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CHAPTER VI EFFECTS OF IONIZING RADIATION ON GROWTH AND DEVELOPMENT I. Introduction 74 II. Effects of Radiation on Human Development and Growth 74 A. Intrauterine Irradiation 74 B. Postnatal Irradiation 76 C. Acute Effects of Radiation on the Human Fetus 76 III. Biologic Basis of the Special Vulnerability of Developing Organisms 77 IV. Experimental Irradiation of Mammals 78 V. Effects of Radiation on the Development of Behavior and other Functions 78 VI. Effects of Irradiation from Radionuclides 79 VII. Estimates of Risks from Irradiation in Early Life 80 VIII. Summary 80 References 81 73
CHAPTER VI EFFECTS OF IONIZING RADIATION ON GROWTH AND DEVELOPMENT I. Introduction This chapter reviews briefly the effects other than neoplasia of in utero and juvenile expo- sure to ionizing radiation. Effects on human beings are of major concern, but, since data on human effects are limited, experimental animal data are included. Morphologic changes pro- duced by radiation, effects on behavioral devel- opment, and other functional alterations are considered, with particular attention to the special vulnerability of the young and to the lowest exposure levels at which radiation ef- fects can be observed. The references cited treat special points or provide broad coverage and lead to more extensive bibliographies. II. Effects of radiation on Human Development and Growth Ionizing radiation has three major effects on human development: impairment of growth, microcephaly, and mental retardation. Knowl- edge about the dose levels at which these ef- fects occur comes principally from data relat- ing to: 1) patients irradiated for medical rea- sons, 2) the Hiroshima-Nagasaki survivors of the atomic bombs, and 3) the people of the Mar- shall Islands who were exposed to nuclear fallout in 1954. A. Intrauterine Irradiation Among the earliest reports of* the deleterious effects of radiation on human development were Zappert,s (65) 1926 account of 21 persons and the 1929 reports by Goldstein and Murphy (22) (see also Van Cleave (59) for review) on 75 individuals exposed in utero when their moth- ers were being treated with radiation to the pelvic area. Although it is impossible now to estimate the range of the doses, they were of the magnitude (several hundred rads delivered by x ray or radium) used at that time for treat- ment of such gynecological conditions as myoma of the uterus, cancer, and abnormal uterine bleeding. Microcephaly, with concomi- tant mental retardation, as well as eye defects and general impairment of body growth were frequently found among those offspring. In the Goldstein and Murphy series, 38 of the 75 were considered to be in ill health, and of these 18 were microcephalic and severely mentally defective. The authors attributed the condition of two of these children to causes other than radiation. Two other children were mongoloid, but were considered also to have radiogenic microcephaly. The finding of 14 or more mental- ly retarded microcephalies among 75 individu- als exposed in utero to therapeutic levels of radiation indicated a strong association be- tween radiation and abnormal development. Dekaban (12), in a retrospective study of 26 cases of in utero exposure, attempted to corre- late developmental abnormalities with estimat- ed dosage and gestation age at time of expo- sure. He found that in one case in which the exposure was believed to have occurred be- tween 2 and 4 weeks after conception no abnor- mality was reported in the offspring. In 22 cas- es in which the exposure was reported to have occurred from 3 to 20 weeks after conception, either microcephaly or mental retardation, or both, occurred in every case. In three cases, exposed 19 to 25 weeks after conception, no abnormalities were apparent. In the 22 cases of mental retardation and microcephaly, doses varied but were estimated to have been 250 R or more. Again, the cause-effect association is strong, although in such a study, based entire- ly on published data, such possibly confounding 74
factors as maternal diseases, genetic factors, and environmental influences cannot be ruled out as potential contributors. From a sample of 1,265 subjects exposed in utero at Hiroshima, the cases of 183 who were then available were analyzed by Miller (28) and Wood (62, 63) in 1954 and 1967. Of these, 78 were fetuses of less than 16 weeks at the time of irradiation; 105 were 16 weeks or more. Of the 78, 25 showed a significant degree of micro- cephaly (head circumference more than two standard deviations below the mean for age and sex), and 11 were mentally deficient. Of the 105, 7 were microcephalic as defined and 4 were mentally deficient. The likelihood of microce- phaly was proportional to proximity to the hypocenter. In 14 of the offspring with smaller than normal head circumference who were also mentally deficient, 10 were >2. S.D. below the mean height