
Smokers. New England Journal of Medicine 273: 1343–1351.
ues
Lorenz, E., L. O. Jacobson, W. E. lleston, M. Shimkin, A. B. Eschenbrenner,
M. K. Deringer, J. Doniger, and R. Schweisthal. 1954. "Effects of Long-
Continued Total-Body Gamma Irradiation on Mice, Guinea Pigs, and Rabbits.
20
III. Effects on Life Span, Weight, Blood Picture, and Carcinogenesis
and the Role of the Intensity of Radiata on. Biological Effects of
External X and Gamma Radiation. R. E. w kle, Ed. New York, N. Y.
McGraw-ilill Book Company. Pp. 24-148.
Lorenz, E. K. and C. C. Congdon. 1955. Some Aspects of the Role of
Hematopoietic Tissues in the Pathogenesis and Treatment of Experimental
Leukaemia. Revue d'Hematologie, Tome 10, No. 2: 476-484. .
Lorenz, E., J. W. Hollcroft, E. Miller, C. Ć. Congdon, and R. Schweisthal. 1955.
Long-term Effects of Acute and Chronic Irradiation in Mice. I. Survival
and Tumor Incidence Following Chronic Irradiation of 0.11 r per Day.
Journal National Cancer Institute 15: 1049-1058.
-57-
Loutit, J. F. 1964. "The Biology of Radiation-Induced Cancer."
Unusual Forms and Aspects of Cancer in Man, N. Henry Moss, Consulting
Editor. Annals of the New York Academy of Sciences, Vol. 114, art. 2.
Pp. 816-322.
McClellan, R. O. and L. K, Bustad. 1961. Toxicity of Significant Radionuclides

in Large Animals. Annals New York Academy of Science 3: 973-811.
McEndy, D. P., M. C. Boon, and J. Furth. 1942. Induction of Leukeria in
Mice by Méthylcholanthrene and X-rays. Journal National Cancer Institute 3
(No. 3): 227-247.
Vacilahon, B. 1962. Prenata.. X Ray Exposure and Childhood Cancer. Journal
National Cancer Institute 28: 1173-1191.
MacMahon, B. and G. B. Hutchinson. 1964. Prenatal X-Ray and Childhood C.
:
A Review. Acta linio. Internat. Contra. Cancrum 20: 1172-74.
Maisin, J. P. Maldague, A. Dunjic, and H. Maisin. 1957. Syndromes mortels
et Effets Tardifs des Irradiations Totales et Subtotales chex le Rat.
J. Belge Radiol. 40: 346-398.
jarinelli, L. D. 1958. Radioactivity and the fluman Skeleton. American
Journal Roentgenology 80: 729-739.
Miller, R. W. 1964.
Radiation, Chromosomes and Viruses in the Etiology of
Leukemia: Evidence from Epidemiologic Research. New England Journal
Medicine 271: 30-36.
Miller, Robert W. 1965. Epidemiologic Research into Radiation Leukemogenesis:
A Brief Review: Paper presented at a Meeting on Epidemiologic Studies
in fiuman Radiobiology Sponsored by the World Health Organization with the
Cooperation of the Division of Radiological Health, United States
Public Health Service, December 13-17, 1965, Washington, D. C.
-58-
Mola, R. H. 1958a. The Development of Leukaemia in Irradiated Animals.
British Medical Bulletin 14: 174-177.
Mole, R. H. 19586.
The Dose-response Relationship in Radiation Carcinogenesis.
British Medical Bulletin .14: 184-189.
Mole, P. H. 1959. Effects of Dose-rate and Protraction: A Symposium. I.
Patterns of Response to Whole-Body Irradiation: The Effect of Dose
Intensity and Exposure time on Duration of Life and Turrour Production.
The Eritish Journal of Radiology 32 (No. 380): 497-501.
