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OCR for page 352
6
Other Somatic and Fetal Effects
CANCER IN CHILDHOOD FOLLOWING EXPOSURE IN UTERO
Human Epidemiologic Studies
Preliminary results of the Oxford Survey of Childhood Cancers, pub-
lished over 30 years ago, suggested an association between the risk of
cancer, primarily leukemia, in childhood (within 15 years of birth) and
prenatal exposure to diagnostic x rays in utero (St56, 58~. A subsequent
survey of 734,243 children born in New England supported this suggestion
(Madly. The initial results of follow-up of prenatally irradiated atomic-
bomb survivors during the first 10 years of life had failed to support the
suggestion (Jamb. However, in a more recent, 1950-1984, follow-up based
on DS86 dosimetry (Yo88), two cases of childhood cancer have been ob-
served among 1,630 in utero-exposed survivors during the first 14 years
of life, both of which occurred in persons who had been heavily exposed
(1.39 and 0.56 Gy). The occurrence of these two cases corresponds to an
upper bound risk estimate (95% confidence level) of 279 cases/104 PGy, an
estimate consistent with Bithell and Stiller's estimate on reanalysis of the
Oxford survey data (Bidet.
An extension of the New England survey to include cancer deaths in
1,429,400 children born between 1940 and 1960 in 42 hospitals in New
England and the mid-Atlantic states (Mo84) also showed an excess of
cancers among those exposed to diagnostic x rays in utero. In this study,
cases were compared with age- and sex-matched nonirradiated controls.
For leukemia and other cancers, the relative risks were 1.52 and 1.27,
352
OCR for page 353
OTHER SOMATIC AND FETAL EFFECTS
353
respectively, with no evidence that the excess was attributable to risk
factors other than radiation or was limited to a particular subpopulation
(Mo844.
To explore the possibility that both prenatal x-ray examination and
childhood cancer might be attributable to a separate, common risk factor,
and since radiographic examination of women who are pregnant with twins
has usually been performed because of the twin pregnancy rather than
because of other diagnostic concerns, the incidence of cancer has been
investigated in irradiated twins. The first such study, conducted in the
United Kingdom, found the relative risks of childhood leukemia and other
cancers in irradiated twins (versus nonirradiated twins) to be 2.0 and 1.7,
respectively. It also found as many excess cases of cancer in irradiated
dizygotic and monozygotic twins as in irradiated singleton births (Modal.
The second study, conducted on twins in Connecticut, likewise found the
relative risks of childhood leukemia and other cancers in irradiated twins
versus those in nonirradiated twins, especially at ages 10-14 years, to be
1.6 (90% C.I. 0.4, 6.8) and 3.2 (0.9, 10.7), respectively (Hands; however,
the excess was restricted largely to children of mothers with a history of
previous pregnancy loss, in whom the overall relative risk of cancer was 7.8
(1.2, 50.4), compared with 1.4 (0.5, 4.3) in irradiated twins born to mothers
without a history of pregnancy loss (Handy.
Because of the comparatively small magnitude of the average radiation
dose to the fetus from diagnostic radiography, which has been estimated as
5-50 mGy, the data imply that susceptibility to radiation carcinogenesis is
relatively high during prenatal life (NRC72, NRC80, UN77, Mogul. Such
an interpretation is complicated, however, by the fact that little increase
in susceptibility has been evident in prenatally x-irradiated experimental
animals and there is no known biological basis for such an increase in
susceptibility or for the suggested equivalence in magnitude of the leukemia
excess with that of other childhood cancers (Might. These complications
notwithstanding, the concordance of the studies of twins with the studies
of prenatally irradiated singleton births prompts the tentative conclusion
that susceptibility to the carcinogenic effects of irradiation is high during
prenatal life.