for age and sex. In 16 children with small heads who were not mentally deficient, there was no reduction in stature. Table 1 summarizes some of the characteristics of the 78 exposed in utero before the 16th week of ges- tation (28, 63). Other studies of the Japanese, 1613 in all, exposed in utero to radiation from the atomic bombs revealed a more general deleterious ef- fect of radiation on body growth (64, 57). These subjects were examined annually to assess the effects of the bombs; by age 17, when mature growth had largely been obtained, about 80% were available for examination. This sample was divided into three main comparison groups: those exposed within 2000 meters of the hypocenter of the bomb; those between 3000 and 5000 meters from the hypo- center; and those entirely outside of the cities. In the group less than 2000 meters from the bomb, the mean head circumference, height, and weight were less than in the two groups exposed at greater distances. In a narrower comparison of subsamples, children exposed within 1500 meters of the hypocenter of the Table 1 Distance from Mentally Retarded Normal Intelligence Total Hypocenter (meters) Head Circumference Head Circumference Examined ii Exposure within 15 weeks of mother,s last menstrual period >3SDi 2to3SD* <2SDi >3SDi 2to3SDi <1200 6 â¢2 0 1 0 11 1201-1500 0iii 0 0 2 6 23iii 1501-1800 0 1 0 0 5 22 1801-2200 0 0 0 0 0 20 Exposure after 15 weeks since mother,s last menstrual period <1200 2 0 0 0 0 13 1201-1500 0 0 1 1 1 46 1501-1800 0 0 0 0 2 46 Numbers of children with small head circumference and/or mental retardation following intrauterine exposure to the Hiroshima bomb according to distance from the hypocenter and gestational age category (after Wood et al. (63)) i SD = Standard deviations below the average for age and sex. ii Some children were normal with respect to both intelligence and head circumference; thus the numbers in columns 2-6 do not add to the totals in column 7 iii Excludes 2 with pre-existent Down,s syndrome 75
Hiroshima bomb were, on the average, 2.25 cm. shorter, 3 kg lighter, and 1.1 cm less in head cir- cumference than those in the outer groups. The dose in this zone was estimated in 1957 at 50 rads or more; however, a revision of the dose estimates in 1965, applied to those samples, reduces the dose estimate to about 25 rads Assigning a cause in any case of mental re- tardation is difficult because few specific caus- es are known, and when the primary cause is established, secondary contributory factors may worsen or ameliorate the condition. In the Japanese children the diagnosis was applied only if the individual was unable to perform simple calculations, to make simple conversa- tion, to care for himself, or if he were complete- ly unmanageable, or had been institutionalized. The first three of these criteria are usually those which are used to categorize individuals as "profoundly" mentally retarded; the other two criteria are not rigidly defined. This "pro- found" mental retardation was not observed below 50 rads of maternal exposure (5, 67). Irradiation of the fetus from diagnostic pro- cedures up to a few rads has not been observed to cause developmental abnormalities (32), al- though an excess of malignancy later in child- hood has been attributed to the source (54). Irradiation of the fetal thyroid by iodine-131 administered therapeutically to the mother might be expected to mimic the effects experi- enced by Marshall Islanders, (discussed below) but the evidence seems inconclusive (38, 2). B. Postnatal irradiation. Apart from the Hiroshima-Nagasaki data, and that relating to the effects of nuclear fall- out on the Marshall Island of Rongelap, dis- cussed below, most of the data available about the effects of radiation on infants and children is derived from case reports on individuals. Large doses to a part of the body have resulted iThese dose estimates, drawn from ABCC data, are of air doses to the mother. The degree of attenuation of the dose in reaching the fetus would depend on such factors as fetal age; e.g., the younger the fetus, the greater the attenua- tion. An equation to allow for this attenuation in comput- ing fetal dose has not been formulated. (See p. 166, Somatic Report: "Under the conservative assumption that half of the dose was attenuated by the mothers, bodies...") in impairment of skeletal growth(Il, 49, 58). As much as 1000 rads (in divided doses) adminis- tered therapeutically to the spine in children of various ages had no visible effect, but 2000 rads led to deformity (31). Less radiation, 800 rads, to the epiphyses of long bones in infancy permanently stunted growth of the bone. A recent survey compared children whose scalps were x-irradiated for depilatory purpos- es in the treatment of fungus infections be- tween 1940 and 1959 with children treated with drugs. Age at irradiation varied from 3 to 12 years and the dose to the scalp ranged from 