EFFECTS
OF
IONIZING
RADIATION
FROM
THE
ATOMIC
BOMB
ON
JAPANESE
CHILDREN
Robert W. Miller, M.D.
NC!, National Cancer Institute, NIH, Bethesda, Maryland
TABLE I
S
INCE 1948 the Atomic Bomb CasualtyCommission (ABCC) has been
study-ing the delayed effects of ionizing
radia-tion on the atomic-bomb survivors in
Hiro-shima and Nagasaki and on their
prog-eny. In the two cities a large number of
people were exposed to a wide range of
ex-ternal radiation dosage, but to virtually
none from fallout.’ It is the purpose of this
presentation to summarize the ABCC
re-ports to date of radiation effects on children
which may have been induced before
con-ception, during intra-uterine life, or during
childhood.
GENETIC EFFECTS
Laboratory experimentation leaves no
doubt that radiation causes mutations. A
major task of the ABCC was to determine if
genetic damage was apparent in the
chil-dren conceived after their parents had been
exposed to the atomic bomb. The outcome
of pregnancies which occurred in
Hiroshi-ma and Nagasaki between 1948 and 1953
was determined by follow-up study of
71,280 subjects ascertained during
pregnan-cy (93% of all pregnancies which went to
term in that interval) P2,3 The liveborn
in-fants were examined soon after birth, and
40% were re-examined at 8 to 10 months of
age. Six indicators of genetic damage have
been evaluated with cognizance taken of
the minimal effect which the study
proba-bly would have detected. The data were
distributed according to five levels of
radia-tion exposure for each parent. The results
pertaining to the several indicators are
summarized in Table I. Five showed no
re-lationship to parental radiation exposure.
The sixth, the sex ratio (males/females),
revealed a small shift of uncertain
sig-nificance in the decade following the
bomb. The shift was in the direction
antici-pated on the basis of genetic theory
(in-crease in sex ratio if the father only was
ex-posed; decrease if the mother only was
exposed
)
.“ The composite results thus farindicate that genetic effects were not great
enough to be revealed under the conditions
of the investigation. A panel of experts in
genetics has advised the ABCC against
study of the second generation because of
difficulties in following the sample, and
be-cause of the low probability of finding an
effect.
CONGENITAL MALFORMATIONS DUE TO
INTRA-UTERINE RADIATION EXPOSURE
In the early 1920’s there were at least 14
cases reported of microcephaly in children
born of mothers with pelvic disease treated
during pregnancy with x-ray (cited by
INDICATORS OF TIlE GENETIC EFFErS OF RADIATION
Indicator
(:otgeiiital malformations
Stillbirths and neonatal deaths Birth weight
Anthropoiiietric values at 8-10 months Sex ratio
Cl,ildhood (F,) mortality
*90% prol)abihty.
Result
Increase, if any, less than twofold*3
Increase, if any, lessthan one and eight tenthsfold*3
RADIOACTIVITY IN THE INDIVIDUAL
TABLE II
HAUl ATION EFFECT ON HEAD CIHCUM FERENCE AND INTELLIGENCE AMONG (‘ii ILI)IIEN ExPOSF:l) TO TIlE
hililoslIlMA ATOMIC Bosia BETWEEN TIlE SEVENTH AND FIFTEENTH \\EEK OF INTIIA-UTE1IINE LIFE”
Distance from Ifypocenter (Meters)
head ___________________ _____________
Intelligence - ____________________ ______________
(‘ircuinferenee <1,200 1,2oJ-1,r(N) l,;501-1,X(MI 1,01-2,2(k)
-3 5.1). or worse Retarded 8 4 1 0
- to -3 SI). Nornial 0 6 4 0
Nornial Normal 0 12 11 19
NnInher Exposed 8 22 18* 19
* Iwo tot exalllineol.
Murthv).’ An additional 16 cases were
de-scribed the following year by Goldstein and
Murphy.s It was to be expected, then, that
microcephaly would be found among
chil-dren exposed in utero to the atomic bombs
in Japan, and, indeed, in Hiroshima there
were 15 such children.#{176}” Thirteen of them
were born of mothers who last menstruated
7 to 15 weeks before the bomb.” This
ob-servation sharply localized the gestational
age of greatest susceptibility. The frequency
of microcephaly diminished as the distance
from the hvpocenter increased (Table II).
