BIOLOGICAL EFFECTS OF IONIZING RADIATION ON TISSUES, ORGANS AND SYSTEMS

Types of cellular damage Norma Mutation repair When cells come into contact with ionizing radiation sufficient to cause cellular damage, one of three possible actions will occur. If the damage is too severe, the cell may die. If the cell is not severely damaged, it might be able to repair itself and continue functioning, but could lose its ability to divide. This is known as reproductive (mitotic) cell death. A damaged normal cell might mutate, which may cause cancer or genetic effects. Changes of metabolism & function Interphase cell death Mitotic cell death

Radiosensitivity of tissues Bone marrow Skin CNS Radiosensitivity varies in different types of tissue. While all cells can be destroyed by a high enough radiation dose, highly radiosensitive cells or tissue exhibit deleterious effects at much lower doses than others. As stated in the Bergonié-Ttribondeau law, rapidly dividing, undifferntiated cells in tissue are the most sensitive to radiation effects. Several of the most sensitive tissues and systems follow this law. Highly radiosensitive tissue - lymphoid, bone marrow elements, gastrointestinal epithelium, gonads (testis and ovary), and foetal tissue. Moderately radiosensitive tissue - skin, vascular endothelium, lung, kidney, liver, lens and thyroid in childhood. Least radiosensitive tissue - central nervous system, endocrine (except gonad), thyroid in adults, muscle, bone and cartilage, and connective tissue. The least radiosensitive tissue, although radioresistant, is less capable of cell renewal than highly sensitive tissue. Some - especially neurons, glial cells of the brain, and muscle cells - has essentially no ability to regenerate. Once these cells are killed, the area is repaired by fibrosis or scarring. Highly radiosensitive Lymphoid tissue Bone marrow Gastrointestinal epithelium Gonads Embryonic tissues Moderately radiosensitive Skin Vascular endothelium Lung Kidney Liver Lens (eye) Least radiosensitive Central nervous system (CNS) Muscle Bone and cartilage Connective tissue

Relative radio sensitivity Chief mechanism of parenchymal hypoplasia Relative radiosensitivity of various organs based on parenchymal hypoplasia Organs Relative radio sensitivity Chief mechanism of parenchymal hypoplasia Lymphoid organs; bone marrow, testes & ovaries; small intestines Embryonic tissue High Destruction of parenchymal cells, especially the vegetative or differentiating cells Skin; cornea & lens of eyes; gastrointestinal organs: cavity, esophagus, stomach, rectum Fairly high Destruction of vegetable and differentiating cells of the stratified epithelium Growing cartilage; the vasculature; growing bones Medium Destruction of proliferating chondroblasts or osteoblasts; damage to the endothelium; destruction of connective tissue cells & chondroblasts or osteoblasts Mature cartilage or bone; lungs; kidneys; liver; pancreas; adrenal gland; pituitary gland Fairly low Hypoplasia secondary damage to the fine vasculature and connective tissue elements Muscle; brain; spinal cord Low Hypoplasia secondary damage to the fine vasculature and connective tissue elements, with little contribution by the direct effects on parenchymal tissues The relative sensitivity of an organ to direct radiation injury depends upon its component tissue sensitivities. Table lists various organs in decreasing order of radiosensitivity on the basis of a direct radiation effect, parenchymal hypoplasia.

Haematopoietic system Most sensitive are the stem cells of the bone marrow, which give rise to all circulating blood cells and platelets, and the lymphoid tissue found in the spleen, liver, lymph nodes and thymus. Normal cellularity of bone marrow is characterized by a heterocellular population consisting of progenitor cells, fat (or adipose) cells, and supporting reticular cells and stroma. The progenitor cells include the erythroid, myeloid, and megakaryocytic stem cell series. Normal bone marrow Normal bone marrow cellularity appears in this photomicrograph as clear spaces that are fat cells, pink-stained angular bodies that are spicules on normal bone, and diffuse haematopoietic tissue. Bone marrow