Although, mortality from cancer now appears to be increased in pre-
natally exposed atomic-bomb survivors more than four decades after they
were irradiated (Yo88), it remains to be established that the risk of cancer
in adult life is increased by prenatal irradiation. During the observation
period 1950-1984, however, the relative risk of fatal cancer at a dose of 1
Gy to the mother's uterus (DS86 organ dose), among a total of 1,630 in
utero-exposed A-bomb survivors has been estimated as 3.77 (90~O C.I. 1.14,
13.48), corresponding to an absolute risk of 6.57 (90% C.I. 0.47, 14.49)
per 104 PYGy and an attributable risk of 40.9% per Gy (90% C.I. 2.9%,
OCR for page 354
354 EFFECTS OF EXPOSURE TO LOW LEVELS OF IONIZING RADIATION
90.2%). Thus, these results also suggest that susceptibility to radiation-
induced cancer is higher in prenatally exposed survivors than in postnatally
exposed survivors (Yo88~. Comparable late-occurring carcinogenic effects
from prenatal irradiation have been observed in laboratory mice (Comb.
Summary
Based on the limited epidemiologic data available through the early
1970s, the 1977 UNSCEAR committee (UN77) estimated the risk per unit
absorbed dose to be about 200 to 250 excess cancer deaths/104 person
Gy in the first 10 years of life, with one-half of these malignancies being
leukemias and one-quarter tumors of the nervous system. Bithell and
Stiller's (Bi88) recent estimate from the Oxford survey, 217 cases/104
person Gy, falls within this range. The epidemiologic studies also suggest
that an association exists between In utero exposure to diagnostic x rays
and carcinogenic effects in adult life; however, the magnitude of the risk
remains uncertain.
EFFECTS ON GROWTH AND DEVELOPMENT
Animal Studies
The effects of prenatal irradiation on the growth and development
of the mammalian embryo and fetus, mediated through direct radiation
injury of developing tissues (Br87), include gross structural malformations,
growth retardation, embryo lethality, sterility, and central nervous system
abnormalities (UNTO. Major anatomical malformations have been pro-
duced in all mammalian species by irradiation of the embryo during early
organogenesis; however, the time of maximal susceptibility is sharply cir-
cumscribed, and the evidence suggests that there may be a threshold for
many, if not most, major malformations (NRC80~. Retardation of postna-
tal growth also has been observed to be produced over a broad range of
mammalian gestational ages in experimental animals and humans (NRC80~.
The developing central nervous system exhibits a particular sensitivity
to ionizing radiation (ICRP87~. In experimental animals, the central ner-
vous system malformations most likely to be produced by irradiation during
early organogenesis include hydrocephaly, anencephaly, encephalocele, and
spine bifida. In rats, mice, and monkeys, radiation has been shown to induce
functional and behavioral effects too, including motor defects (Ya62), emo-
tionality (Fu58), impairment of nervous reflexes and hyperactivity (Ma66),
and deficits in learning (Legal. In rodents, disturbances of conditional
reflexes, impairment of learning ability, and locomotor damage also have
OCR for page 355
OTHER SONG TIC AND FETAL EFFECTS
355
been reported after doses that were large enough to cause gross structural
damage (UNBID.
Human Studies
The most definitive human data concerning the effects of prenatal
irradiation are those relating to brain development (UNBID.
Severe Mental Retardation
Injurious effects of ionizing radiation on the developing human brain
have been documented in Japanese A-bomb survivors who were exposed
in utero (B173, B175, IC86, Mi76, Ot83, Sc86a, Sc86b, UN86, Wo67), in
whom the prevalence of mental retardation and small head size increases
with increasing exposure. In recent studies based on a cohort of 1,598 such
individuals, all of the 30 children who were found to have severe mental
retardation were diagnosed before the age of 17. Nine of the mentally
retarded individuals, only 3 of whom had doses greater than 0.5 Gy, also
had other health problems, presumably not related to radiation, which
might account for their severe mental retardation. Two individuals had
conditions unlikely to be casual for mental retardation, neonatal jaundice
and, possibly, neurofibromatosis. Three have or have had Down syndrome,
one a retarded sibling and another Japanese encephalitis during infancy.