The head circumference in those cases
ob-served who were 1,200 meters or less from
the hypocenter was three or more standard
deviations below the average for age and
sex, and the children were mentally
re-tarded. In the intermediate distance groups
(1,201 to 1,800 meters) there were 10
chil-dren with transitional head circumferences
-two to three standard deviations below
the average for age and sex-and normal
intelligence. The number of women
ex-posed during pregnancy to the Nagasaki
atomic bomb was too small to show a
com-parable effect, but the results obtained
were consistent with those observed in
Hiroshima.” The findings among the
atomic-bomb survivors showed a response
which was proportionate to the dose and
was in accord with the results of animal
experimentation and clinical observations
on the effects of pelvic radiotherapy early
in pregnancy. No other malformation
oc-curred more than once among the groups
exposed during intra-uterine life to the
atomic bombs. A re-examination of the
chil-dren exposed ill
utero
to the Iliroshimabomb was made when they were 17 years
of age. The results do not alter the
interpre-tation of the observations made previously.’4
FETAL AND INFANT MORTALITY
FOLLOWING INTRA-UTERINE
RADIATION EXPOSURE
In a retrospective study 6 years after the
event, evaluation was made of the effect of
the Nagasaki bomb on pregnancies in
prog-ress at the time of exposure.” The study
related the outcome of pregnancy to major
signs of acute radiation injury (epilation,
oropharyngeal lesions, purpura and
pete-chiae) suffered by the mother. The
re-sults are shown in part in Table III. Among
women who were within 2,000 meters of
the hypocenter, the rate for fetal or infant
loss was much higher if the mother had one
or more major signs of acute radiation
inju-ry than if she had none (43.3% versus
8.8%). The difference is statistically
sig-nificant at the 0.1% level (y’ = 12.03).
The results for the women without major
radiation signs were similar to those for
women who were minimally, if at all,
ex-posed at 4,000 to 5,000 meters from the
hy-pocenter. It is possible that the data in
Table III are influenced to some extent by
factors other than radiation, such as blast or
* One or more of the following: epilation, oropharyngeal lesions, purpura, or petechiae.
t Differs significantly from value for group <‘2,000 meters without radiation signs: p< .001.
GROWTH
In 1951, as part of a comprehensive
med-ical examination, 12 anthropometric deter-minations were obtained on about 2,400
Hiroshima children 6 to 19 years of age
who were exposed to the bomb 6 years
ear-her, and comparison was made with an
equal number who were not exposed.
About 78% of the sample was re-examined
in 1952 and 53% in 1953.’ Multivariate
analysis revealed that as radiation exposure
increased there were small but statistically
significant decreases in body measurements
at all age levels and in growth rate at
post-pubertal age levels.16 To some extent these
differences may be due to variables other
than radiation exposure. For example, the
closer the family property was to the
hypo-center, the greater was the damage with its
consequent effect on socioeconomic status
towhich nutrition and growth are related.
Nagasaki adolescents who were exposed
in utero to the atomic bomb have been
studied with respect to the mean values for
several anthropometric variables.” The
sample of heavily exposed subjects was
small. Only 16 boys and 15 girls were
esti-mated to have received 50 rads or more,
and only 9 of these were exposed in the first
trimester. Some significant differences were
found which were consistent with a
radia-tion effect.
CANCER
From the observations made by the
Atomic Bomb Casualty Commission, there
is no doubt that radiation in sufficient dose
can induce leukemia in man.” The effect
is proportionate to the dose, is
consis-tent with the results from animal
experi-mentation, and can be attributed to no
known variable except radiation. The most
recent data on leukemia published from
ABCC concerns the average incidence of
confirmed cases, 1947-1958, in residents of
Hiroshima and Nagasaki.18 These data
mdi-cate that the leukemogenic effect of
radia-tion was greater in children exposed to the
bomb than in older persons. Among those
under 10 years of age, the leukemia rate
was 26 times higher if exposure was within
1,500 meters of the hypocenter than when it
was beyond that distance. In the next
age-group, 10 to 19 years of age at the time of
exposure, the corresponding increase was
eighteenfold.