Hierarchical organization of haematopoiesis BFU-E CFU-E red blood cell BFU-MK CFU-MK platelets CFU-GEMM CFU-M CFU-GM monocytes CFU-G neutrophils CFU-Ba Stem cell basophils Haematopoiesis takes place in the bone marrow, except for T-lymphocytes, which are generated in the thymus. All haematopoietic lineages arise from the stem cell. The stem cell progressively differentiates towards the stage of progenitor until the mature cells which are released in the blood. Abbreviations: CFU : Colony forming unit BFU: Burst forming unit GM: Granulocyte-Macrophage MK: Megakaryocyte GEMM: Granulocyte erytrocyte megakaryocyte monocyte L: Lymphoid BL: B lymphoid TL: T lymphoid E: Erythroid Ba: Basophil Eo: Eosinophil CFU-Eo CFU-L eosinophils CFU-BL B lymphocytes Thymus CFU-TL T lymphocytes Proliferation Bone marrow Differentiation Blood

Bone marrow kinetics Normal physiological situation Resting stem cells Proliferating compartment: stem cell and progenitors Differentiating compartment: precursors Mature cells Blood exit differentiation The bone marrow contains three cell renewal systems: the erythropoietic (red cell), the myelopoietic (white cell), and the thrombopoietic (platelet). The time cycles and cellular distribution patterns and postirradiation responses of these three systems are quite different. Studies suggest that a pluripotential stem cell gives rise to these three main cell lines in the bone marrow. Besides this stem cell, each cell renewal system consists of stem cell compartments for the production of erythrocytes, leukocytes (lymphocytes, granulocytes, monocytes, etc.) or platelets; a dividing and differentiating compartment; a maturing (non-dividing) compartment; and a compartment containing mature functional cells. Research studies suggest that each of these cell renewal systems operates under the influence of regulating factors, primarily at the stem cell level, through a negative feedback system initiated in large measure by the level of mature circulating cells in the peripheral blood. Normally, a steady state condition exists between new cell production by the bone marrow and the number of functional cells. Morphological and functional studies have shown that each cell line, i. e. erythrocyte, leukocyte and platelet, has its own unique renewal kinetics. The time related responses evident in each of these cell renewal systems after irradiation are integrally related to the normal cytokinetics of each cell system. activation proliferation, differentiation Stem cells: immature cells with autorenewal capability Progenitors: primitive cells, high proliferative potential Mature cells: no proliferative capability

Effects of radiation on haematopoiesis Proliferating compartment: stem cell and progenitors Differentiating compartment: precursors Mature cells Blood Resting stem cells activation IRRADIATION proliferation, differentiation differentiation The compartmentalization of haematopoiesis, a model for the effects of irradiation on haematopoietic cells The main effect of ionizing radiation is to induce the death of proliferating cells within the stem cell and progenitor compartment. This induces an absence of renewal of the next compartments, the precursor and mature cell populations, leading to the progressive depletion of all haematopoietic compartments, and the depletion of peripheral blood cells. It was shown that stem cells are more radioresistant than previously described and have a high repair capacity (Ploemacher et al. Int. J. Radiat. Biol.,61:489-499, 1992). The resting stem cells may be the subset of cells that are responsible for the haematopoietic recovery. Block of proliferation, cell death Depletion by absence of renewal Depletion of proliferating compartment BLOOD APLASIA

Effect of radiation on bone marrow Peak cell degeneration, consisting of massive destruction and necrosis of bone marrow stem cells, occurs within 48 hours after a lethal dose of radiation. In the irradiated bone marrow shown, the precursor haematopoietic cells are no longer present. Four days after 9 Gy of cobalt-60 irradiation, all that is left in the irradiated canine bone marrow shown is a fine network of reticular stroma. The red areas are vascular sinusoids engorged with red blood cells and occasional plasma cells. The clear areas indicate where the haematopoietic tissues were. The plasma cells, being differentiated cells, are relatively radioresistant at this stage. Irradiated bone marrow lacks all precursor haematopoietic cells Normal bone marrow

Model of blood renewal system Cell pools in normal steady state Stem cell Dividing & maturing Maturing only Blood ? 2 days 1 day 1 day 1 day Time After Irradiation Transit time Changes after irradiation 1 hour 1 day 2 days Relative Number of Cells 3 days 4 1/4 days 5 days

