Also see:
Inflammation from Radiation
Radiation Increases Breast Cancer Incidence
Maternal Ingestion of Tryptophan and Cancer Risk in Female Offspring
Nutrition and Brain Growth in Chick Embryos
Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring
PUFA, Estrogen, Obesity and Early Onset of Puberty
Fukushima Fallout Damaged the Thyroids of California Babies
We Are Giving Ourselves Cancer

Radiat Res. 1998 Sep;150(3):330-48.
Mortality in beagles irradiated during prenatal and postnatal development. II. Contribution of benign and malignant neoplasia.
Benjamin SA, Lee AC, Angleton GM, Saunders WJ, Keefe TJ, Mallinckrodt CH.
To evaluate the lifetime carcinogenic hazards of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days postcoitus or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, neoplasia was a major disease, contributing to mortality in 40% of the dogs. There was a significant increase in benign and malignant neoplasms occurring in young dogs (<4 years old), including fatal malignancies, after irradiation in the perinatal (late fetal and neonatal) periods. The lifetime incidence of fatal neoplasms was also increased in dogs irradiated perinatally. Three malignancies-lymphomas, hemangiosarcomas and mammary carcinomas-accounted for 51% of all fatal tumors. There was an apparent lifetime increase and earlier onset of lymphomas in dogs exposed as fetuses. Fatal hemangiosarcomas were increased in dogs irradiated early and late in gestation. Fatal mammary carcinomas were not increased by irradiation, although non-fatal carcinomas were increased after perinatal exposure. Myeloproliferative disorders and central nervous system astrocytomas appeared to be increased in perinatally irradiated dogs. These data suggest that irradiation in both the fetal and neonatal periods is associated with increased early onset and lifetime cancer risk.

Health Phys. 1988 Aug;55(2):295-8.
Intrauterine radiation exposures and mental retardation.
Miller RW.
Small head size and mental retardation have been known as effects of intrauterine exposure to ionizing radiation since the 1920s. In the 1950s, studies of Japanese atomic-bomb survivors revealed that at 4-17 wk of gestation, the greater the dose, the smaller the brain (and head size), and that beginning at 0.5 Gy (50 rad) in Hiroshima, mental retardation increased in frequency with increasing dose. No other excess of birth defects was observed. Otake and Schull (1984) pointed out that the period of susceptibility to mental retardation coincided with that for proliferation and migration of neuronal elements from near the cerebral ventricles to the cortex. Mental retardation could be the result of interference with this process. Their analysis indicated that exposures at 8-15 wk to 0.01-0.02 Gy (1-2 rad) doubled the frequency of severe mental retardation. This estimate was based on small numbers of mentally retarded atomic-bomb survivors. Although nuclear accidents have occurred recently, new cases will hopefully be too rare to provide further information about the risk of mental retardation. It may be possible, however, to learn about lesser impairment. New psychometric tests may be helpful in detecting subtle deficits in intelligence or neurodevelopmental function. One such test is PEERAMID, which is being used in schools to identify learning disabilities due, for example, to deficits in attention, short- or long-term memory, or in sequencing information. This and other tests could be applied in evaluating survivors of intrauterine exposure to various doses of ionizing radiation. The results could change our understanding of the safety of low-dose exposures.

Br J Radiol. 1984 May;57(677):409-14.
In utero exposure to A-bomb radiation and mental retardation; a reassessment.
Otake M, Schull WJ.
The prevalence of mental retardation in children exposed in utero to the atomic bombs in Hiroshima and Nagasaki has been re-evaluated in reference to gestational age and tissue dose in the fetus. There was no risk at 0-8 weeks post-conception. The highest risk of forebrain damage occurred at 8-15 weeks of gestational age, the time when the most rapid proliferation of neuronal elements and when most, if not all, neuroblast migration to the cerebral cortex from the proliferative zones is occurring. Overall, the risk is five or more times greater in these weeks than in subsequent ones. In the critical period, damage expressed as the frequency of subsequent mental retardation appears to be linearly related to the dose received by the fetus. A linear model is not equally applicable to radiation-related mental retardation after the 15th week, the observed values suggesting that there a threshold may exist. The data are consistent with a probability of occurrence of mental retardation of 0.40% per cGy or 40% per gray.