Twenty cases of leukemia developed
among children within 1,500 meters of the
hypocenter who were exposed before their
tenth birthday. The cell types were as
fol-lows: eight acute lymphocytic, three acute
granulocytic, five chronic granulocytic, and
four other or unspecified. Acute
lympho-cytic leukemia occurred only among those
within 1,500 meters exposed before 20 years
of age. Thus, the type of leukemia induced
by radiation is variable and depends to
some extent on the age of the host. One
major form, chronic lymphocytic leukemia,
is apparently not induced by radiation at
all ‘‘#{176}
TABLE III
It has been reported that diagnostic x-ray
FETAL AND INFANT MOIITALITY FOLLOWING INTRAUTERINE ExeosultE TO THE NAGASAKI ATOMIC BOMB”
<‘2,0(8) with, major radiation
signs* 30 3 4 3 3 13 43.3t
<‘2,000 without major radiation
signs* 68 1 ‘2 3 0 6 8.8
.lge (yr)
PIIEvALENCE OF VISUAL ACUITY Loss WITH SNELLEN SCORE OF ‘20/70 ORW’oHsE IN ATLEAST ONE EYE, NOT DUE
TO OuGs.xIc DISEASE, AMONG HIROSHIMA ChILDREN (9-19 YEARs OLD) EXAMINED IN 195411
J94,5*
Distance from hlypocenter (Meters)
19;5., .\‘u mber Exauiined
1,500 and Under I 1,501-1,800 Over 1,800
0-2t
3-6
7-10
8-Il
1’2-15
16-19
437
491
171
With Vision Loss
___________________ A umber Examined
Aumber %
‘2’2 5.0 981
39 8.6 906
35 ‘21.1 361
JJ’ith J lemon Los,s
Number
33 4.0
74 8.’2
33 9.1
* At time of bomb.
t Includes cl,ildren who were exposed in utero.
1)iffers significantly from group over 1,800 meters, P< .05. §Differs significantly from group over 1,800 meters. P <.001.
exposure of the abdomen during pregnancy
increases the risk of leukemia in the child
by 44 to 92%.50,21 In Hiroshima 98 children were exposed
in
utero to heavy doses ofradiation (within 1,500 meters of the
hypo-center). A recent study by Wood, Johnson,
and Omori” has revealed that in the 20
years after exposure, none of the seven
deaths that occurred in the group was
at-tributed to leukemia. In a sample of 98
per-sons observed over two decades, the
ex-pected number of leukemia cases is close to
zero.
From a retrospective study, Graham and
his associates” have reported that
expo-sures of mothers or fathers to diagnostic
x-ray before conception of their children can
increase the risk of childhood leukemia by
30 to 100%. Results obtained at ABCC,
however, cast doubt on this relationship.
Hoshino, Itoga, and Kato” found that
much heavier doses of preconception
radia-tion, in a sample of 17,700 children whose
parents were exposed within 2,000 meters
of the bomb, have produced no excess of
leukemia as compared with the experience
of similar children whose parents were
ei-ther lightly or not at all exposed to the
atomic bomb.
The only cancer other than leukemia
which has occurred in excess of normal
ex-pectation among those exposed to the
atomic bomb was thyroid carcinoma, which
has been reported’4 to be significantly more
prevalent than usual among heavily
ex-posed survivors of all ages. Twenty-one
cases were found in adults between 1958
and 1961. Five of these survivors had been
exposed to the bomb as children between
the ages of 6 and 16 years.