National Committee on Radiation Protection. 1954: Permissible Dose from
External Sources of Ionizing Radiation. National Bureau of Standards,
U. S. Department of Commerce, Handbook 59, September 21, 195.), Washir:"..;
D. C., p. 48.
Xilsson, Agnar. 1962. Histogenesis of Sr90-induced Osteosarcomas. Acta
Veterinaria Scandinavica 3: 1-16.
Norman, A., M. Sasaki, R.E. Ottoman, and R. C. Veomett. 1964.
Chromosome
Aberrations in Radiation Workers. Radiation Research 23: 282–289.
Nowell, P. C. and L. J. Cole. 1959. Late Effects of Fast Neutrons versus
X-rays in Mice: Nephrosclerosis, Tumors, Longevity. Radiation Research ll:
545-556.
Odell, T. T., G. E. Cosgrove, and A. C. Upton. 1960. "Modification of
Delayed Somatic Effects of Ionizing Radiation. Radiation Protection and ..
· Recovery. A. Hollaender, Ed. Oxford, England. Pergamon Press. PP. 303-315.
Odell, T. T., Jr. and A. C. Upton. 1960. "Late Effects of Internally Deposited
Radioisotopes.": "Radioactive Isotopes in Physiology Diagnostics and Therapy,
-
.
=
H. Schwiegk and F. Turba, Eds. Second revised and enlarged edition.
Springer-Verlag/Berlin. Pp 375-392.
-
.
"
.
-
..
.
1
.
ifi
.
.
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.
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2 OF 2
ORNL P
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.
.
MICROCOPY RESOLUTION TEST CHART
NATIONAL BUREAU OF STANDARDS – 1963
-59-
Parsons, ..., h. C. Upton, 4. A. Bender, V. K. Jenkins, :. S. kelson,
R?. ??. Jonnson. 1962. Electron Kicroscopic Observations on Primary
20 Serially Pussaged Radiation-Induced Myeloid Leukemias of the
??? :ouse. Cancer Research 22: 728-730.
Pifer, J. i., 2. T. Toyooka, R. W. víurray, et al. 1963. Peoplasms in C:12. run
WICE
12awa
Treated witii 7-rays for Thymic Enlargement. I. Neoplasms arü ortality.
Journal .iztional Concer Institute 31: 1333-1356; v.e. United nations
Docurer.t A/AC. 82/3/L.891.
2011:ari, .. and T. Matsuzawa. 1961. Radiation-Induced Leukemia in Germfree
nice. Proceedings Society Experimental Biology 16 (No. 1): 967-971.
Potter, G. O., S. Lindsay, and I. L. Chaikoff. 196). Induction of
topla in zat Thyroid Glards sy Low Doses of Radioiodine. io...
P:31c1o: 7 69: 257-269.
Rei?, 4. 2. 1961. Radiation Carcinogenesis at High Dose-Response Levels:
i llypothesis. Blature (London) 190: 115-1:17.
rosen, V. J., T. J. Castanera, D. J. Kimeldorf, and D. C. Jones. 1961.
SIS
Renal Peoplasms in the Irradiated and Nonirradiated Sprague-Dawley pat.
De Amcrican Journal of Pathology 38 (ito. 3): 359-369.
Pussell, W. L. 1965. Studies in Mammalian Radiation Genetics. i!ucleonics 23:
Russell, W. L., Liane Brauch Russell, and Elizabeth M. Kelly. 1960.
US se
"Dependence of Hlutation Rate on Radiation Intensity." Immediate
and Low Level Effects of Ionizing Radiations. A. A. Buzzati-Traverso, Ed.
London, England. Taylor & Erancis, Ltd. PP. 311-320.
Sacks, R. 1959. Life Table Technique in the Analysis of Response-Time Data
from Laboratory Experiments on Animais.
Toxicology and Applied
Pharinacology 1: 119-134.
-60-
псе
Seltser, Raymond and Philip E. Sartwell. 1965. The Influence of
Occupational Exposure to Radiation on the Mortality of American
Radiologists and Other Medical Specialists. American Journal of
Öni dericlony, Vol. 81, No. 1, pp. 2-22.
