Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Special Susceptibility of the Child to Certain Radiation-induced Cancers
Robert W. Miller
Clinical Epidemiology Branch, National Cancer Institute, Bethesda, Maryland
Abstract
The carcinogenic effects of exposure to ionizing radiation vary markedly
with age, as revealed by studies of Japanese atomic bomb survivors and of
Marshall Islanders exposed to fallout from U.S. nuclear weapons tests in
the South Pacific in 1954. An increase in cancers of adulthood after intrauterine
exposure, as reported in 1988, has not been sustained. After childhood exposure,
increases in leukemia, breast cancer, and thyroid cancer are well established.
The carcinogenic effects of radiation on the young have been reported after
intrauterine exposures and after exposures during childhood. Cancers with
short latent periods such as leukemia occur during childhood, but those
with long latent periods such as breast cancer occur in adulthood. -- Environ
Health Perspect 103(Suppl 6):41-44 (1995)
Key words: radiation carcinogenesis, pediatrics, leukemogenesis,
breast cancer, thyroid cancer
This paper was presented at the symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1993 in Washington, DC.
This article is extracted and updated from DP Merke and
RW Miller. Age differences in the effects of ionizing radiation. In: Similarities
and Differences between Children and Adults. Implications for Risk Assessment
(Guzelian PS, Henry CJ, Olin SS, eds). Washington:ILSI Press, 1992;139-149.
Address correspondence to Dr. Robert W. Miller, Clinical
Epidemiology Branch, National Cancer Institute, EPN-400, Bethesda, MD 20892.
Telephone (301) 496-5785. Fax (301) 496-1854.
Intrauterine Exposures
Since 1956, Stewart and her associates (1) have published observations
on cancer during childhood after a maternal history of exposure to diagnostic
radiation during pregnancy [see, for example, Bithell and Stewart (2)].
Initially their observations were confirmed by a more objective study of
obstetric records in New England by MacMahon (3). Extension of his
findings, both geographically and in time, still showed a 1.5-fold excess
of childhood leukemia, but no longer showed any increase in the relative
risk of other childhood cancers (4). Other studies also failed to
show any increase, notably among the Japanese atomic bomb survivors exposed
in utero (5). In 1985, in an editorial in the New England
Journal of Medicine (6), MacMahon wrote, "It seems likely
that the question of the association between fetal irradiation and childhood
cancer will fade into medical history unresolved and remain a source of
more confusion than enlightenment."
An excess of cancer among the Japanese exposed in utero has been
reported in a study through 38 years of age (until 1984) (7). The
cancers are listed in Table 1, and a dose-response effect is shown in Figure
1. The authors concluded that further follow-up is needed, but the results
to date suggest "that susceptibility to radiation-induced cancers is
higher in pre- than in postnatally exposed . . . adults." It should
be noted, however, that the cancers in the several dose categories show
no greater frequency of types known to be induced by radiation in the heavily
exposed as compared with the lightly exposed or nonexposed. Of the six cancers
observed at 0.30+ Gy (gray, unit of absorbed dose of ionizing radiation),
three are not known to be induced by radiation exposure: histiocytosis,
liver cancer, and Wilms' tumor. Of the seven cancers in the 0.01 to 0.29
Gy dose-category, only choriocarcinoma has not been linked to radiation
exposure. In this group, there is as yet no breast cancer, the solid tumor
most easily induced by radiation. In the nonexposed, three of the five cancers
were breast cancers and the other two were uterine cancer, which has not
been related to radiation exposure. The group with intermediate exposures
(0.01-0.29 Gy) had the highest proportion of cancers known to be radiogenic.
From this perspective, the distribution of diagnoses by exposure category
does not yet reveal a dose-response effect.
Figure 1. Cumulative
hazard rate for cancer among survivors of intrauterine radiation in Hiroshima
and Nagasaki through 1984 for three exposure groups. From Yoshimoto et al.
(7).
