TERATOGEN UPDATE
Small Head Size After Atomic Irradiation 1 ROBERT W. MILLER
AND JOHN J. MULVIHILL Clinical Epidemiology Branch, National Cancer Institute, NZH, Bethesda, Maryland 20014
In 1920 reports began to appear about children born with small head circumference and who developed mental retardation, after therapeutic exposure of women to X-rays during pregnancy. These cases and others- total of 16 in the world literature-were reviewed by Goldstein and Murphy in 1929. By then it was known that these effects occurred only when radiation was given early in pregnancy. The information available had been obtained by retrospective study, as is usual in first identifying new human teratogens. A prospective study became possible when the atomic bombs were exploded over Hiroshima and Nagasaki in 1945. In 1952 Plummer described microcephaly and mental retardation in 7 of 11 Hiroshima children exposed within 1200 m of the hypocenter. Further studies revealed 4 more cases, excluding 2 with Down syndrome, and the effect was related to the distance from the hypocenter ke., dose) and to gestational age (Miller, '56). At intermediate dose-levels the effects were intermediate between normal and the pronounced effects seen in the heavily exposed, with no increase in the frequency of gross mental retardation. The last-mentioned evaluation was made when the children were 9 years old. The scientific design of the study was then improved, with observations limited to children who came for examination between 10 and 19 years of age. Some affected children seen earlier did not appear at the clinics during this interval, and were excluded from the analysis. Careful estimates of dose had been made (Milton and Shohoji, '681, and the new data showed small head size and mental retardation when exposure was at under 18 weeks of gestational age, the frequency of these TERATOLOGY, 14: 355-358
effects being related to the dose (Miller and Blot, '72; Blot and Miller, '73). In Hiroshima an increase in the frequency of small head circumference was detectable even when the dose in air to the pregnant woman was 10-19 rad. Her body screened out some of the radiation, so an even smaller dose reached the fetus. The doseresponse relation was dramatically shown in a chart published by Blot in 1975 (fig. 1). A new three-dimensional graphic portrayal of the Hiroshima data (fig. 2) shows the frequency of small head circumference with respect to dose and gestational age. It should be noted that each point is based on only a few observations (table 1). Again, the increased frequency of small head circumference is seen in the group whose maternal exposure was 10-19 rad. At higher doses susceptibility during gestation seemed to begin a little later and last somewhat longer. Figure 2 shows that the most pronounced effect was in the most heavily exposed group (150 rad or more). Among those with the lowest exposure, 0-9 rad, cases unaccountably occurred regardless of the gestational age at exposure. In Nagasaki no effect was demonstrable under 150 rad. The number of intrauterine exposures there, though substantially fewer than in Hiroshima, was ample to show an effect comparable to that in Hiroshima, had there been one. Similar differences between the cities have been observed with regard to other radiationinduced disorders. The differences may be attributable to the dissimilar quality of the radiation in the 2 cities (20% of that in Hiroshima was due to neutrons, as com'Reprint requests to: Robert W. Miller, A521 Landow Building, National Cancer Institute, Bethesda, Maryland 20014.
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356
ROBERT W. MILLER AND JOHN J. MULVIHILL TABLE 1
Frequency of small head circumference by dose and gestutionul age (Hiroshima) Dose (rad)
Gestational
age (weeks)
< 10
10-19
20-29
30-39
40-49
50-99
100-149
150+
0- 1 2-3 4-5 6-7 8-9 10-11 12-13 14-15 16-17 18-19 20-21 22-23 24-25 26-27 28-29 30-31 32-33 34-35 36-37 38+
012
-
011
-
-
111 118 117 216 1/11 013 018 0111 011 013 016 014 013 013 119 012 016 013 015 7/100
-
-
013 119 116 015 118 014 019 1/12 014 016 015 113 015 014 118 019 011 118 114 81115
011 011 013 113 113
Total
114 113 113 114 011 012 011 015 011 013
-
011 Of3 Of1 6/43
111 113 112
011
-
113 112 011
214 313 213 114 0/1 115 013
-
-
-
111
113
011
-
-
011
-
011
-
011
012
011 011
-
-
112 012 014 012
-
0/5 012
-
111
-
112
-
011 011 011 011
-
414 212 013 112 011
-
212
111 O/I
-
-
-
011 011 012
012
-
-
-
O/I
-
3/15
11/45
2/13
11/20
I__
014
011
4/15
-
114
O/I
011 111
-
Total
014 117 3/22 6/23 13/25 8/32 4/21 3/24 4/37 0110 3/18 2/17 1/16 0115 0112 2/23 0/18
0112 1/19 1111
521366
Fig. 1 Relation of dose to head circumference in Hiroshima children exposed in utero before the 18th week of gestation. Heads considered small were those with a circumference 2 or more standard deviations below the age- and sex-specific mean on at least 1 medical examination and 1or more standard deviations below average at all other examinations during the ages (10-19years) studied. (From Blot, '75.)
ATOMIC RAYS
357
Fig. 2 Relation of dose to head circumference and gestational age among Hiroshima children exposed in utero to the atomic bomb.
pared with a negligible percent in Nagasaki),or to an interaction in Hiroshima with other adverse influences on brain growth, such as malnutrition or severe illness during early life. LITERATURE CITED Blot, W. J. 1975 Growth and development following prenatal and childhood exposure to atomic radiation. J. Radiat. Res., 16 (Suppl.): 82-88. Blot, W. J., and R. W. Miller 1973 Mental retardation following in utero exposure to the atomic bombs of Hiroshima and Nagasaki. Radiology, 106: 617-619. Goldstein, L., and D. Murphy 1929 Etiology of illhealth in children born after maternal pelvic ir-
radiation. 11. Defective children born after postconception pelvic irradiation. Am. J. Roentgen., 22: 322-331. Miller, R. W. 1956 Delayed effects occurring within the first decade after exposure of young individuals to the Hiroshima atomic bomb. Pediatrics, 18: 1-17. Miller, R. W., and W. J. Blot 1972 Small head size following in utero exposure to atomic radiation. Lancet, 2: 784-787. Milton, R. C., and T. Shohoji 1968 Tentative 1965 radiation dose estimation for atomic bomb survivors, Hiroshima and Nagasaki. ABCC Tech. Report, pp. 1-68. Plummer, G. W. 1952 Anomalies occurring in children exposed in utero to the atomic bomb in Hiroshima. Pediatrics, 10: 687-692.
The Editors welcome contributions to “Teratogen Update.” Manuscripts should be sent to Lk.John L. Sever, Teratology Update Editor, Building 36, Room 50-04, National Institutes of Health, Bethesda, Maryland 20014. Articles should concisely summarize the clinical manifestations, etiology, pathogenesis, treatment, and prevention of the phenomena; and be accompanied by highquality photographs of affected individuals. Color illustrations will be at the author’s expense. Please address reprint requests to the author.