Dosimetry: Estimates of the dose received by the children as fetuses
are not yet available from the DS86 system, but the intrauterine doses
received by their mothers should provide a useful approximation. DS86
organ dose estimates for the uterus have been computed for most of the
exposed mothers who were within 1600 m of the hypocenter in Hiroshima
and 2000 m in Nagasaki (Ot87, Romp. Organ doses were modeled individ-
ually to take account of house shielding and the orientation and posture of
the exposed individuals. For exposed individuals with incomplete shielding
histories, the calculated free-in-air (FIA) kerma was adjusted by means of
average house and body transmission factors to obtain an average organ
dose. Under the DS86 dose system, neutrons are not a significant contrib-
utor to most fetal exposures; the DS86 FIA neutron kerma in Hiroshima
at 2000 meters was only 0.0004 Gy and in Nagasaki, 0.0003 Gy (Romp.
Gestational Age: Gestational age is an important factor in determining
the nature of the radiation injury to the developing brain of the embryo
or fetus (B173, B175, Mi76, Ot83, Ot86, Ot87, Sc86a, Sc86b). Gestational
ages have been grouped to reflect the known phases in normal brain
development. The four categories measured from the time of conception
were 0-7, 8-15, 16-25, and >26 weeks. During the first period (0-7 weeks),
the precursors of the neurons and neuroglia emerge and are mitotically
active (Mash. During the second period (8-15 weeks), a rapid increase in
OCR for page 356
356 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
100 1 _
> 0 80 O All Ages
an ~E:3 8-15 weeks
O C) ~ 9-25 weeks
`~ ~60 ~ > 26 weeks
Z ~
a) z 40 _
CL~ _
20
O _
4
9224~ ~,~,~O~ ~;\O~OI r
O O
1 1
12 .
3
·:-:-:-
::::
:::
::::
:-:-:-:
:::::::
·:::
::-:-:-
::::
::::
~ O I ,
Control 0.01-0.09 0.10 0.49 0.50 0 99 ~ Do+
(0.00) (0.05) (0.23) (0.64) (1 38)
FETAL DOSE (Gy)
FIGURE 6-1 Percentages of severe mental retardation at various fetal doses in the
combined Hiroshima and Nagasaki data. The number of cases is given at the top of the
histogram (Ot87~.
the number of neurons occurs; they migrate to their developmental sites
and lose their capacity to divide, (Ra75, Ramp. During the third period
(16-25 weeks), differentiation in situ accelerates, synaptogenesis that began
at about week 8 increases, and the definitive cytoarchitecture of the brain
results. The fourth period (~26 weeks) is one of continued architectural
and cellular differentiation and synaptogenesis of the cerebrum with, at the
same time, accelerated growth and development of the cerebellum.
Among atomic-bomb survivors exposed in utero, a dose-dependent
increase in the incidence of severe mental retardation occurred in the
gestational age group 8-15 weeks after conception and, to a lesser extent,
in the gestational age group 16-25 weeks after conception (Figure 6-1~.
No subjects exposed to radiation at less than 8 weeks or >26 weeks of
gestational age were observed to be mentally retarded. The relative risk
for exposure during the 8-15 week period is at least 4 times greater than
that for exposure at 16-25 weeks after conception.
Dose-Response Models: The dose response for severe mental retarda-
tion has been examined in depth by Otake, Yoshimaru, and Schull (Otter.
Their results are shown in Figure 6-2. Within the critical gestational age
period of 8-15 weeks, the prevalence of severe mental retardation can be
linearly related to the absorbed dose received by the fetus. There is a
highly significant increase in the occurrence of severe mental retardation
OCR for page 357
COPIER SOMATIC AND FETAL EFFECTS
357
with dose In Hiroshima and in the combined data from both cities. This in-
crease Is strongest in the children irradiated at 8-15 weeks after conception
but a suggestive increase Is also seen at 16-25 weeks after conception. In
the data for both cities, the variation in frequency of occurrence with dose,
when exposure occurred 8-15 weeks after conception, can be accounted
for by a linear model, although there is some suggestion of a nonlinear
component in the dose-response function for both the 8-15 and the 16-25
week periods (Figure 6-2~.