In the 5 years that have passed since Yoshimoto et al. (7) published
their report, the excess has not been sustained (8). The fetus should
be susceptible to radiation carcinogenesis, and an excess of radiogenic
cancers may well occur in the next few years as cancer rates rise with further
aging. It is difficult to see, however, why exposure to ionizing radiation
late in gestation should be more carcinogenic than exposure in early childhood.
Childhood Exposures
Leukemia
The relationship of leukemia occurrence to age of exposure to ionizing
radiation has been well demonstrated (Figure 2) (5). Among survivors
exposed at under 15 years of age, the peak occurred 5 years after exposure
and was sharp. The leukemogenic effect disappeared at about 23 years after
exposure. In successively older cohorts, the effect occurred later and the
peak flattened.
Figure 2. Schematic
diagram of the leukemia frequency among atomic bomb survivors by age at
exposure, latent period, and city (Hiroshima, crosshatched; Nagasaki hatched).
ATB, at time of bomb. From Ichimaru et al. (5).
The distribution of cases by cell type, from 1950 to 1978, is shown in
Table 2. Although the numbers are small, it can be seen that chronic myelogenous
leukemia (CML) occurred in children, among whom it is usually rare, as well
as among adults. Acute myelogenous leukemia (AML) was rare when exposure
was under age 15 at the time of the bomb (ATB); acute lymphocytic leukemia
(ALL) was rare among those who were over 30 years ATB. Thus, the type of
leukemia induced by radiation was related to age at exposure, and, except
for CML, followed the distribution of leukemia by cell type in nonirradiated
populations. A more accurate evaluation has been made through a reanalysis
of leukemia cases through 1980 using the French-American-British classification
method and the most recent revision in dosimetry (DS-86), but the interpretation
of the age effect on cell type has not changed (9).
Breast Cancer
Among atomic bomb survivors exposed to 1+ Gy, age ATB has been found
to be a strong influence on the risk of breast cancer (10) (Figure
3). Risk was greatest among those under 15 years ATB and fell thereafter
until 39 years of age. Only a small increase occurred after age 40. The
latent period was at least 10 years, and the increase did not occur before
age 30, i.e., the usual age for developing breast cancer. By contrast, the
risk of leukemia increases within a few years after exposure, regardless
of age ATB.
Figure 3. Relative
risk of breast cancer by age at exposure to 1 or more Gy. From Tokunaga
et al. (10).
Thyroid Cancer
Studies of human populations exposed to radioisotopes of iodine have
not shown an increase in the frequency of thyroid cancer except in the Marshall
Islands. There, the population was exposed to both internal and external
irradiation fallout from a nuclear weapons test in 1954. The internal dose
was mostly from short-lived I-133 and I-135, and only about 10 to 20% came
from I-131 (11). Exposures elsewhere, as at Chernobyl, were originally
thought to be mainly due to I-131, which, at its lower dose-rate, is far
less damaging. An unpublished report of about 200 cases of childhood thyroid
cancer in Belarus since the accident may signal that other radioiodines
were involved.
The heaviest exposure to I-131 was in the Marshall Islands in 1954, where
fallout from a nuclear weapons test occurred. Sixty-four people on the island
of Rongelap received 10 to 50 Gy to the thyroid from radioiodines, plus
1.9 Gy whole-body exposure from external radiation. The 18 people on Ailingnae
received up to 13 Gy to the thyroid, plus 1.1 Gy of external radiation.
On Uterik 159 people received up to 6.7 Gy to the thyroid and 0.11 Gy from
external radiation (11,12). These doses were far greater than those
in Ukraine and Belarus.
Two of the nine children exposed on Rongelap at 1 year of age, when the
thyroid was small and its activity was great, developed myxedema and short
stature (Table 3). The remaining seven developed thyroid nodules. Although
hypofunction occurred in people who were older when exposed, none was of
the severity observed in the two who were exposed at 1 year of age (13).