450 to 850 rads. Subsequent incidence of personali- ty disorders was four and a half times higher in the irradiated group than in the other. For psychoses, the incidence was 21/2 times great- er and, for psychoneurosis, 3 times greater in the irradiated group (1, 48). Among the Rongelap children exposed to ra- dioactive fallout, two boys who were infants at the time of exposure developed atrophy of the thyroid before puberty. Their whole body dose from externally deposited fallout has been esti- mated at 175 rads, but owing to concentration of iodine-131 in the thyroid, between 700 and 1400 rads was absorbed by that organ. The atrophy was associated with hypothyroidism, and the resultant retardation of body growth and sluggishness of behavior were attributed to the thyroid deficiency rather than directly to the whole body exposure (9, 55,56). The most conclusive evidence of postnatal radiation effects comes from a multivariate analysis of anthropometric data on children exposed to the Hiroshima bomb and examined periodically up to eight years later (30). As ra- diation exposure increased, there were, in those receiving doses of 100 rads or more, small but statistically significant decreases in body mea- surements among children of all ages and in growth rate among adolescents. The extent to which such differences may be due to variables other than radiation exposureâsuch as socio- economic inequalities due to blast or fireâis unknown. C. Acute Effects of Radiation on the Human Fetus There are almost no published reports of autopsies on individuals exposed to radiation 76
in utero or in early postnatal life, in respect to either immediate or late effects. Driscoll et al. (14) were able to study the acute effects in two human fetuses exposed to radiation from the radium with which their mothers were being treated for cancer of the cervix. The fetuses, 15 cm and 21 cm in crown-rump length, were examined 2 and 10 days after the beginning; of irradiation, which lasted 48 hours in the first case and 4 days in the second. The crowns of the heads were about 5 cm distant from the source and received about 800 R and 1600 R, respec- tively. Destruction of primitive proliferative and migratory cells in the brains and of granu- lopoietic cells in the hematopoietic tissues oc- cured in both, but evidence of acute necrosis of lymphoidandmesenchymalcells was still visi- ble only in the smaller fetus exposed for 48 hours. Mesenchyme cell necrosis extended as far as the kidney, where the dose may have been of the order of 50 to 100 rads in this fetus. In the larger fetus exposed for 4 days, more degenerating ova were seen than in comparable unirradiated subjects. These observations provide a link between human and laboratory animal data, suggesting that patterns of cellu- lar radio-sensitivity in man are similar to those in other mammals. III. Biologic Basis of the Special Vulnerability of Developing Organisms. The developing organism is especially vul- nerable to radiation damage, not because the primary interactions between radiation and its biological system differ from those in the adult, but because of properties peculiar to that peri- od of life. The embryonic, fetal, and infant mammals are organizations of progressively changing cell populations whose proliferating, interacting, and differentiating members are never long in a steady state. The cells are not only changing at the molecular level, but are often migrating. This changing cellular mosiac responds differently to radiation from moment to moment, and the changes in sensitivity ac- companying different stages of development combined with different doses of radiation pre- sent a staggering number of possible combina- tions of effects (39-42, 52). Nonetheless, various mammalian species show some fundamental similarities in response when the irradiations occurs at comparable stages of fetal develop- ment (7, 10,14,20,22-24,39-41, 52, 59). Radiation exposure may kill or damage pro- liferating and primitive cells. While such losses can often be made up by the regulative (rege- nerative) capacity of the embryo, the death or injury of large numbers of cells engaged in key inductive processes can cause serious failures of development (23, 36). Radiation effects in the early mammalian embryos closely mimic the effects caused by surgical extirpation as prac- ticed in classical experimental embryology. Gross anatomic abnormalities of entire organ systems may follow radiation exposure in the early periods of organogenesis. In addition to its effects directly on the cell, radiation exposure can permanently alter the differentiation of large populations of matur- ing cells by destroying or altering some of the DNA or other biologically active molecules es- sential at the moment to ensure the sequence of proteins necessary for the cells, normal growth and development (13, 45); somatic mutations, also, may occasionally be established