Shellavarger, C. J., E. P. Cronkite, V. P. Bond, and S. W. Lippincott.
1957. The Occurrence of Mammary Tumors in the Rat after Sublethal Whole-
Body Irradiation. Radiation Research 6: 501-512.
Snubik, P., A. R. Goldfarb, A. C. Ritchie, and 11. Lisco. 1953. Latent
Carcinogenic Action oï Beta-irradiation on Mouse Epidermis. Vature 171:
934-934.
Simon, 1., 1. Brucer, R. Hayes, 1960. Radiation and Leukemia in Carcinoma ci
the Cervix. Radiclory 7!: 205-911.
Thompson, H. C., W. J. Bair, S. Karks, and 1. F. Sullivan. 1958. Evaluatis.
of Internal Exposure Hazards for Several Radioisotopes Encountered in
Peactor Operations. Second United Nations International Conference on
ne
Peaceful Uses of Atomic Energy, Geneva, Vol. 23, p. 283.
Trung, P. J. 1953. De iiistogenese van Ovariumgeziellen Bij lens En Muis.
ese van
Overdruk Negende Jaaeboek van Kankeronderzoek en Kankerbestrijding in
Nederland, pp. 101-118.
Traenkle, li. Is. 1963. "X-Ray-Induced Skin Cancer in Man." Biolory of Cutaneous
.
Cancer, National Cancer Institute Monograph No. 10, pp. 423-432.
United Nations. 1964. Report of the United Nations Scientific Committee on
the Effects of Atomic Radiation. General Assembly Official Records:
Nineteenth Session, Supplement No. 14 (A/5814), p. 1-119.
Upton, A. C. 1959. "Studies on the Mechanism of Leuk ameogenesis by Ionizing
Radiation. Carcinogenesis: Mechanisms of Action (Ciba Foundation
Symposiw), G. E. W. Wolstenholme and C. M. O'Connor, Eds. London, England.
J. & A. Churchill Ltd. Pp. 249-273.
no
-bl-
Orton, Arthur C. 19úla. "Radiation as an Etiologic Factor." Proceedings
of in. Pourth latior al Cancer Conference, University of innesota,
inneapolis, Minnesota, J. 3. Lippincott Co., Philadelphia. Fy 63-69.
Upton, :1. . 19ólb. The Dese-response Relation in Padictior.-Induced Car.ce?'.
C:!30! ?Seard? 21 (io. 6): 717-729.
Upton, A. C. and i. Furt.. 1954. The Effects of cortisone on the developerit
03 5:52taneous Leukemia in rice and on Its Induction by Irradiation.
5.Loou :): 636-655..
Upton, Artiur C. 1962. "Leukemogenesis - Role of Viruses and Cytological
spects." Proceedings Symposium on Cellular Easis and Setiolosy of
Lite Somatic Effects or Ionizing Radiations, R. J. C. llarris, Bå. (in Pro..
upcorn, A. º. 261. Shoughts on the contributions of Badiatio: bicioz.
Cancer Research 24: 1861-68.
Upton, á. C., J. Furth, and W. T. Burnett, Jr. 1956. Liver Damare and
Hepatomas in ice Produced by Radioactive Colloidal Gold. Cancer Researa ló:
0:1.7 Cena
211-215.
Uiton, A. C. and J. Furth. 1957. "Host Factors in the Pathogenesis of Louisia
OC
CE
S
O
in Anima's and in Wan." Proceedings of the Third Wational Cancer Coutances,
mote American Cancer Society, Inc., J. B. Lippincott Company, pp. 312-32.
Upton, a. C., V. K. Jenkins, li. E. Walburg, Jr., R. L. Tyndall, and J. %.
Conklin. 2966. Observations on Viral, Chemical, and Radiation-Induced
lyeloid and Lymphoid Leukemias in RF lice. International Conference on
iurine Leukersia, Philadelphia, Pennsylvania, October 13-15, 1965. To
be published in Journal National Cancer Institute.