J Radiat Res. 1991 Mar;32 Suppl:249-64.
A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Brain damage among the prenatally exposed.
Otake M, Schull WJ, Yoshimaru H.
Significant effects on the developing brain of exposure to ionizing radiation are seen among those individuals exposed in the 8th through the 25th week after fertilization. These effects, particularly in the most sensitive period, 8-15 weeks after fertilization, manifest themselves as an increased frequency of severe mental retardation (SMR), a diminution in IQ score and in school performance, and an increase in the occurrence of seizures. Of 30 SMR cases, 18 (60%) had small heads. About 10% of the individuals with small head sizes observed among the in utero clinical sample were mentally retarded. When all of the cases of mental retardation are included in the analysis, a linear dose-response model fits the data adequately and no evidence of a threshold emerges; however, if the two probable nonradiation-related cases of Down’s syndrome are excluded from the 19 SMR cases exposed 8-15 weeks after fertilization, the evidence of a threshold is stronger. The 95% lower bound of the threshold based on the new dosimetry system appears to be in the range of 0.12-0.23 Gy. In the 16-25 week period, the 95% lower bound of the threshold is 0.21 Gy both with and without inclusion of two probable nonradiation-related retarded cases. In a regression analysis of IQ scores and school performance data, a greater linearity is suggested with the new dosimetry (DS86) than with the old (T65DR), but the mean IQ score and the mean school performance of those exposed in utero to doses under 0.10 Gy are similar, and not statistically different from the means in the control group. The risk ratios for unprovoked seizures, following exposure during the 8th through the 15th week after fertilization, are 4.4 (90% confidence interval: 0.5-40.9) after 0.10-0.49 Gy and 24.9 (4.1-191.6) after 0.50 Gy or more when the mentally retarded are included and 4.4 (0.5-40.9) and 14.5 (0.4-199.6), respectively, when they are excluded.

Nihon Eiseigaku Zasshi. 1991 Aug;46(3):747-54.
[Effect on school performance of prenatal exposure to the Hiroshima atomic bomb].
[Article in Japanese]
Yoshimaru H, Otake M, Fujikoshi Y, Schull WJ.
As a part of the continuing assessment of the effects on the developing embryonic and fetal brain of exposure to ionizing radiation, the school performance of prenatally exposed survivors of the atomic bombing of Hiroshima and a suitable comparison group have been studied. In this report, the changes in performance in seven school subjects according to dose are compared under the dosimetry system (DS86) instituted in 1986 at the Radiation Effects Research Foundation. The sample involves 929 children whose fetal absorbed dose are known and includes 14 severely mentally retarded persons. The findings can be summarized as follows: 1) Damage to the 8-15 week fetal brain appears to be linearly related to the absorbed dose, as judged by the simple regression of average school-performance score on dose. Damage to the fetus exposed at 16-25 weeks after fertilization appears similar to that seen in the 8-15 week group. Canonical and multiple correlations also show a highly significant relationship of exposure 8-15 weeks and 16-25 weeks after fertilization to achievement in school. This trend is stronger, however, in the earliest years of schooling. 2) In the group exposed within 0-7 weeks following fertilization, or 26 or more weeks after fertilization, there was no evidence of a radiation-related effect on scholastic performance. 3) These results parallel those previously found in prenatally exposed survivors with respect to achievement in standard intelligence tests in childhood and development of severe mental retardation.

Stem Cells. 1997;15 Suppl 2:129-33.
Brain damage among individuals exposed prenatally to ionizing radiation: a 1993 review.
Schull WJ.
Mental retardation as a result of prenatal exposure to ionizing radiation is not a common phenomenon when compared to the incidence of cancer, but it has nevertheless been well-documented. This article describes results from studies of individuals who were exposed prenatally to radiation in Hiroshima and Nagasaki. The critical time of exposure, when the most significant damage was done, was during the 8th-15th week of gestation, with a lesser effect at 16-25 weeks. Individuals in the study were assessed by measurement of an intelligence quotient and by examination of school performance. Studies show that the period of 8-15 weeks of gestation coincides with a key time for neuronal cell migration in the developing brain. There is continuing investigation of the mechanism of this migration and how it might be disrupted by ionizing radiation.

Int J Radiat Biol. 1998 Aug;74(2):159-71.
Radiation-related brain damage and growth retardation among the prenatally exposed atomic bomb survivors.
Otake M, Schull WJ.
Many studies of prenatally exposed survivors of the atomic bombings of Hiroshima and Nagasaki have shown that exposure to ionizing radiation during gestation has harmful effects on the developing human brain. Data on the occurrence of severe mental retardation as well as variation in intelligence quotient (IQ) and school performance show significant effects on those survivors exposed 8-15 and 16-25 weeks after ovulation. Studies of seizures, especially those without a known precipitating cause, also exhibit a radiation effect in survivors exposed 8-15 weeks after ovulation. The biologic events that subtend these abnormalities are still unclear. However, magnetic resonance imaging of the brains of some mentally retarded survivors has revealed a large region of abnormally situated gray matter, suggesting an abnormality in neuronal migration. Radiation can induce small head size as well as mental retardation, and a review of the relationship between small head size and anthropometric measurements, such as height, weight, sitting height and chest circumference, shows that individuals with small head size have smaller anthropometric measurements than normocephalics. This suggests that radiation-related small head size is related to a generalized growth retardation. Finally, the issue of a threshold in the occurrence of one or more of these effects, both heuristically and from a regulatory perspective, remains uncertain. Simple inspection of the data often suggests that a threshold may exist, but little statistical support for this impression can be advanced, except in the instance of mental retardation.