Maximum likelihood analyses based on a simple linear model were
made to estimate a possible threshold dose and its 95% confidence intervals
(Otter. When all cases were considered, the estimated lower bound of the
threshold for the most sensitive period of 8-15 weeks after conception was
zero. However, exclussion of cases with a possible nonradiation related
etiology yields a threshold with a lower bound of 0.12 Gy for ungrouped
data and 0.23 Gy when the data is stratified by dose interval. Both of
the estimated thresholds, 0.39 and 0.46 Gy, respectively, are significantly
different from zero. Further investigation, using an exponential linear
model, found an estimated lower bound for a threshold of 0.09 Gy for
70
60,
L' 50
~ Z
2 °
cn A: 40
O
Lll
~ MU 30
Cl:
Z
10
_
0] {
/
~._-'
8-15 wee/ 1
~gestational
/ ages
I/ A,' ,,,'
,
,""'\
' ,' 16-25 weeks
1
0 0.10 0.20 0.30 0.50 1.00 1.50
FETAL DOSE (Gy)
FIGURE 6-2 The percentage of severe mental retardation among those exposed in utero
by dose and gestational age in Hiroshima and Nagasaki. The vertical lines indicate 90~o
confidence intervals (Ot873.
OCR for page 358
358 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION
the grouped data and 0.15 Gy for the individual data for those exposed
in the 8-15 week period. Similarly, a threshold was also indicated for the
16-25 week-period, with a lower bound of 0.21 Gy, based on a linear model
with either the individual or the grouped data, and 0.22-0.25 Gy with the
exponential linear model. However, the case for a threshold is not clear;
linear regressions using a threshold predict a larger response than was
actually observed at large doses (W. J. Schull, personal communication).
In summary, analysis of the epidemiologic data has identified the
maximal sensitivity of the human brain to occur between 8 and 15 weeks of
gestational development. During this period, the dose-effect relationship
resulting from the new DS86 dosimetry system indicates a frequency of
severe mental retardation of 43% at 1 Gy and suggests that a threshold for
the effect may exist in the range 0.2 to 0.4 Gy (Ot87, ICED.
Uncertainties: A number of uncertainties are associated with these risk
estimates. These include the limited number of cases, the appropriateness
of the comparison group, errors in the estimation of the absorbed doses
and the calculated prenatal ages at exposure, variation in the severity
of mental retardation, and other confounding factors in the postbombing
period, including malnutrition and disease (Sc86a).
Discussion: Significant harmful effects of radiation on the developing
brain of children exposed in utero during the atomic bombings of Hiroshima
and Nagasaki were observed only for those exposed during the periods 8-15
and 16-25 weeks after conception. During the period at 8-15 weeks, the
period of maximum sensitivity, the dose-response relationship appeared
to be different from that at subsequent gestational ages, indicating that
radiation effects on cerebral growth and development vary with gestational
age at exposure. This period of maximum radiation sensitivity is the time of
the most rapid cell proliferation and migration of immature neurons from
the ventricular and subventricular proliferative layers to the cerebral cortex
(Do73, Ra75, Ramp. Radiation exposure during this period may be inferred
to induce neuronal abnormalities and misarrangement of neurons, as well
as decreasing the number of normal neurons. This inference appears to be
supported by nuclear magnetic resonance images of the brains of severely
mentally retarded children, in which abnormal collections of neurons in
areas of disturbed brain architecture have been demonstrated (W. J. Schull,
personal communication).
The data for 8-15 weeks after conception, based on the DS86 doses, fit
either a linear or linear exponential dose-response relationship without a
threshold. Otake et al. have pointed out that estimating a threshold for this
effect is difficult and may depend on the clinical criteria for severe mental
retardation. If exposure to radiation moves the distribution of intelligence
downward in proportion to dose, as described below, the number of individ-
uals with levels of intellectual function below the diagnostic threshold must
OCR for page 359
OTHER SOMATIC AND FETAL EFFECTS
359
necessarily increase as the dose increases (Ot87~. Clinical selection of an
arbitrary level for severe mental retardation dichotomizes the distribution
of intelligence levels and could lead to an apparent threshold for this effect.