in devel- oping cell lines (43). Both mechanisms can initi- ate modifications in structural and functional development. Radiation effects may appear almost at once, they may be delayed, or they may set in motion a chain of recognizable secondary events. Thus, the destruction of primitive and prolifer- ative cells in many organs and tissues in em- bryos during organogenesis may begin to ap- pear within an hour after irradiation, in which case altered morphogenesis rapidly ensues. In contrast, injury to precursors of bone marrow (21, 23) or to male gonadal germinal cells in infant rats is not immediately visible, but is expressed, after a long latent period, in failure to form hematopoietic and spermatogenic cells. An example of a complex chain of developmen- tal events following irradiation is that of the Rongelap people who, exposed to fallout radia- tion in early childhood, developed atrophy of the thyroid, with consequently impaired body growth and sluggish mental functions (9). 2In this chapter, the radiation exposures referred to are usually "acute," that is, of relatively short duration, usually minutes or hours. 77
Rats exposed during late fetal life to only a few rads a day showed an altered response to typhoid vaccine for several months after birth. In the same period, too, there was diminished phagocytic activity of circulating leukocytes (33). It has been known that germ cells in the early ovary and testis are especially vulnerable to destruction by radiation at certain stages (7), but only recently have changes in gonadal en- docrine functions following irradiation been studied. In laboratory animals, prenatal expo- sure to a few hundred rads of male or female gonads at several stages of development dimin- ished later hormone secretion by these organs (4, 15). This effect was paralleled by elevated levels of pituitary gonadotropin secretion in females and diminished size in secondary sex organs in the male (53). Virtually all of the effects that have been mentioned are primarily owing to direct irra- diation of the developing organism. There are indirect effects on development of the embryo owing to irradiation of the mother that carries it, but the mechanisms are unknown. In one example, normal fertilized rabbit ova trans- planted to the uterus of an irradiated mother rabbit showed delayed implantation or failed to develop (8). IV. Experimental Irradiation of Mammals Developmental abnormalities resulting from irradiation of the embryos of laboratory ani- mals occur most often when from 50-400 rads are given in the early stages of organogenesis, from the formation of the body axis, first som- ites, and the neural plate through the laying down of the urogenital system and skeleton. Higher doses are likely to be lethal, whereas low 100,s of rads may regularly initiate malfor- mative processes and disturbances of differen- tiation and growth,âbut the affected organism may survive depending on the nature of the abnormalities. These effects become less and less likely to be observed as the dose descends below 100 rads. Permanently altered nerve cells in the brain (10) and loss of substantial numbers of germ cells result from as little as 10 rads in infant rats (7), but in neither circum- stance has an associated functional deficit been recognized. Exposure of mouse embryos to a few R at various stages, including preimplan- tation, has been followed by developmental abnormalities which, however, are not distin- guishable from those that occur spontaneously and sporadically (25, 37). Factors other than radiation may increase the incidence of such "spontaneous" abnormalities; Jacobsen showed, for example, that the incidence of a particular abnormality was greater in winter than in summer. Thus, if the results of control studies done in summer were compared with those of radiation experiments conducted in winter, the harmful effects of radiation might be overestimated; or if the experiments were reversed, radiation effects might be camou- flaged. Experiments with a little more than 1 rad per day, over weeks or months, have result- ed in life shortening and defective development of gonads and some other organs. The effects of very low levelsâmillirads per dayâof continu- ous radiation on early development have been little explored experimentally, but evidence at hand has shown no harmful effects (29, 44). There is no uniformly gradual diminution in radiosensitivity as the organism develops. The changing sensitivity to radiation of each organ system has to be considered in its own right. The architectural plan of the urogenital sys- tem can be altered only during a relatively short period in early embryonic life, but sus- ceptibility of the skeletal system to malforma- tion waxes and wanes in different parts over a longer period. The brain has the longest period of sensitivity, as it is being formed from primi- tive "embryonic" cells over a longer time than is any other tissue, this building process ex- tending well into postnatal life in most mam- mals. The developmental abnormalities ob- served in man, although almost exclusively externally observed, correspond well to what would be expected on the basis of animal expe- riments. V. Effects of Radiation on the Development of Behavior and Other Functions The ultimate concern about irradiation of the fetus or neonate is for what it may do to the organism,s capacity to function, to perform, to behave. In analyzing this complex attribute, function, in man or animal, the investigator must select from a vast number of possible 78