Erythrocytes changes as a function of dose 1 Gy 3 Gy The function of this cell renewal system is to produce mature erythrocytes for the circulation. The transit time from the stem cell stage in the bone marrow to the mature red cell ranges from 4 to 7 days, after which the life span of the red cell is approximately 120 days. The immature forms, i.e. erythroblast and proerythroblast, undergo mitosis as they progress through the dividing and differentiating compartment. Because of their rapid proliferating characteristics, they are markedly sensitive to cell killing by ionizing radiation. Cell stages within the maturing (non-dividing) and functional compartments, i.e. normoblast, reticulocyte, and red cell, are not significantly affected by mid-lethal to lethal range doses. The death of stem cells and of those within the next compartment is responsible for the depression of erythropoietic marrow and, if sufficiently severe, is responsible together with haemorrhage for subsequent radiation induced anaemia. Because of the relatively slow turnover rate, e.g. approximately 1% loss of red cell mass per day, in comparison with leukocytes and platelets, evidence of anaemia is manifes subsequent to the depression of the other cell lines, provided that significant haemorrhage has not occurred. The erythropoietic system has a marked propensity for regeneration following irradiation from which survival is possible. After sublethal exposures, marrow erythropoiesis normally recovers slightly earlier than granulopoiesis and thrombopoiesis and occasionally overshoots the base-line level before levels at or near normal are reached. Reticulocytosis, occasionally evident in peripheral blood smears during the early intense regenerative phase occurring after maximum depression, often closely follows the temporal pattern of marrow erythropoietic recovery. Although anaemia may be evident in the later stages of the bone marrow syndrome, it should not be considered a survival limiting sequalae.

Leukocytes changes as a function of dose Normal <1Gy Neutrophils, per cent of normal 1-2 Gy 2-5 Gy The function of the myelopoietic marrow cell renewal system is mainly to produce mature granulocytes, i.e. neutrophils, eosinophils, and basophils, for the circulating blood. Of these, the neutrophils, because of their role in combating infection, are the most important cell type in this cell line. The stem cells and those developing stages within the dividing and differentiating compartment are the most radiosensitive. These include the myeloblast, progranulocyte and myelocyte stages. As with the erythropoietic system, cell stages within the maturing (non-dividing) compartment and the mature functional compartment, i.e. granulocytes, are not significantly affected by radiation doses within the mid-lethal range. 3-7 days are normally required for the mature circulating neutrophil granulocyte to form from its stem cell precursor stage in the bone marrow. An ionizing radiation dose of 2 Gy or less usually causes a very gradual depression of counts to 50% or less with a nadir at more than 40 days. Doses greater than 2 Gy cause an initial paradoxical rise in counts, a rise that lasts only hours or days and is followed by a precipitous drop. This is caused by prompt demargination of white cells into the circulation. Any CBC taken during this paradoxical rise may be misinterpreted as evidence of infection. Doses greater than 5 Gy usually cause the precipitous drop to continue relentlessly to a nadir of zero or near zero in 3-4 weeks. Doses of 2-5 Gy cause a second abortive rise, which interrupts the precipitous drop in counts for several days and possibly as long as a week. This second abortive rise is caused by the products of final differentiation and entry into circulation of marrow PMN (polymorphic nucleated cell) precursor cells, which do not need to undergo further mitotic divisions. The extent and duration of this second rise varies; but classically, it lasts for approximately a week with a rise from about 50% to about 75% of normal. Then the neutrophil count continues dropping to a nadir of near zero to 20% of normal at around 25-35 days after exposure. Recovery of myelopoiesis lags slightly behind erythropoiesis and is accompanied by rapid increases in numbers of differentiating and dividing forms in the marrow. Prompt recovery is occasionally manifest and is indicated by increased numbers of band cells in the peripheral blood. >5-6 Gy Time after exposure, days

Thrombocytes changes as a function of dose Normal <1Gy Platelets, per cent of normal 2-5 Gy 1-2 Gy The thrombopoietic cell renewal system is responsible for the production of platelets (thrombocytes) for the peripheral circulating blood. Platelets along with granulocytes constitute two of the most important cell types in the circulation, the levels of which during the critical phase after mid-lethal doses markedly influence the survival or non-survival of irradiated persons. Platelets are produced by megakaryocytes in the bone marrow. Both platelets and mature megakaryocytes are relatively radioresistant; however, the stem cells and immature stages are very radiosensitive. During their developmental progression through the bone marrow, megakaryocytic precursor cells undergo nuclear division without cell division. The transit time through the megakaryocyte proliferating compartment in humans ranges from 4 to 10 days. Platelets have a lifespan of 8-9 days. Although platelet production by megakaryocytes may be reduced by a high dose of ionizing radiation, the primary effect is on stem cells and immature megakaryocyte stages in the bone marrow. As with the erythropoietic and myelopoietic systems, the time of beginning depression of circulating platelets is influenced by the normal turnover kinetics of cells within the maturing and functional compartments. Early platelet depression, reaching thrombocytopenic levels by 3-4 weeks after mid-lethal range doses, occurs from killing of stem cells and immature megakaryocyte stages and from maturation depletion of maturing and functional megakaryocytes. Regeneration of thrombocytopoiesis after sublethal irradiation normally lags behind both erythropoiesis and myelopoiesis. Supranormal platelet numbers which overshoot the preirradiation level have occurred during the intense regenerative phase in human nuclear accident victims. The mechanism of the prompt rapid recovery of platelet numbers after acute sublethal irradiation may be explained by the response of the surviving and regenerating stem cell pool to a human feedback stimulus from the acute thrombocytopenic condition. and marked increases in size of megakaryocytes contribute to the intense platelet production and eventual restoration of steady state levels. Blood coagulation defects with concomitant haemorrhage constitute important clinical sequalae during the thrombocytopenic phase of bone marrow and gastrointestinal syndromes. >5-6 Gy Time after exposure, days