Int J Radiat Biol. 1993 Feb;63(2):255-70.
Radiation-related small head sizes among prenatally exposed A-bomb survivors.
Otake M, Schull WJ.
Of 1566 individuals prenatally exposed to the atomic bombings of Hiroshima and Nagasaki, 1473 had the circumference of their head measured at least once between ages 9 and 19. Among these 1473 individuals, 62 had small heads–the circumference of the heads was two standard deviations or more below the observed specific-age-at measurement mean. Of 26 cases with severe mental retardation, 15 (58%) had small heads. Most (86%) of the individuals with small heads were exposed in the first trimester (about < 12 weeks postovulation) or second trimester (about 12-24 weeks postovulation)–55% in the former period and 31% in the latter. Various dose-response relationships, with and without a threshold, have been fitted to the data grouped by the trimester or postovulatory age (weeks after ovulation) at which exposure occurred. A significant effect of radiation on the frequency of individuals with atypically small heads is observed only in the first and second trimesters and for the intervals postovulation of 0-7 weeks and 8-15 weeks. Although the risk of a small head at 0-7 weeks postovulation increases significantly with increasing dose, no increase in risk for severe mental retardation is noted in this period. No excess risk of a small head was seen in the third trimester (about > or = 25 weeks postovulation) or among individuals exposed at 16 weeks or more postovulation. The mean IQ values of mentally retarded cases with and without small heads were 63.8 and 68.9, respectively. No significant difference exists between these two IQ means, but both were significantly smaller than 96.4, the IQ value for individuals with small heads without severe mental retardation and 107.8, the value for the overall sample.

Teratology. 1999 Apr;59(4):222-6.
Cognitive function and prenatal exposure to ionizing radiation.
Schull WJ, Otake M.
It is clear from the many studies of the prenatally exposed survivors of the atomic bombing of Hiroshima and Nagasaki that exposure to ionizing radiation during gestation has harmful effects on the developing human brain, particularly if that exposure occurs at critical stages in the development of the neocortex. Data on a variety of measures of cognitive function, including the occurrence of severe mental retardation as well as variation in the intelligence quotient (IQ) and school performance, show significant effects on those survivors exposed 8-15 weeks and 16-25 weeks after ovulation. Studies of seizures, primarily those without known precipitating cause, also exhibit a radiation effect on those individuals exposed in the first 16 weeks after ovulation. The cellular and molecular events that subtend these abnormalities are still largely unknown although some progress toward an understanding has occurred. For example, magnetic resonance imaging of the brain of some of the mentally retarded survivors has revealed a large region of abnormally situated gray matter, suggesting an abnormality in neuronal migration, but cell killing could also contribute importantly to the effects on cognitive function that have been seen. The retardation of growth in stature observed in individuals exposed in the first and second trimesters of pregnancy suggests that the development of an atypically small head size, without conspicuously impaired cognitive function, may reflect a generalized retardation of growth.

Rinsho Byori. 1994 Apr;42(4):313-9.
[Health effects of atomic bomb radiation].
[Article in Japanese]
Shigematsu I.
The health effects of atomic bomb radiation have been studied by the Atomic Bomb Casualty Commission (ABCC) and its successor, the Radiation Effects Research Foundation (RERF) based on a fixed population of atomic bomb survivors in Hiroshima and Nagasaki which had been established in 1950. The results obtained to the present can be classified into the following three categories: (1) The effects for which a strong association with atomic bomb radiation has been found include malignant neoplasms, cataracts, chromosomal aberrations, small head size and mental retardation among the in utero exposed. (2) A weak association has been found in the several sites of cancers, some non-cancer mortalities and immunological abnormalities. (3) No association has been observed in some types of leukemia, osteosarcoma, accelerated aging, sterility and hereditary effects.