behaviors and other manifestations of function that he might test. Obviously, no single test measures all functions, and generalizations about normality from even a battery of tests are qualified. Only a few rather general corre- lations have been found between the stage of development at the time of irradiation, mor- phologic changes in the nervous systems, and the kind of decrement in performance that is observed. In general, investigators have been unable to find changes in various behavioral and functional parameters from exposures be- low 25 rads. It has been found that certain re- flexes and locomotor functions were altered in rats exposed in utero to 50 R (51, 61), and more complex motor performances, such as travers- ing a narrow path, were affected by as little as 25 R (18). Certain behavioral responses in the open field and some forms of conditioning have been altered by 25 R (19). One study (47) claimed that exposure of rat fetuses to 1 R at 16 days of gestation affected the rate at which, on reaching adulthood, they became condi- tioned to experimental circumstances. Howev- er, a replication of this study (20, 60), employ- ing the precision of presenting the conditioning stimuli automatically, failed to show effects in rats exposed to less than 100 R. In assessing the behavioral effects of in utero exposure of Japanese children to the atomic bombs, we have no simple, single-mea- sure tests comparable to those which indicated a significant though small diminution in body growth and head size among those closest to the hypocenter. Owing to the lack of appropri- ate and sensitive tests of brain function, men- tal retardation has had to be severe to be rec- ognized, even using a number of measures; it was rare below 100 rads and not observed to excess below 25 rads. VI. Effects of Irradiation from Radionuclides Radionuclides, ingested medicinally or from fallout, pose special problems in that they are often unevenly transported and distributed to different parts of the body. Because of their special affinities for various tissues, they may localize in certain developing tissues; radioac- tive iodine concentrates in the thyroid (though not until that organ has reached a certain stage of differentiation), plutonium and stron- tium in bone, and polonium in kidney. The na- ture of the compound carrying the nuclide may determine how it is transported in the body and where it is ultimately localized (46). Substances emitting beta or alpha particles irradiate lo- cally their areas of concentration whereas those emitting more penetrating gamma rays have remote effects. The time that the radioac- tive compound remains in the body (expressed as biological half-life) is a major determinant of its radiation effects. Because juveniles differ from adults in age-related metabolic ways as well as in size, the above factors may be differ- ent in the juvenile than in the adult. The young may differ from adults in suscepti- bility to injury from radionuclides for a varie- ty of reasons. The skin of the juvenile human and laboratory mammal is more easily injured by radiation than is that of the adult (9, 26). In another example, plutonium and cerium are more readily absorbed from the juvenile gas- trointestinal tract that from that of the adult (3, 27). Some examples illustrate the diversity of radiation effects of radionuclides. The conse- quences of a concentration of radioactive io- dine in the thyroids of Marshallese children has already been discussed. Radioactive phospho- rus given to mice and rats in early pregnancy has resulted in embryonic death or malforma- tive growth, depending on the dose and stage of development (50). At later stages, it tended par- ticularly to malform the teeth and jaws (6). Administration of radioactive strontium has retarded growth and caused malformation of the developing fetal skeleton in several mam- malian species (16). Plutonium makes the bones of infant and especially juvenile mice become fragile, and spontaneous fractures follow. Plu- tonium-239 may accumulate in lethal amounts in the yolk sac of early rat embryos; in later gestation, no effect on the fetus has been ob- served from similar accumulations. The doses of radionuclides used to produce the pathologic developments just noted were relatively large and carried substantial doses of radiation to the tissues involved. The use of these substances in experiments cannot usual- ly be related directly to the use of radioisotopes in human nuclear medicine. When they are used in man, the amounts of radiation brought to fetal, infant, and juvenile tissues are ordinari- ly kept at far lower levels than in the experi- ments. 79