Effects of radiation on lymphatic tissue B Normal monkey lymph node Germinal centre of normal monkey lymph node C D Lymphatic tissue and organs are highly sensitive to radiation. A. Normal lymph node from monkey. Normal architectural features include the capsule, cortex, paracortical regions, germinal centres, and medulla. The clear, sharp cortical-medullary delineation is evident. The medulla, cortex, germinal centres, and paracortical areas are well defined. B. Normal germinal centre The germinal centre of a normal monkey lymph node is shown magnified. The centre of the follicle, which stains light pink, is an area of predominantly B cell proliferation. A mantel zone of mixed T and B cells surrounds this central area. The paracortical regions, which are deep and lateral to the follicles, are predominantly T lymphocyte regions within the lymph node. C. Depleted lymph node The depleted lymph node shown is from a canine that received 9 Gy of cobalt-60 gamma irradiation. It shows moderate edema in the subcapsular sinuses. The sharp cortical- medullary functional architecture is not well defined because of the overall depletion of lymphoid cells within the cortex. D. Irradiated germinal centre Shown is a section of a germinal centre from a lymph node of a human who received 40 to 60 Gy of whole body irradiation. There is extensive necrosis of lymphocytes, characterized by pyknotic and karyorrhectic nuclei. The necrotic debris is being phagocytized, or cleaned up, by macrophages. Such destruction occurs within hours of irradiation. This patient died 35 hours after exposure. Lymphoid cells depleted in cortex of canine lymph node Germinal centre of irradiated human lymph node

Early changes in peripheral blood lymphocyte counts 0.25-1.0 Gy 1.0-2.0 Gy Early changes in peripheral blood lymphocyte counts depending on the dose of acute whole body exposure Circulating lymphocytes are quite sensitive to radiation and a measurable drop in the normal titre (1500-3000/mm3) can meter radiation exposure and indicate dose levels. Lymphocyte counts are usually the first blood counts to drop after exposure to ionizing radiation. A drop in lymphocytes occurs 24 to 48 hours after the injury. The speed and extent of the lymphocyte drop is linearly proportional to the severity of the dose to the bone marrow. A minor drop is noted after doses of 0.25 to 1 Gy. At about 1.5 Gy, the drop is around 20%. At 3 Gy, the count drops to 700/mm3; at 4 to 5 Gy, it drops to less than 500/mm3. A drop to zero (within 2 days) implies a dose greater of 6 Gy. Thus, the drop in lymphocyte count is a crude but simple and sensitive, and therefore important, estimation of severity of injury within 48 hours of exposure. For example, a patient whose lymphocyte count stays above 1500/mm3 after 48 hours may have received a clinically significant dose, but the overall prognosis is quite good. On the other hand, a patient whose count drops to less than 500/mm3 in 24 hours demonstrates a profound life threatening injury. 2-4 Gy 4-6 Gy >6 Gy

Lymphocytes changes as a function of dose <1 Gy Lymphocytes, per cent of normal 1-2 Gy The first detectable sign of whole body exposure is a decrease in blood lymphocytes. This decrease appears a few hours or days after irradiation and is related to the dose received, but also to the volume of irradiated bone marrow. This is due to the direct effect of ionizing radiation on lymphocytes, but also to the radiation induced death of proliferating haematopoietic cells that are not able to ensure the renewal of blood cells. 2-5 Gy >5-6 Gy Time after exposure, days