SPECIAL SENSES
Radiation cataracts have occurred in a
few adults exposed to the atomic bombs,”
but have not been observed in children.11
An excessive impairment of visual acuity,
seemingly due to refractive error, was
ob-served among about 4,400 children 8 to 19
years of age who were screened with the
Snellen chart in Hiroshima in 1954. It was
found that children who had been exposed
within 1,800 meters of the hypocenter at 7
to 10 years of age (16 to 19 years old at the
time of examination) had twice the
fre-quency of visual acuity of 20/70 or worse
in at least one eye as compared with
chil-dren who were beyond 1,800 meters (Table
IV). The finding has not been verified as
yet, but its reality is supported by animal
experimentation; visual acuity loss has
oc-curred among monkeys whose heads were
heavily exposed to xirradiation.26 No effect
TABLE IV
With Vision Loss
_____________________ Aumber Examined
\ umber %
31 7,1 441
4’2 8.6 451
TABLE V
OBSERVED AND EXPECTED DEATHS (DEATH-CERTIFICATE DIAGNOSIS) FROM ALL CAUSES
ExcEP’r TRAUMA AMONG THOSE EXPOSED TO THE ATOMIC BOMB UNDER ‘20 YEARS OF AGE,
BY DISTANCE FROM HYPOCENTEB AND CITY, 1950_196029
Age at Death (1ears)
Distance from Ilypoeenter (Meters)
1,00+
-hhiro,s’hima Nagasaki Total Ihirosh ima Nagasaki Total
59 Observed Expected
10-19 Observed
Expected
5+ (3)t
1.4
3+ (3)
4.4
0+ (‘2) 0.5
4+ (4)
4.7
5+ (5)
1.9
7+ (7) 9,1
6+ (‘2) 3+ (0) 9+ (‘2)
1’2.4 4.1 16.5
40+ (0) 47+ (0) 87+ (0)
39.3 41 .1 80.4
* No data available fordeaths under 5 years ofage.
t Numbers of leukemia deaths given parenthetically.’0
on vision was observed in younger children,
3 to 6 years of age at the time of the bomb
(
12 to 15 years old at the time ofexamina-tion in 1954
)
. It would be of interest tode-termine if this group developed increased
rates for vision loss during adolescence
(
now past)
comparable to those of theolder group.
The visual acuity loss already observed
suggests a subtle radiation effect which can
be much more easily studied in man than in
experimental animals. Other subtle effects
of radiation
(
for example, on hearing orin-telligence
)
have not yet been described.OTHER MORBIDITY
Routine medical examination has
re-vealed no diseases other than those
men-tioned here in excess of normal expectation
among Hiroshima children exposed to the
atomic bomb.”4” The possibility has
been raised that survivors handle infection
less effectively than usual. Dr. M. Hachiya,
Director of the Communications Hospital
in Hiroshima, has the clinical impression
that heavily exposed children developed
less of a leukocytosis than usual in response
to such severe infections as appendicitis or
meningitis. Experimental challenges to test
the physiologic reserve of survivors
gener-ally are not feasible. It would be of interest,
however, to study in cell culture the
immu-nological competence of leukocytes from
survivors.
CHILDHOOD MORTALITY
Animal experimentation has shown that
ionizing radiation can induce a shortening
of life span which is attributed to no
specific disease but to an accelerated
occur-rence of disease in 28 The ABCC
has conducted a study of life span among
the survivors of the atomic bombs. An
anal-ysis has been made of deaths in Hiroshima
and Nagasaki, 1950-1960, in a sample of
99,393 persons-survivors of all ages and a
similar group which was not exposed to the
bomb.’9 The number of deaths within 1,400
meters of the hypocenter among children 5
to 19 years of age is shown in Table V. Of
the 24 who died in this age group, there
were 12 with a death-certificate diagnosis
of leukemia.#{176} No conclusions can be drawn
about excessive mortality from other
dis-eases from the remaining 12.
CONCLUSION
The total number of delayed organic
effects of atomic irradiation among
Japa-nese children has been small. The most
prevalent late effect, difficult to document,
unfortu-262
nate circumstance in view of the small risk
indicated by the results to date.
REFERENCES
1. Arakawa, E. T. : Residual radiation in Hiro-shima and Nagasaki. Atomic Bomb Casual-ty Commission Technical Repo.t 02-62. Ihiroshimo, l1l)aI : 1962.
2. Ned, J. V., and Schull, W. J.: The Effect of Exposure to the Atomic Bombs on Preg-nancy Termination in Hiroshima and Naga-saki. Washington, D.C. : National Acad-en,\’ of Sciences-National Research Coun-cii. Publication No. 461, 1956.