VII. Estimates of Risks from Irradiation in Early Life Although, as noted earlier, the variety of possible radiation effects on the developing mammal is almost infinite, numerous experi- ments have nevertheless shown a predictable orderliness in what happens in any given set of circumstances. Generalizations about risks can be made, based on what has been observed in man and laboratory animals. In man, diminished body growth, head size, and mental development has been observed af- ter 50 rads to the mother during the earlier months of gestation, and some disturbances of growth may occur after as little as about 25 rads. In experiments with laboratory mam- mals, in which more precise observation of dose and stage of development is possible, doses as low as 25 rads have produced some impairment of neurologic functions and behavior. Perma- nent alterations in the morphologic develop- ment of some brain neurons and certain other cellular changes have been regularly observed after as little as 10 to 20 rads in fetal and in- fant rats, but tests thus far have not revealed corresponding changes in function. The developmental effects of radiation on the embryo and fetus result from the destruction or injury of vast numbers of cells. Innumerable developmental processes are sensitive to radia- tion, as to other environmental teratogenic agents, and each process has its individual threshold dose-range below which radiation has no visible effect. In radiogenic microcepha- ly or impaired body growth, the development of the abnormality depends on the summation and interaction of the interruptions of a vast num- ber of processes characteristic of the stage of development, and there are threshold dose- ranges below which these effects are not ob- served. On the basis of animal experiments, one would expect that a 2-months human fetus that received 200 rads would develop a small mal- formed brain, with reduced head size; that mal- formation and diminished brain size would be considerably less marked at 100 rads; and that from 100 rads downward the cellular effects would continue to diminish until alterations of development resulting from them would no longer be measurable. A particular category of risk estimates re- lates to therapeutic abortion, which has been recommended after abdominal exposures of 5 to 10 rads in early pregnancy (34). The evidence to be weighed in this regard includes three observa- tions: 1) exposure to radiation as low as 5 rads has produced biological effects (e.g., presence of bilobed lymphocytes) though no clinical dis- ease, in man and experimental animals; 2) though reports conflict, and experimental ani- mal data are lacking, some studies in man (see pp. 160-167) indicate that doses of 1-3 rads, usually late in pregnancy, increase the relative risk of death from cancer in the child during the first 10 years of life by a factor of 1.5 (an increase of 1 cancer death among about 2,000 children per rad); and 3) radiation doses as low as about 25 rads affect the behavior of animals exposed in utero. Recent studies suggest that. after intrauterine exposure the gross effects (small head size and mental retardation) seen among atomic-bomb survivors, after substan- tial doses, may undergo a continuous grada- tion to small impairment in behavior at lower doses (68). It should be noted that the risk of clinical disease following intrauterine expo- sure to low doses of radiation is very small, even though cellular damage of indeterminate clinical significance does occur. VIII. Summary It has long been recognized that fetal and juvenile mammals are especially sensitive to harm by exposure to ionizing radiation. The mechanisms by which radiation alters the de- velopment of structure, behavior, and other functions are extremely complex. With single brief exposures, the lowest doses observed to bring about these various effects at certain stages in experimental mammals range from a few rads to 50 rads: Occasional germ cells, at certain stages in early life, are killed by a few rads, with no detectable func- tional effects. Subtle but permanent altera- tions in nerve cells, at some stages, occur after 10 to 20 rads, but no alterations in behavior are recognized until about 25 rads are given at some stages in prenatal life. The threshold for morphologic alterations in man following irra- diation in prenatal life are less precisely known, but observations on the Japanese ex- posed to atomic bomb radiation place it be- tween 50 and 25 rads to the mother. 80
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