Biological effects after prenatal irradiation (embryo and fetus). A report of the International Commission on Radiological Protection.

In its 1990 recommendations, the ICRP considered the radiation risks after exposure during prenatal development. This report is a critical review of new experimental animal data on biological effects and evaluations of human studies after prenatal radiation published since the 1990 recommendations.Thus, the report discusses the effects after radiation exposure during pre-implantation, organogenesis, and fetogenesis. The aetiology of long-term effects on brain development is discussed, as well as evidence from studies in man on the effects of in-utero radiation exposure on neurological and mental processes. Animal studies of carcinogenic risk from in-utero radiation and the epidemiology of childhood cancer are discussed, and the carcinogenic risk to man from in-utero radiation is assessed. Open questions and needs for future research are elaborated. The report reiterates that the mammalian embryo and fetus are highly radiosensitive. The nature and sensitivity of induced biological effects depend upon dose and developmental stage at irradiation. The various effects, as studied in experimental systems and in man, are discussed in detail. It is concluded that the findings in the report strengthen and supplement the 1990 recommendations of the ICRP.

Effect of whole-body irradiation on phagocytic cells in mouse blood measured by chemiluminescence.

In investigations with mice the influence of an X-irradiation on the chemiluminescence yield of granulocytes from the peripheral blood was measured. The measurements were carried out with diluted freshly drawn blood by adding luminol as chemiluminogenic substance. The granulocytes were stimulated by zymosan. The following dependencies were investigated: dose from 1 to 8 Gy and time twelve hours to 32 days after a whole-body irradiation. In general the chemiluminescence yields from blood of irradiated animals are reduced in dependence of dose compared with the findings in controls. In unirradiated animals (controls) there exists a good correlation between the numbers of granulocytes and the chemiluminescence. This correlation is diminished after an irradiation. For the fourth day after a whole-body irradiation the chemiluminescence shows an exponential dose dependence. If chemiluminescence counts are related to the number of granulocytes (relative chemiluminescence) an increased chemiluminescence per single granulocyte is recorded up to the eighth day after an irradiation with 1 Gy. It may be assumed that subpopulations of granulocytes with enhanced ability to form oxidative metabolic products are responsible for this effect.

The effect of endotoxin on preirradiated mice.

Adult male mice were given a whole body irradiation with non-lethal doses of 2.5 or 5 Gy. Unirradiated animals served as controls. The animals (including controls) received a single injection of endotoxin (LPS from Salmonella abortus equi) with doses of 100, 200 or 400 micrograms one day up to one year after irradiation. Twelve, 24 or 48 hours after lipopolysaccharide (LPS) application the animals were killed and dissected. Animals which died spontaneously were also examined. Liver, lung, kidney, small intestine, and stomach were histologically investigated. The histological findings showed, that differences exist between irradiated and unirradiated mice and that the cause of death is also different for animals dying spontaneously. The investigations have shown that after irradiation phases of different degrees of sensitivity with regard to the endotoxin response exist. This behaviour can be observed by different lethality rates or in the light of the histological results. Moreover, the histological findings have shown, that distinct regenerative changes occur first of all in the liver, in the mucosa of small intestine, and the gastric mucosa, in which the number of differentiated cells compared with the mitotic active cells is reduced. It can be ascertained, that a whole body irradiation with 2.5 to 5 Gy enhances an additional injury by endotoxin weeks to months later. Contrary to this a preirradiation a few days before endotoxin application leads to a "protection" against the efficacy of endotoxin. These findings can be explained by modes of action described in literature, according to which endotoxins induce the formation of highly active mediators especially the tumor necrosis factor.

Prolonged radioprotective activity of WR-2721 linked to dextran.

The radioprotective agent WR-2721 was linked to dextran and poly(glutamic acid) respectively, to obtain a prolonged radioprotective ability. Male mice were administered these water soluble polymer conjugates one to 72 hours prior to a whole body irradiation with X-rays. A prolongation of radioprotective efficiency was achieved with two dextran-(WR-2721)-conjugates. For a period of 24 hours between administration, and irradiation dose reduction factors of 1.14 +/- 0.04 and 1.10 +/- 0.03 respectively were found. After 72 hours, no protective effect was observed. Histopathological investigations of the liver for formation of tumors 200 to 600 days after irradiation seems to indicate that a protective effect is not produced by the dextran-(WR-2721)-conjugates.

[Effect of static magnetic fields on the prenatal development of the mouse]. / Untersuchungen über den Einfluss statischer Magnetfelder auf die pränatale Entwicklung der Maus.

Developmental effects were studied in pregnant albino-mice after exposures to a static homogeneous magnetic field (1 T) on days 7, 10 or 13 post conception (p.c.). These days correspond approximately to the 16th, 28th or 42nd day p.c. in human development and represent stages of increased sensitivity. Intrauterine effects (after exposures on days 7 or 10 p.c.) were evaluated. They included lethality, external malformations, disorders in the fetal skeleton and fetal weights. The evaluation of postnatal effects (after exposure on day 13 p.c.) included body-weight, brain weight, diameter of neocortex and commissures and the alignment of cortical neurons up to day 46 p.c. According to all these criteria, no development effects were observed after exposure to the magnetic field. Transient effects, that can be compensated or have no biological relevance cannot be excluded.