Upton, A. C., A. W. Kimdall, J. Furth, K. W. Christenberry, and W. H. Benedicti.
1960. Sone Delayed Effects of Atom-bomb Radiation in slice. Cancer
Research 20 (20. 8, part 2): 1-62.
ncer
-62-
üytor., ... C., "'. F. Wolff, and E. P. Sniffen. 1961. Leukorogenic Effect
ofylure on the rouse Trymus. Proceedings Society Experimental Piolo
91cdicine 103: 164-467.
Unston, A. C., *. Á. Kastenbaum, anci J. W. Conklin. 1963. "Age-specific
-
.
Death Rates of rice Exposed to Ionizini Radiation and Radiomiretic
Agents." Proceedings Symposium on Cellular Basis and Aetiology of Late
Bogatic Effects of Ionizing Radiations, R. J. C. iiarris, 2d. (1962, in
S
press).
Van Dike, D. C., %. E. Simpson, A. A. Knoff, and C. A. Tobias. 1959.
Y
Loos-tera effects of Deutron Irradiation of the Rat Pituitary.
docrinoloxx 64: 240-261.
Hasoner, Joseph K., Victor E. Archer, Frank E. Lundin, Jr., Duncan á.
..
und J. William Lloyd. 1965. Radiation as the Cause of Lung Cancer Amoras
rs.
K
Vraniw viners. The lew England Journal of Medicine, Vol. 273, 30.4.,
pp. 101-103.
isahä, voicii. 1958. Clinical and Statistical Research of Leukemia in
Japan, Especially in the Kinki District. Acta Haem. Jap. 21 (2):
Suppl. 21:0-258.
.
Walburi, 1. E., Jr., A. C. Upton, R. L. Tyndall, W. W. llarris, and G. E.
Cosgrove. 1965. Preliminary Observations on Spontaneous and Radiation-
Inriuced weusemia in Germfree Mice. Proceedings Society Experimental
Biolo, and Ne dicine 118: 11-14.
Wasserman, 3. 11. 1960. "Radioisotope Absorption and lethods of Elimination:
A Critical Review." Radioisotopes in the Biosphere, Richard S. Caldecott
and Leon A. Snyder, Eds. University of Minnesota, Minneapolis. Pp. 5666-573.
Heller, C. 7. 1956. Causal Factors in Cancer of the Lung. Charles C. Thoras,
Syrinsfield. Pp. 43-47.
ace
-63-
Coliman, s. 1955. Comments on the Analysis oi Dose-Response Data in
Experimental carcinogenesis. Journal ilational Cancer Institute 16:
195-2011.
Yerior), Kenjiro, Jacob Furth, and teclama laran-Ghera. 1961. Induction :
Hancotropic Pituitary Tu.ors by X-rays in Rats and Mice: the Role
of annatropes in Development of Marmar; Tumors. Cancer Research 21 (:10. 2):
.
173-126.
-6);-
TABLE 1
Lewis's Estimates of the Probability of Radiation-Induced Leukemia*
in Various Populations
Population
Byposer
Type of
Radiation
Region
Irradiated
Probability of
Leukemia**
A-bomo survivors
Gamma rays,
neutrons
Whole-body
2 x 10-6
Spine
Patients with
X rays
ankylosing spondylitis
1 x 10-6
X rays
Chest
1 x 10-6
Children irradiateä
for thymic enlarge-
zent
Sadiologists
2 x 10
X rays,
radium, etc.
Partial to
whole body
*From Lewis (1957).
**Probability of leukemia of specified type per individual per year
ter ren to region irradiated.
.
.
.
.
.
. .
'
'io.
,
-
.
insis.
.
.