Effect of radiation on gastrointestinal tract The vulnerability of the small intestine to radiation is primarily the cell renewal kinetics of the intestinal villi. The renewal system is in the crypt and villus structures where epithelial cell formation, migration and loss occur. The four cell renewal compartments are: stem cell and proliferating cell compartment, maturation compartment, functional compartment, and the extrusion zone. Stem cells and proliferating cells move from crypts into a maturing only compartment at the neck of the crypts and base of the villi. Functionally mature epithelial cells than migrate up the villus wall and are extruded at the villus tip. The overall transit time from stem cell to extrusion on the villus for man is estimated as being 7 to 8 days. Because of the high turnover rate occurring within the stem cell and proliferating cell compartment of the crypt, marked damage occurs in this region by whole‑body radiation doses above the mid-lethal range. Destruction as well as mitotic inhibition occurs within the highly radiosensitive crypt and proliferating cell compartments within hours after high doses. Maturing and functional epithelial cells continue to migrate up the villus wall and are extruded albeit the process is slowed. Shrinkage of villi and morphological changes in mucosal cells, i.e., columnar to cuboidal to squamoid, occur as new cell production is diminished within the crypts. Continued extrusion of epithelial cells in the absence of cell production can result in denudation of the intestinal mucosa. Concomitant injury to the microvasculature of the mucosa and submucosa in combination with epithelial cell denudation results in hemorrhage and marked fluid and electrolyte loss contributing to shock. These events normally occur within 1 to 2 weeks after irradiation. A second mechanism of injury has recently been detected at the lower range of the gastrointestinal syndrome, or before major denudation occurs at higher doses of radiation. This response is a functional increase in fluid and electrolyte secretion on the epithelial cells without visible cell damage. This second mechanism may have important implications for fluid replacement therapy. Irradiated gastrointestinal mucosa

Pathogenesis of the gastrointestinal syndrome Depletion of the epithelial cells lining lumen of gastrointestinal tract Intestinal bacteria gain free access to body Haemorrhage through denuded areas Loss of absorptive capacity Denuding of sections of bowel, in turn, causes a host of pathophysiological sequelae. They include invasion of lumenal bacteria into the circulation, loss of fluid and electrolytes, loss of absorptive capability, significant gastrointestinal haemorrhage and loss of blood, and dysfunctional bowel motility, resulting in severe bloody diarrhoea, anaemia, ileus, severe electrolyte disturbances, and malnutrition.

Reproductive cell kinetics and sterility – male The cells of the reproductive system are highly sensitive to radiation effects. In the human male, stem cells and proliferating spermatogonia are highly sensitive. However, spermatids and mature sperm show considerable resistance. Also resistant are the interstitial cells of the testis, which control hormone production and secondary sexual characteristics. Therefore at sterilizing doses of 6 Gy, potency, fluid production of the prostate and seminal vesicles, as well as voice, beard and male social behaviour are not affected. With a turnover time for spermatogenesis (stem cell to mature sperm) of 64 to 72 days, sterility is never seen immediately after the radiation dose, because mature sperm are resistant to the killing effects of radiation. They can sustain inheritable genetic damage, however. Doses of about 6 Gy are required to permanently sterilize males (sterility occurs after several months). Although lower doses can also cause sterility after several months, the effect is temporary. Fertility and near-normal sperm counts return after 1 to 2 years. Dose rate has an unusual effect on the incidence of sterility in males. In animals it was found that dose protraction and fractionation were more effective in causing permanent sterility. This may be a result of synchronizing the sperm stem cells. Proliferating stem cells in the G2 phase or M phase of the cell cycle are killed by radiation. But since the dose is protracted at a constant low rate, resistant S and G1 cells eventually progress to the sensitive phases and are killed.

Reproductive cell kinetics and sterility – female Radiation destroys both ovum and maturing follicles. This reduces hormone production. Therefore radiogenic sterility in females can be accompanied by artificial menopause, with significant effects on sexual characteristics and secondary genitalia. Total dose, dose rate, and age are important factors in the final effect. Younger women seem better able to recover fertility than do older women. A dose of 2 Gy permanently sterilizes women over 40 but causes temporary sterility in women aged 35 and under. Menopouse was caused in 50% of younger women exposed to doses of 1.5-5 Gy. Women over 40 showed 90% menapouse at 1.5 Gy.

Human skin structure Cellularity Normal human skin exhibits a uniform layered appearance of cellularity, beginning with the basal layer. Epidermis – its average thickness is 70 µm, but basal cells are located in hair follicles at a depth of 200 µm. Derma - its average thickness is 1-3 mm.