3. Ned, j. V., and Schull, W. J.: Genetic effects of the atomic bombs: rejoinder to Dr. de Bellcfeuille. Acta Radiol., 58:385, 1962. 4. Ned, J. V. : Changing Perspectives on the
Genetic Effects of Radiation. Springfield, Illinois: Charles C Thomas, 1963. 5. Schull, \V. J., Neel, J. V., and Hashizume,
A.: Some further observations on the sex ratio among infants born to survivors of the atomic bombings of Hiroshima and Naga-saki. Amer. J. Hum. Genet., 18:328, 1966. 6. Kato, H., Schull, W. J., and Neel, J. V. : A
cohort-type study of survival in the chil-dren of parents exposed to atomic bomb-ings. Amer. J. Hum. Genet., 18:339, 1966. 7. Murphy, D. P. : Ovarian irradiation; its effect
on the health of subsequent children:
re-view of the literature, experimental and clinical, with a report of 320 human preg-nancies. Surg. Gynec. Obstet., 47:201, 1928.
8. Goldstein, L., and Murphy, D. P.: Etiology of the ill-health in children born after ma-ternal pelvic irradiation. Part II. Defective children born after posteonception pelvic irradiation. Amer. J. Roentgen., 22:322, 1929.
9. Plummer, G.: Anomalies occurring in chil-dren exposed in utero to the atomic bomb in Hiroshima. PEDIATRICS, 10:687, 1952. 10. Sutow, \V. W.: Summary of studies on
chil-dren exposed in utero to the atomic bomb in Hiroshima City. Atomic Bomb Casualty
Commission Technical Report, May 10, 1954.
11. Miller, R. XV.: Delayed effects occurring within the first decade after exposure of young individuals to the Hiroshima atomic
bomb. PEDIATRICS, 18:1, 1956.
12. Yamazaki, J.N., Wright, S. W., and Wright, P. el.: Outcome of pregnancy in women exposed to the atomic bomb in Nagasaki. Amer. j. Dis. Child., 87:448, 1954. 13. Burrow, C. N., Hamilton, H. B., and Hrubec,
Z.: Study of adolescents exposed in utero
to the atomic bomb, Nagasaki, Japan. II. Growth and development. J.A.M.A., 192: 357, 1965.
14. Wood, J. W., Johnson, K. C., and Omori, Y.: In utero exposure to the Hiroshima atoniic bomb; an evaluation of head size and men-tat retardation : twenty years later.
PEDI-ATRICS, 39:385, 1967.
15. Reynolds, E. L. : Growth and development of Hiroshima children exposed to the atomic bomb. Three year study (1951-195.3). Atomic Bomb Casualty Commission, Tech-nical Report 20-59, 1954.
16. Nehemias, J. V. : Multivariate analysis and the IBM 704 Computer applied to ABCC data on growth of surviving Hiroshima children. Health Phvs., 8:165, 1962. 17. Folley, J. H., Borges, W., and Yamawaki, T.:
Incidence of leukemia in survivors of the atomic bomb in Hiroshima and Nagasaki, Japan. Amer. J. Med., 13:311, 1952.
18. Brill, A. B., Tomonaga, M., and Heyssel, R. M. : Leukemia in man following expo-sure to ionizing radiation. A summary of the findings in Hiroshima and Nagasaki, and a comparison with other human ex-perience. Ann. mt. Med., 56:590, 1962. 19. Court Brown, W. M., and Doll, R. :
Mortal-ity from cancer and other causes after radiotherapy for ankylosing spondylitis. Brit. Med. J., 2:1.327, 1965.
20. Stewart, A., Webb, J., and Hewitt, D. : Sur-vey of childhood malignancies. Brit. Med.
J., 1:1495, 1958.
21. MacMahon, B. : Prenatal x-ray exposure and childhood cancer. J. Nat. Cancer Inst., 28: 1173, 1962.
22. Graham, S., Levin, M. L., Lilienfeld, A. M., Schuman, L. M., Gibson, R., Dowd, J. E., and Hempelmann, L.: Preconception, in-trauterine and postnatal radiation as re-lated to leukemia. Nat. Cancer Inst., Monogr. 19, 347-371, 1966.