.
rijeme
-65-
TABLE 2
INCIDENCE OF ZONE CANCER IN RELATION TO SKELETAL RADIATION DOSZ
C

5cietal
Incidence po
per year
coce
persons
Male
Female
10.8
1900
5.2
1336
3.0
493
6.20
0.26
2.2 x 10-3
1.0 X 10-2
9 x 10-4
2.53
1.62
1.91
4X 206
3.5 X 106
1.97€
1.59€
prom Marinelli (1958).
skeletal dose in units equivalent to l uc: of Ra 220 + 0.3 uc daughters
permanently fixed in skeleton.
rmane
“Iata for population of Chicago 1940-1950 (excluding cancer of jaw).
-66-
LEGENDS FOR FIGURES
'ipure 1.
Incidence of leukemia in relation to age.
i Acute and chronic leukemia in irradiated spondyliüics, in
relation to age at first exposure (Doll, 1962)
Acute and chronic leukemia, chronic lymphatic type excluded,
in England and Wales, in relation to age (Doll, 1962).
Acute granulocytic leukemia in survivors exposed within to
A-bomb radiation within 1500 M at Hiroshima and Hagasaki, in
relation to age at exposure (Brill et al., 1962).
☺ Acute granulocytic leukemia in Japan, Kinki district, in
relation to age (Wakisaka, 1958).
Figure 2.
Annual incidence of leukemia, all types, in relation to radioni:
dose.
rs
O Nagasaki A-bomb survivors (Brill et al., 1962).
Hiroshima A-bomb survivors (Prill et al., 1962 with
Sur
Ors
revision of dose estimates as per J. A. Auxier, personal
communication).
A Irradiated spondylitics, radiation exposure expressed in
me an dose (R) to spinal marrow (Court Brown and Doll, 1957).
Tro,
Figure 3. Incidence of thyroid cancer, expressed in percentage of those
exposed, in relation to thyroid dose (from Beach and Dolphin, 1962).
Caricer &
Figure 4. Annual incidence of respiratory cancer among uranium miners in
relation to duration of occupational exposure (from Wagoner, et al., 1965).
-67-
Figure 5. Latent period in radiogenic skin cancer of man (after Feyzin, 191!).
TO
con time after onset of radiodermatitis.
w time after first irradiation.
D
Figure 6. Dose-incidence relation for lympho:nas in whole-body-irradiated
60
female RF mice, as influenced by protraction or fractionation of irradiation.
(All nice were 10 weeks old at start of irradiation.) O Single, acute exposure
to cool ganna rays at 7 r/min. A Daily exposure to cool gamma rays at
0.0005 rad3/min. V Ivo exposures to 3000-kvp X rays, at 75 rads/min, 270
days clapsing between exposures. Ten exposures to 300-kvp X rays at
75 rads/inin, 30 days elapsing between successive exposures. Daily expcem
to fast neutrons at 0.0006-0.006 rads/min. (A. C. Upton, J. 7. Conklin,
ures.
en Succe
Pe%**
and M. L. Randolph, unpublished data).
Figure 7.
Dose--incidence relation for granulocytic leukemia in whole-body-
irradiated RF male mice, as influenced by protraction of irradiation.
(All
nice were 8-10 weeks old at start of irradiation). O Single, acute
exposure to X rays at 50-100 rads/min. A Daily exposure to coºl gamma
SUY
rays at 0.0006 rads/min. A Daily exposure to fast neutrons at 0.0006-0.006
rais/min. (A. C. Upton, J. W. Conklin, and M. L. Randolph, unpublished data).
Figure 8. Average probability of dying with a malignant bone tumor as a
function of isotope dose (from Finkel, 1959).
Figure 9. Daily probability of bone tumor development (P+) in mice as a
function of time after beginning of monthly injections of Srºy. The figures
beside the curves indicate dosages of Srº in uc/8 (from Brues, 1949).
Figure 10. Incidence of thyroid tumors in male Long-Evans rats injecteä with
various doses of 1434 (from Linday et al., 1957, and Potter et al., 1960).
S
2
-GE..
Var
10
sama rays, beginning at 10 weeks of age (A. C. Unton, unpublished data!.
poze rate: 7 rads per min.
. Dose rate: 0.0035 rad per min. (5 rad per day).
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