The formation of tigroid substance during postnatal maturation of the brain of mice after pre- and perinatal X-irradiation.

Using Nissl stained slices of postnatal brain, tigroid formation in neurons of the cortex, thalamus, cerebellum, hippocampus, gyrus dentatus and nucleus mot. trigemini was examined in X-irradiated mice. Following exposure on days 13, 16, 18.5 or 22 post conception with doses ranging from 0.5 Gy to 3.0 Gy tigroid formation was studied by means of a selective microphotometrical measurement technique. After irradiation, a fluctuating diminution in the tigroid density was observed in relation to the controls. It was dependent both on the dose and on the stage of development during exposure. In several brain regions fluctuating tigroid responses, being most pronounced during the "critical periods" of postnatal brain maturation, resulted in a longterm compensation of a deficit in the tigroid density after irradiation with 0.05 Gy. After the higher doses the density diminution was either not compensated or was progressive. The late tigroid responses decrease from irradiation on day 13 p.c. to irradiation day 22 p.c. Hence, this type of late maturation impairment was either extended through several cell generations or it was induced to a lesser degree in the early postmitotic neurons. Changes in the total RNA-content of the brain are concomitant with the range of the tigroid responses during the second and the beginning of the third week after birth. The tigroid reactions were interpreted as a chain of interdependent processes of retardation and stabilization. Accordingly, to obtain a better understanding of long-term maturation defects, a comprehensive evaluation of the whole chain of events will be required.

Effects of acute X-irradiation on pre-implantation embryos and on the implantation reaction in the mouse.

Pregnant mice were treated on the 1st, 2nd, and 3rd day of pregnancy by a single dose of 300 R X-rays. Uterine dissections at day 6 p.c. topographically revealed decrease of the implantation sites from 9.67 per female in the controls to 8.00 in females irradiated on day 1, to 6.63 in females irradiated on day 2, and to 7.00 in females irradiated on day 3 p.c; Among a number of 22 implantations after irradiation on day 1, 19 after irradiation on day 2 and 11 after irradiation on day 3, however no living embryo could be detected on histological examination. The degree of damage as indicated by the total resorptions was highest (94,7%) after irradiation on day 2 p.c., and lowest (31,8%) after irradiation on day 1 p.c. Since the decidual cell reaction was either unaffected or only slightly reduced after irradiation on day 2 p.c. as indicated by cytomorphological criteria and the alkaline phosphatase reaction, not maternal effects but direct effects only of the irradiation on the embryo must account for embryonic deaths.

[Periodic compensation reactions in the course of postnatal growth of mouse liver following fractionated roentgen radiation during embryogenesis. 1]. / Periodische Kompensationsreaktionen im Verlaufe des postnatalen Wachstums von der Leber der Maus nach fraktionierter Röntgenbestrahlung während der Embryogenese. 1. Teil

Following daily fractionated X-irradiation in utero, a postnatal study of the mouse liver was made with regard to compensatory growth responses depending on the radiation dose and on the age of the germ while irradiated. Exposure to doses between 10 R/d and 60 R/d was performed during blastogenesis (1st to 5th day p.c.), organogenesis (6th to 13th day p.c.), fetogenesis (14th to 18th day p.c.), as well as during the early (6th to 10th day p.c.) and the late embryogenesis (11th to 15th day p.c.). Besides deviations of the increase in weight and of the nucleic acid content, the incorporation of 3H-thymidine into DNA was measured by means of scintilation counts and radioautographs. As compared with controls, all irradiated experimental groups exhibit a periodical increase of the proliferative hepatic growth especially towards the end of the first and of the second post-natal week. The possibility of inducing compensatory responses decreases, however, with increasing age of the germs, a gradation thus appearing from overcompensation effects after exposures during blastogenesis down to poor proliferation responses after irradiations in the course of fetogenesis. The dose dependence of proliferation responses after irradiations during organogenesis is characterized by an overstrain of the capacity for recovery following 60 R/d, by maximum compensatory growth after 40 R/d, and by a slight stimulation of growth following 10 R/d, in the otherwise apparently normal animals. Late proliferative responses of the developing liver are regarded as a self-stabilisation towards the predetermined norm of growth. Essential differences in comparison with a stress - or a strain - stimulated growth (as in the adult regenerating liver) are suggested by the observation that (a) cytogenesis in the functionally independent populations of blood cells and of parenchymal cells is stimulated partly at the same time and to a similar extent, (b), that stimulation effects reach a peak always within equal stages of development independent of the X-ray doses and the age at irradiation and (c) that an acceleration of growth is possible with a normal or even augmented ratio of organ-weight to body-weight.