At 16-25 weeks after conception, differentiation accelerates, synapto-
genesis that begins at about week 8 increases, and the functional cytoarchi-
tecture of the brain takes place. During this period radiation may impair
synaptogenesis, producing a functional deficit in brain connections. The re-
sponse seen among the atomic-bomb survivors, irradiated during the period
16-25 weeks after conception, suggests that the evidence for a threshold is
stronger during this period than during the 8-15 week interval.
No evidence of a radiation-related increase in mental retardation has
been observed in survivors exposed earlier than 8 weeks after conception
or later than 26 weeks after conception. The absence of an effect prior to
the eighth week suggests that either the cells that were killed or inactivated
at this stage of development are more readily replaced than those that were
damaged later, or that the embryo fails to develop further. The final weeks
of gestation are largely a time of continued cytoarchitectural and cellular
differentiation and synaptogenesis, and the basic neuronal structure of the
cerebrum is nearing completion at this time. Since differentiated cells are
generally less radiosensitive than undifferentiated ones, measurable damage
may require much higher doses and, given the small number of atomic-
bomb survivors at these doses, may be more difficult to detect (Otter.
Nonradiation-related explanations for the observed effects on the em-
bryonic and fetal central nervous system that could affect these findings
include: (1) genetic variation, (2) nutritional deprivation, (3) bacterial and
viral infections during pregnancy, and (4) embryonic or fetal hypoxemia. It
is possible that one or more of these factors could have confounded the
observations. It is commonly presumed that radiation-related damage to
the developing brain results largely, if not solely, from neuronal death. This
assumption rests in part on the relatively large proportion of the mentally
retarded who have small heads. There is a need, therefore, to determine
what role, if any, these other possible causes of a relatively small brain may
play in the radiation-related risk of mental retardation.
Intelligence Test Scores
Intelligence test (Koga) scores of individuals of 10-11 years of age who
were exposed prenatally to the Hiroshima and Nagasaki atomic bombs have
been analyzed, using estimates of the uterine absorbed dose based on the
DS86 system of dosimetry (Scaly. As indicated in Figure 6-3, no radiation-
related effect on intelligence is evident among survivors who were exposed
in utero during the first seven weeks after conception or during week 26
or later. In contrast, children exposed at 8-15 weeks after conception and,
OCR for page 360
360 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
130
120
~ 110
o
(a
a
LL
100
90
80
70
(') I!~
1
(~( ANTI art
I AT I
(2) I{H > 1.0 Gy
_ _ ~1 0.5-.99 Gy
r ~ c ] I ~ 1 0.1-.5 Gy
T I ~ I .01~.9 Gy
l ~ CONTROL
ALL AGES 0-7 8-15 16-25 26 +
AGE IN WEEKS AFTER CONCEPTION
FIGURE 6-3 Mean IQ scores and 95~o confidence limits by gestational age in weeks and
fetal dose. The numbers in parentheses are severely retarded cases, IQ < 64 (Sc86a).
to a lesser extent, those exposed at 16-25 weeks after conception show a
progressive shift downward in individual scores with increasing exposure.
Within the group exposed 8-15 weeks after conception, a linear model fits
the regression of intelligence scores on dose somewhat better than linear-
quadratic models. The diminution in intelligence score under the linear
model is 21-29 points at 1 Gy and is somewhat greater (24-33 points) at
1 Gy when controls who received less than 0.01 Gy are excluded from the
analysis (Scaly.
School Pe~fom~ance
In a study of the school performance of prenatally exposed atomic-
bomb survivors, the DS86 sample included 929 children. As judged by
a simple regression of school performance as a function of fetal dose,
there is a highly significant decrease in school achievement in children
exposed 8-15 weeks and 16-25 weeks after conception (Figure 6-4) (Other.