Penetration of radiation through skin stuctures Alpha radiation is absorbed in superficial layers of dead cells within the stratum corneum Beta radiation damages epithelial basal stratum. High energy ß-radiation may affect vascular layer of derma, with lesion like thermal burn Gamma radiation damages underlying tissues and organs Skin layers The tissue of the skin most sensitive to radiation is the rapidly developing germinal or basal layer of epithelial cells. In the normal epidermal layer of skin, the cells that make up the basal germinal layer through the superficial layers are uniform in appearance and are well differentiated. Irradiation damages the moderately radiosensitive basal germinal cells. It disrupts the normal cellular appearance, causes atypical and bizarre cells in the upper layers, and results in a general loss of cohesiveness at the intercellular junction. Cellularity Normal human skin exhibits a uniform layered appearance of cellularity, beginning with the basal layer. The irradiated human skin is from the back of the hand of a patient exposed to 100 to 150 Gy of X rays. There is a decrease in the number of cells in the basal layer, and the remaining cells are irregular in shape and size. Some are separated, exhibiting acantholysis. There are occasional bizarre mitotic figures. In this condition, the entire epithelial layer will eventually ulcerate and slough.

Effect of radiation on skin The irradiated human skin is from the back of the hand of a patient exposed to 100 to 150 Gy of X-rays. There is a decrease in the number of cells in the basal layer, and the remaining cells are irregular in shape and size. Some are separated, exhibiting acantholysis. There are occasional bizarre mitotic figures. In this condition, the entire epithelial layer will eventually ulcerate and slough. Normal Irradiated

Pulmonary effects Irradiated lung tissue Pulmonary fibrosis Radiation doses in the 10-30 Gy also produce potentially life threatening pulmonary effects of respiratory insufficiency and pneumonitis, which will be seen 14-30 days after exposure. Pneumonitis is likely caused by a complex of factors, including breakdown of vascular permeability, fluid imbalance, free radical tissue interactions, infectious agent, biological and chemical toxin damage, and inhalation injury from heat, smoke, and fumes. Irradiated lung tissue Pulmonary fibrosis

Summary of lecture Bone marrow consists of progenitor and stem cells, the most radiosensitive cells in the human body and the most important in controlling infection Doses in tens of gray produce central nervous system syndrome, causing death before appearance of the haematopoietic or gastrointestinal syndromes The latter syndromes may occur after doses of as low as 2.5 and 8 Gy, respectively. Lesions in the brain are usually caused by damage to the vascular endothelium Lung lesions do not usually appear at radiation doses less than 10 Gy. Significant concern in partial-body irradiation and in radiation therapy Summary of lecture Bone marrow consists of progenitor and stem cells, the most radiosensitive cells in the human body and the most important in controlling infection Doses in tens of gray produce central nervous system syndrome, causing death before appearance of the haematopoietic or gastrointestinal syndromes The latter syndromes may occur after doses of as low as 2.5 and 8 Gy, respectively. Lesions in the brain are usually caused by damage to the vascular endothelium Lung lesions do not usually appear at radiation doses less than 10 Gy. Significant concern in partial-body irradiation and in radiation therapy

kindly given by doctor Elena Buglova, were used Lecture is ended THANKS FOR ATTENTION Quiz 1. Select the list that includes only highly radiosensitive tissues. a) bone marrow, lymphoid tissue, gastrointestinal epithelium b) lung, lens, central nervous system c) skin, connective tissue, muscle 2. Select the list of least radiosensitive tissues: a) vascular endothelium, lymphoid tissue, muscle b) muscle, central nervous system, bone c) skin, lung, embryonic tissues 3. Select the radiation induced lesion which is responsible for the majority of the radiation induced pathology. a) haematopoietic b) microvascular lesion c) central nervous system d) gastrointestinal 4. Select the foetal absorbed dose level at 7-13 weeks with a substantial risk of IUGR and CNS damage, so pregnancy termination is considered: a) 5 Gy b) 0.5 Gy c) 0.01 Gy 5. Granulocyte and thrombocyte counts drop to their nadir level after 2-5 Gy whole body exposure: a) immediately after exposure b) 48 hours after exposure c) 3-4 weeks after exposure In lecture materials of the International Atomic Energy Agency (IAEA), kindly given by doctor Elena Buglova, were used