JAMA. 1990 Aug 1;264(5):605-9.
Perinatal loss and neurological abnormalities among children of the atomic bomb. Nagasaki and Hiroshima revisited, 1949 to 1989.
Yamazaki JN, Schull WJ.
Studies of the survivors of the atomic bombing of Hiroshima and Nagasaki who were exposed to ionizing radiation in utero have demonstrated a significant increase in perinatal loss and the vulnerability of the developing fetal brain to injury. These studies have also helped to define the stages in the development of the human brain that are particularly susceptible to radiation-related damage. Exposure at critical junctures in development increases the risk of mental retardation, small head size, subsequent seizures, and poor performance on conventional tests of intelligence and in school. The most critical period, 8 through 15 weeks after fertilization, corresponds to that time in development when neuronal production increases and migration of immature neurons to their cortical sites of function occurs. The epidemiologic data are, however, too sparse to settle unequivocally the nature of the dose-response function and, in particular, whether there is or is not a threshold to damage. If a threshold does exist, it appears to be in the 0.10- to 0.20-Gy fetal-dose range in this vulnerable gestational period.

Adv Space Res. 1986;6(11):223-32.
Learning disabilities in individuals exposed prenatally to ionizing radiation: the Hiroshima and Nagasaki experiences.
Schull WJ, Otake M.
The brain, undoubtedly the most complex organ in the mammalian body, is the culmination of a long and interrelated sequence of molecular, cellular and tissue events. Brain function hinges on the orderly progression of these, each of which must occur correctly, temporally and spatially. Impingement on any one will give rise to a less developed system of cellular connections, and hence impaired function. Moreover, the neurons of the central nervous system are not self-renewing and thus neuronal loss cannot be repaired through repopulation. Reanalysis of the data on the prenatally exposed survivors of the atomic bombing of Hiroshima and Nagasaki suggests that severe mental retardation occurs primarily, if not exclusively in the period from the 8th through the 15th week following fertilization. Within this window of vulnerability, the increase in mental retardation appears linear with dose and without threshold. More subtle functional effects also occur as reflected in diminished performance on intelligence tests and in school. These findings and their implications for space travel and regulatory agencies charged with the specification of acceptable risks should not require further elaboration in this article given the focus of the radiobiological presentations at this meeting.

Health Phys. 1990 Jul;59(1):57-61.
Effects of prenatal exposure to ionizing radiation.
Miller RW.
Prenatal exposure to ionizing radiation induces some effects that are seen at birth and others that cannot be detected until later in life. Data from A-bomb survivors in Hiroshima and Nagasaki show a diminished number of births after exposure under 4 wk of gestational age. Although a wide array of congenital malformations has been found in animal experimentation after such exposure to x rays, in humans only small head size (exposure at 4-17 wk) and mental retardation (exposure primarily at 8-15 wk) have been observed. In Hiroshima, small head size occurred after doses of 0.10-0.19 Gy or more, and an excess of mental retardation at 0.2-0.4 Gy or more. Intelligence test scores were reduced among A-bomb survivors exposed at 8-15 wk of gestational age by 21-29 IQ points per Gy. Other effects of in-utero exposure to atomic radiation include long-lasting complex chromosome abnormalities.

JAMA. 2004 Apr 28;291(16):1987-93.
Antepartum dental radiography and infant low birth weight.
Hujoel PP, Bollen AM, Noonan CJ, del Aguila MA.
CONTEXT:
Both high- and low-dose radiation exposures in women have been associated with low-birth-weight offspring. It is unclear if radiation affects the hypothalamus-pituitary-thyroid axis and thereby indirectly birth weight, or if the radiation directly affects the reproductive organs.
OBJECTIVE:
To investigate whether antepartum dental radiography is associated with low-birth-weight offspring.
DESIGN:
A population-based case-control study.
PARTICIPANTS AND SETTING:
Enrollees of a dental insurance plan with live singleton births in Washington State between January 1993 and December 2000. Cases were 1117 women with low-birth-weight infants (<2500 g), of whom 336 were term low-birth-weight infants (1501-2499 g and gestation > or =37 weeks). Four control pregnancies resulting in normal-birth-weight infants (> or =2500 g) were randomly selected for each case (n = 4468).
MAIN OUTCOME MEASURES:
Odds of low birth weight and term low birth weight by dental radiographic dose during gestation.
RESULTS:
An exposure higher than 0.4 milligray (mGy) during gestation occurred in 21 (1.9%) mothers of low-birth-weight infants and, when compared with women who had no known dental radiography, was associated with an adjusted odds ratio (OR) for a low-birth-weight infant of 2.27 (95% confidence interval [CI], 1.11-4.66, P =.03). Exposure higher than 0.4 mGy occurred in 10 (3%) term low-birth-weight pregnancies and was associated with an adjusted OR for a term low-birth-weight infant of 3.61 (95% CI, 1.46-8.92, P =.005).
CONCLUSION:
Dental radiography during pregnancy is associated with low birth weight, specifically with term low birth weight.