This trend is strongest in the earlier school years. In the groups exposed
within 0-7 weeks, or >26 weeks after conception, there is no evidence of
a radiation-related effect on scholastic performance. These results parallel
those obtained for prenatally exposed atomic-bomb survivors with regard to
achievement on standard intelligence tests in childhood as discussed above
(Scaly.
Summary Japanese Results: The DS86 in utero sample consisted
OCR for page 361
OTHER SOMATIC AND FETAL EFFECTS
5
En
CC
8 4
111
a:
J
o
o
I 3
En
11
o
't 2
llJ
1
361
,(6) i: :~(3) :+I- ~ 1:
(4) COW > 1.0 Gy
I I ~ 1 0.1-0.49Gy
4 1 · 1 0,- 099 Gy
l ~ Control < 0.01 Gy
0-7 8-15 16-25 26 +
GESTATIONAL AGE (WEEKS)
FIGURE 6-4 Average school subject score in the fimt grade with 95~o confidence limits
by gestational age and fetal dose (Ot88~.
Of almost 1,600 atomic-bomb survivors, including 30 individuals who were
severely mentally retarded. A variety of dose-response models with and
without a threshold have been fitted to the individual, as well as grouped,
dose data. The highest risk of radiation damage to the embryonic and
fetal brain occurred in individuals irradiated 8-15 weeks after conception.
The frequency of severe mental retardation in the 8-15 week-old fetus is
described by a simple linear, nonthreshold model. The risk at 1 Gy is
about 43% with the DS86 dosimet~y systems under a simple linear model,
and about 48% when a linear exponential model is used. There is some
indication of a threshold for severe mental retardation, but this is difficult
to assess because there is a continuous diminution of intelligence with
increasing dose. Using a 95% confidence interval, the grouped dose data
suggest a lower bound on the threshold dose of about 0.1 Gy, whereas
regressions using individual doses yield a lower bound of about 0.2 Gy.
However, linear regressions which include thresholds are not consistent
with the observations at doses greater than 1 Gy. When individual doses
are used, damage to the fetus exposed at 16-25 weeks after conception
seems to fit a linear-quadratic or quadratic regression and suggests a lower
bound of about 0.2 Gy on a possible threshold dose.
Within the group exposed 8-15 weeks after conception, the regression
of the intelligence test (Koga) score on absorbed dose is linear; the range
of the decrease in intelligence test score is between 21 and 29 points at 1
OCR for page 362
362 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
Gy. Similarly, damage to the fetal brain at 8-15 weeks after conception is
linearly related to fetal absorbed dose, as judged by a simple regression of
school performance scores on dose.
Other Epidemiologic Studies
New York Tinea Capitis Study: Albert et al. (A166) reported that
children in New York, treated for tinea capitis by x irradiation, had a
higher incidence of treated psychiatric disorders than those treated with
chemotherapy. Shore et al. (Sh76) and Omran et al. (Om78) confirmed
these observations in this series of 2,215 patients with tinea capitis and
demonstrated a higher frequency of mild, nontreated forms of behavioral
maladjustment and mental disease in the irradiated population.
Israel Tinea Capitis Study: Ron et al. (Ro82) evaluated several mea-
sures of mental and brain function in 10,842 Israeli children treated for
tinea capitis by x-ray therapy (mean brain dose, 1.3 Gy) and two nonir-
radiated, tinea capitis-free comparison groups were used. While not all
measures were statistically significant, there was a consistent trend for the
irradiated children to exhibit subsequent behavioral impairment more of-
ten than those in the comparison group. The irradiated children had lower
examination scores on scholastic aptitude, intelligence quotient, and psy-
chological tests; completed fewer school grades; had increased admissions
to mental hospitals for certain neuropsychiatric diseases; and had a slightly
higher frequency of mental retardation.
Childhood Leukemia Patients: Meadows et al. (Me81) also reported
lower intelligence quotient scores and disturbances in cognitive functions in
children with acute lymphocytic leukemia who were treated with radiation
to the brain.