The proportion with nodules diminished with age at exposure, and only one
person exposed at over 10 years of age was affected. Carcinoma developed
in five of 24 persons exposed at 5 to 29 years of age. In all of the people
exposed on Rongelap, 21 of 54 developed these disorders. Figure 4 shows
the difference in the frequency of nodules or cancer among those on Rongelap
or Ailingnae under 10 years of age as compared with those who were older
at exposure.
Figure 4. Development
of thyroid nodules or carcinoma among Marshallese exposed on Rongelap or
Ailingae, exposure under age 15 compared with 15+. Data from Lessard et
al. (11). Age <10 at exposure (n=28); age >10 at exposure
(n=54). p<0.001.
Thyroid nodules and carcinoma were not diagnosed until 10 years after
exposure, which implies a latent period of this duration regardless of age
at exposure. This latent period is the time from exposure to clinical detection;
the latent period between exposure and thyroid dysfunction may be shorter
(12).
From these data, it is clear that exposure to fallout from a nuclear
weapons test caused effects on the thyroid that were frequent, severe, and
age-related. The dose-estimates, based on age, indicate an increased uptake
of iodine by smaller thyroid glands, resulting in larger doses among the
young.
Research Needs
There are two main needs. The data from those exposed to the atomic bombs
in Japan in utero or during childhood have provided the best data
available on carcinogenic effects from external radiation exposure. This
information, over a wide spectrum of doses, is the basis for national and
international standards for radiation protection. The children who were
in utero or under 10 years of age ATB will be 50 to 60 years old
in 1995. Cancer rates mount rapidly with each passing year. The collection
of incidence data on cancer, far more reliable than death-certificate data,
is about to reveal the full magnitude and the mechanisms of radiation carcinogenesis
in the most cancer-prone age range. The United States and Japan provide
equal funding for these studies. Data collection is in peril due to impending
deep U.S. budget cuts. Influential persons in and out of government must
be enlisted to prevent the collapse of these studies.
The second need is for the training of a few pediatricians in the late
effects of ionizing radiation. Those who were trained in about 1950 are
reaching the end of their careers and, with regard to experts on pediatric
exposures, there are no replacements in sight. An intimate knowledge of
pediatric cancer and of radiation effects is required. The obvious place
to look is in academic pediatrics, possibly pediatric radiology, where a
few young physicians might focus on radiation effects in addition to their
principal interest. The training could be sponsored by a foundation or government
agency as it was in 1950.
Conclusions
Ample data are available for studies of age differences in radiation
effects, based on external exposures among Japanese atomic-bomb survivors
and high thyroid doses among Marshallese exposed to fallout. The increase
in cancer occurrence reported among the in utero-exposed group is
still tentative. As yet, these individuals show no evidence that their risk
of cancer is greater than that of persons who were older when exposed. There
is, however, clear evidence that susceptibility to certain cancers is greater
among those with childhood exposure than among those exposed later in life.
Susceptibility to leukemia was greater and the cell-type distribution was
different among those under 20 years of age than among persons who were
older ATB. The peak leukemia incidence occurred 5 years after exposure.
Age-related host susceptibility apparently affects the frequency and type
of leukemia induced by radiation.
The risk of breast cancer also is highest among those exposed under 20
years of age. Only a small increase was observed among those who were exposed
at 40+ years of age. Breast cancer did not develop among persons exposed
as children or adolescents until they reached the usual age for breast cancer,
in contrast to leukemia, for which the latent period at all ages is similar.
Breast cancer requires aging and is apparently related to hormone status
at exposure and when the neoplasm develops.
Benign thyroid neoplasia from radioiodine fallout on the Marshall Islands
was related to the rate of iodine uptake by the thyroid, which is greatest
early in life. Thus, age is correlated with dose. The excessive occurrence
of thyroid carcinoma among those exposed at 5 to 29 years of age indicates
that something in addition to dose influences malignant transformation.
Radiation effects have been studied over a wide range of age and dose,
more so than other environmental exposures. The marked influence of age
on the frequency of radiation effects is related to fetal or postnatal development.
The diversity of the age relationships indicates that a variety of mechanisms
is involved.
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