23. Hoshino, T., Itoga, T., and Kato, H.: Leu-kemia in the offspring of the parents ex-posed to the atomic bomb at Hiroshima and Nagasaki. Preliminary report. Pre-sented at meeting of the Japanese Associ-ation of Hematology, March 28-30, 1965. 24. Socolow, E. L., Hashizume, A., Neriishi, S.,
and Niitani, B.: Thyroid cancinoma in man after exposure to ionizing radiation. A sum-mary of the findings in Hiroshima and Nagasaki. New Eng. J. Med., 268:406, 1963.
26. McDowell, A., and Brown, W.: Visual acuity performance of normal and chronic focal-head irradiated monkeys. J. Genet.
Psy-chol., 96:139, 1960.
27. Burrow, G. N., Hamilton, H. B., and Hrubec, Z.: Study of adolescents exposed in utero to the atomic bomb, Nagasaki, Japan. I. General aspects: clinical and laboratory data. Yale J. Biol. Med., 36:430, 1964.
28. Storer, J. B.: Radiation resistance with age in normal and irradiated populations of mice. Radiation Res., 25:435, 1965. 29. Jablon, S., Ishida, M., and Yamasaki, M.:
Studies of the mortality of A-bomb stir-vivors. 3. Description of the sample and mortality, 1950-1960. Radiation Res., 25: 25, 1965.
30. Jablon, S.: Unpublished data.
DISCUSSION
DR. YAMAZAKI: Our next speaker is Dr.
\Vataru Sutow. I note that participants are
here from most of the studies that have
been done on effects on human beings or ionizing radiation. When, because of
me-teorological conditions, the bomb in the
Bikini area released fallout over the
Mar-shall Islands, the response of the people in
authority was immediate. The Navy and
Brookhaven National Laboratory group
within a matter of hours was mobilized.
They were airborne promptly and Dr.
Rob-ert Conard and his associates have followed
this group of people for 10 years. Dr. Sutow
was with this team and still is.
Dn. SuTow: Following the experimental
detonation of a high-yield thermonuclear
device at Bikini in the Pacific Proving
Grounds on March 1, 1954, radioactive
fall-out accidentally occurred on three inhabited
atolls of the Marshall Islands 100 to 200
miles east of Bikini. Eighteen people on
Ailingnae were exposed to 69 rads
estimat-ed whole body gamma radiation. Sixty-four
natives on Rongelap received an estimated
gamma dose of 175 rads, and 157
inhabi-tants of Utirik, 200 nautical miles away
from the explosion received about 14 rads.
In addition, the people of Ailingnae and
Rongelap were subjected to beta
irrradia-tion of the skin surfaces and to radiation
from internal deposition of detectable
amounts of radionuclides.’ All inhabitants
of these atolls were evacuated within 2
days. Utirik was considered habitable and
its people were returned to the atoll
im-mediately. Rongelap, however, was not
cleared for habitation until June 1957.
When the people were eventually
repatriat-ed they were accompanied by a large group
of relatives and former Rongelap residents.
These unexposed people have served as the
comparison population for the medical
studies. A brief summary of the positive
findings of the regularly conducted surveys
of these Marshall Island people over tile
past 11 years will be presented. These
corn-ments will be limited to the results of
cx-aminations of those who were under the
age of 20 years at the time of exposure and
whose exposures occurred on Ailingnae or
Rongelap.
Seven children were exposed on
Ailing-nae and 31 Rongelap, a total of 38. In
addi-tion, four children were exposed
in
utero atgestational ages between 40 and 180 days.
Skin lesions and leukopenia occurred in
almost all these children. About 70% had
variable degrees of epilation. The
leuko-penia and thrombocytopenia showed
al-most complete recovery by 1 year after
cx-posure; but thereafter, over a period of 10
years post exposure, the average values
have remained slightly below those of the
comparison population.’
These studies also have demonstrated a
retardation of statural growth and osseous
development among boys exposed at ages 1
through 5 years, as compared to the
com-parison population. This retardation was
most marked among those who were less
than 18 months of age at exposure.3 The
physiologic mechanism for this delay in
stat-ural and skeletal development has not
been explained, although recent findings
suggest that hypothyroidism may be
impli-cated.4
In 1963, 9 years after exposure, the
de-velopment of a thyroid nodule was first