Summary
The consequences of irradiation of the mammalian embryo and fetus
during the period of major organogenesis may include teratogenic effects
on various organs. In humans, mental retardation is the best documented
of the developmental abnormalities following radiation exposure. In the
Japanese atomic-bomb survivors who were irradiated in utero, the preva-
lence of radiation-related mental retardation was highest in those irradiated
between 8 and 15 weeks after conception, decreased in those irradiated
between 16 and 25 weeks, and was negligible or absent in those irradiated
before 8 weeks or later than 25 weeks. In those irradiated between weeks
8 and 15, the prevalence of mental retardation appeared to increase with
dose in a manner consistent with a linear, nonthreshold response, although
the data do not exclude a threshold in the range of 0.2-0.4 Gy.
OCR for page 363
OTHER SOMATIC AND FETAL EFFECTS
CATARACT OF THE EYE LENS
363
Radiation-induced opacification of the lens of the eye, or cataract
formation, has been observed to result from a dose of radiation to the lens
in excess of 0.6-1.S Gy, depending on the dose rate and the linear energy
transfer (LET) of the radiation, as well as on the sensitivity of the method
used to examine the lens (ICRP84~. The threshold for ophthalmologically
detectable opacities in atomic-bomb survivors has been estimated to range,
using T65 dosimetry, from 0.6 to 1.S Gy (Ot82), whereas the threshold in
persons treated with x rays to the eye has been observed to range from
about 2 Gy when the dose was received in a single exposure to more than
S Gy when the dose was received in multiple exposures over a period of
weeks (Me72, ICRP84~. The threshold for neutrons appears to be lower;
that is, in patients treated with 7.5 MeV neutrons in multiple exposures
over a period of 1 month, the threshold for a vision-impairing cataract
was estimated to approximate 3-5 Gy (Romp. By the same token, long-
continued occupational exposure to 0.7-1 Gy of mixed neutron-gamma
radiation has been observed to cause cataracts (Ha53, Lv74), whereas
similar occupational exposure to comparable doses of x rays or gamma rays
has not (ICRP84~.
Although it is clear from the foregoing that detectable injury of the lens
can result from a dose of as low as 1 Gy, depending on the dose rate and
LET of the radiation, the threshold for a vision-impairing cataract under
conditions of highly fractionated or protracted exposure is thought to be no
less than 8 Sv (ICRP84~. This dose exceeds the amount of radiation that can
be accumulated by the lens through occupational exposure to irradiation
under normal working conditions and greatly exceeds that which is likely
to be accumulated by a member of the general population through other
types of exposure.
LIFE SIIORTENING
In laboratory mammals exposed to whole-body radiation, life ex-
pectancy decreases with increasing dose. From early experiments with
rats and mice, the life-shortening eject of irradiation was interpreted as a
manifestation of accelerated aging (Ru39, He44, BrS2, A157, Camp. When
analyzed in relation to the cause of death, however, the effect was not
observed to be the same for all age-related diseases (Up60) but to result
principally from an accelerated onset of neoplasia (Warm.
Mortality from diseases other than cancer has not been consistently or
significantly increased by irradiation in human populations (Be78, UN82),
with the possible exception of an early cohort of U.S. radiologists (Wa56,
Wa66, Se58, Se65, Ma75a, Ma75b) in whom the confounding influence of
OCR for page 364
364 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION
other risk factors cannot be excluded. The bulb of the epidemiologic data
appear to be consistent, therefore, with the data from laboratory animals
(UNTO. Although the data do not support the view that radiation causes a
nonspecific acceleration of the aging process, the life-shortening effects of
a given dose in different species are similar when analyzed in terms of the
upward displacement of the age-specific death rate for the species (Sa66,
Sakes.
In the earlier literature, the mean survival time of animals exposed to
low-level, whole-body radiation was reported, in a few instances, to exceed
that of the controls. This phenomenon has since been interpreted by some
observers as evidence for the existence of a beneficial, or hermetic, effect of
small doses of radiation (Lu82, Hi83~. In each such experiment, however,
the survival of the nonirradiated controls was compromised by mortality
from intercurrent infection. Even if such an effect of low-level irradiation
were reproducible, which is uncertain, its biological significance and its
relevance to human populations living under contemporary conditions of
nutrition and sanitation are questionable (Sa62, UNTO.
