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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

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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%,

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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

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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

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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

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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.

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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

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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,

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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

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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

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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.

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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

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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,

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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

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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~. REFERENCES Al57 A166 Be78 Bi88 Bl73 Bl75 BrS2 Br87 CaS7 Ca68 Co84 Do73 Fa72 Fa72b Fe78 Fe79 Fu58 Fu75 Alexander, P. 1957. Accelerated aging: Long term effect of exposure to ionizing radiations. Gerontologia 1:174-193. Alben, R. E., A. R. Omran, E. W. Brauer et al. 1966. Follow-up study of patients treated by x-ray for tines capital. Am. J. Public Health 56:2114-2120. Beebe, G. W., C. E. Land, and H. Kato. 1978. The hypothesis of radiation- accelerated aging and the mortality of Japanese A-bomb victims. Pp. 3-37 in Late Effects of Ionizing Radiation. Vienna: International Atomic Energy Agency. Bithell, J. F., and C. A. Stiller. 1988. A new calculation of the carcinogenic risk of obstetric x-raying. Stat. Med. 7:857-864. 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. Blot, W. J. 1975. Review of thirty years study of Hiroshima and Nagasaki atomic bomb survivors. II. Biological effect. C. Growth and development following prenatal and children exposure to atomic radiation. J. Radiat. Res. 16(Suppl):82-88. Brues, A. M., and G. A. Sacher. 1952. Analysis of mammalian radiation injury and lethality. Pp. 441-465 in Symposium on Radiobiology, J. J. Nickson, ed. New York: John Wiley. Brent, R. L., D. A. Beckman, and R. P. Jensh. 1987. Relative radiosensitivity of fetal tissue. Adv. Radiat. Biol. 12:239-256. Casarett, G. W. 1957. Acceleration of Aging by Ionizing Radiation. UR-492. Casarett, G. W., and H. A. Eddy. 1968. Fractionation of dose in radiation- induced male sterility. Pp. 14.1-14.10 in Dose Rate in Mammalian Radiation Biology, D. G. Brown, R. G. Cragle, and T. R. Noonon, eds. USAEC CONF-680410. Covelli, V., V. Di Majo, B. Bassani, S. Rebessi, M. Coppola, and G. Silini. 1984. Influence of age on life shortening and tumor induction after x-ray and neutron irradiation. Radiat. Res. 100:348-364. Dobbing, J., and J. Sands. 1973. Quantitative growth and development of human brain. Arch. Dis. Child 48:757-767. Fabrikant, J. I. 1972. Radiobiology. Chicago: Year Book Medical. Fabrikant, J. I. 1920. Cell population kinetics in the eminiferous epithelian under continuous low dose rate radiation. Pp. 805-814 ~n Advances in Radiation Research, Biology and Medicine, Vol. II, J. F. Duplan and A. Chapiro, eds. New York: Ciordon and Breach. Fedorova, N. L., and B. A. Markelov. 1978. Functional activity of dog's testicles at chronic and combined gamma radiation in the course of three yeam. Kosmicheskara Biologua Aviakomicheskaia Meditsina 12:4246. Fedorova, N. C, and B. A. Markelov. 1979. Dog's spermatogenesis after interuption of three year's chronic gamma-irradiation. Rabiobiologiva 12:42-46. Furchtgott, E., and M. Echols. 1958. Activity and emotionality in pre- and neonatally x-irradiated rats. J. Comp. Physiol. Psychol. 51:541-545. Furchtgott, E. 1975. Ionizing radiation and the ne~vous system. In Biology of Brain Disfunction, G. E. Gaull, ed. New York: Plenum Press.

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