Relatively low doses of ionizing radiation can produce certain other
types of effects which might be interpreted as beneficial (Sash. For
example, experimental studies have demonstrated prolongation of the life
span in arthropods and single-celled organisms under certain conditions.
Again however, the various types of molecular and cellular changes in
biological systems (e.g., alterations in cell proliferation kinetics, changes
in cell life cycle, induction of sterility, and other adaptive mechanisms)
through which radiation may produce the observed effects are of doubtful
relevance to the risks of radiation-induced mutagenic and carcinogenic
effects in human populations.
FERTILITY ANI) STERILITY
General Considerations
Depending on their degree of maturation and differentiation, the
germinal cells of the mammalian testis and ovary are highly radiosensitive
(Fa72, Hash.
The seminiferous epithelium of the testis maintains a steady state of
spermatogenesis throughout reproductive life, which involves the active
proliferation and differentiation of spermatogonial stem cells. Through this
process, the stem cells sequentially give rise to type A and type B sper-
matogonia spermatocytes, spermatids, and, ultimately, the functional end
cells, spermatozoa. In contrast, the female is born with a full complement
of maturing oocytes that no longer undergo cell division. On the contrary,
OCR for page 365
OTHER SOMATIC AND FETAL EFFECTS
365
the number of oocytes in the ovary decreases throughout adult life through
physiological attrition and, to a much lesser extent, ovulation.
Radiation damage to the reproductive cells of the mammalian testis or
ovary can impair fertility and fecundity. If the dose is high enough, sterility
may result; however, impairment of fertility requires a dose large enough
to damage or deplete most of the reproductive cells. If the number or
proportion of cells that are damaged remains sufficiently small, fertility is
not impaired. Thus, the effect is dose-dependent, with a threshold which
varies among species and individuals of differing susceptibility (ICRP84,
Upset.
Testis
The germ cells of the human testis may be highly radiosensitive, de-
pending on their degree of maturation (Fa72, Ha87~. Type A spermatogonia
appear to represent the most sensitive cell stage; later stages of spermiogen-
esis are highly radioresistant. Sufficient numbers of type A spermatogonia
are killed by 0.15 Gy of acute x-radiation to interrupt spermatozoa produc-
tion, leading to temporary infertility. After an x ray dose in excess of 3-5
Gy, whether delivered acutely or fractionated over a few days or weeks,
permanent sterility may result (UNTO. An x ray dose of 1.~-1.7 mGy/day
has been observed to be tolerated indefinitely by dogs, without detectable
effects on their sperm production (Ca68, Fe78, Fend. Under continuous
gamma-radiation exposure to 18 mGy/day, the testis of the mouse has been
observed to maintain spermatogenesis, similarly, albeit at reduced levels,
for as long as 16 weeks (Fame.
Ovary
In the human ovary, mature oocytes represent the most sensitive germ
cell stage, being killed in sufficient numbers by an acute exposure to 0.65-
1.5 Gy to impair fertility temporarily. In contrast, a dose of 6-20 Gy may
be tolerated by the ovaries if it is fractionated over a period of weeks
(Lu72, Lump. The threshold for permanent sterilization of the human
ovary decreases with increasing age (UN82, ICRP84, Upend.
Conclusions
The estimated threshold dose equivalent for induction of temporary
sterility in the adult human testis is 0.15 Sv; for permanent sterility it is 3.5
Sv when received as a single exposure. The corresponding threshold dose
equivalent for permanent sterility in the adult ovary is 2.5-6.0 Sv received
OCR for page 366
366 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MENTION
in a single exposure and 6.0 Sv when received In highly fractionated or
protracted exposures (ICRP84~.
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StS8
OCR for page 370
370 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
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UN82
UN86
Up60
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Wo67
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Representative terms from entire chapter:
ionizing radiation
