ECOLOGICAL BIOCHEMISTRY - Study Guide - V. M. Isaienko 2005

Chapter 9. RADIORESISTANCE OF ORGANISMS

9.6.Human Radioresistance

A paramount problem in radiobiology is the protection of humans from the damaging effects of elevated levels of ionizing radiation. The formation of radiation injury in humans, as well as in other mammals, is decisively influenced by the dose, type, and regime of irradiation, as well as sex, age, the observation period, and other factors.

Radiation Safety Standards. Two primary opposing views exist regarding the determination and development of injuries resulting from low Doses of ionizing radiation, where the carcinogenic and Genetic consequences of exposure become paramount. According to one view, a threshold level of ionizing radiation exists below which no effect occurs. The second view posits the absence of any threshold for the BIOLOGICAL EFFECTS OF radiation (the threshold-free concept).

It should be noted that the choice of a concept for regulating the effects of ionizing radiation does not follow directly from the proposed views on threshold behavior. Historically, the regulatory system is based on METABOLISM/2.html">THE CONCEPT OF a threshold for the harmful action of damaging factors, including ionizing radiation. Its revision may be justified not merely by the simple statement that radiation action is threshold-free, but also by social expediency. This expediency, in turn, must be based on objective quantitative assessments of the actual existing risk.

The Radiation Safety Standards of Ukraine establish the following categories of individuals exposed to ionizing radiation: 1) Category A (personnel) — individuals who permanently or temporarily work directly with Sources of ionizing radiation; 2) Category B (personnel) — individuals who do not work directly with sources of ionizing radiation, but who may receive additional exposure due to the Location of their workstations in rooms and on industrial sites of facilities utilizing radiation and nuclear technologies; 3) Category C — the entire population.

The fundamental radiation-hygienic standard, the limit of which is the restriction of exposure for individuals of categories A, B, and C, is called the dose limit. Their numerical values are set at levels that cause deterministic radiation effects—those that appear only when a certain dose threshold is exceeded. The consequences of their manifestation depend on the magnitude of the received dose. In addition, the dose limit guarantees such a low probability of radiation effects occurring that it is deemed acceptable both for individuals and for Selection/30.html">The population as a whole. Stochastic effects of ionizing radiation are defined as threshold-free effects whose probability of occurrence exists at any dose, increases with dose magnitude, and whose relative manifestation does not depend on the dose. Stochastic effects include carcinogenic and genetic (transmitted to offspring) effects.

Different Tissues and Organs possess varying degrees of radiosensitivity. Those reacting most strongly to ionizing radiation include the Cytology/practical/86.html">Red Bone Marrow, Thymus, Spleen, Lymph Nodes AND lymphoid follicles of the digestive tract, and Gonads; to a lesser extent—the eyes, Liver, Lungs, Kidneys, Heart, Brain, nerve trunks, and Skin; while bones and tendons are even more resistant.

The varying sensitivity of organs to ionizing radiation determines the Organism's response depending on whether the entire body is irradiated uniformly (whole-body irradiation) or nonuniformly (partially). General uniform irradiation of the entire body causes the most severe damage.

Numerical values of external exposure dose limits are given in Table 9.8.

Class="center">Table 9.8

EXPOSURE DOSE LIMITS, mSv/year

For Category A individuals, the effective dose limit may not exceed 50 mSv/year, provided that it does not average more than 100 mSv over a 5-year period. Certain restrictions exist for women of reproductive age (under 45 years) and pregnant women classified as Category A: over any two consecutive months, local exposure (of the embryo and fetus) must not exceed a dose of 1 mSv. Furthermore, this dose must not exceed 2 mSv for the entire duration of Pregnancy.

It has been established that acute doses below 0.35–0.5 Gy do not cause radiation syndromes in humans, whereas the effects of chronic exposure at doses comparable to those of acute exposure are 5–10 times smaller.

According to the recommendations of the International Commission on Radiological Protection (ICRP), the recommended value for the maximum permissible dose (MPD) is 0.001 Sv/year for the entire population (Category C). This value is 10–100 times lower than the doses found in certain regions with naturally abnormally high radioisotope content in the soil. At the same time, it is known that individuals permanently residing in such areas show no deviations either in the frequency of carcinogenic or genetic diseases, or in phenotypic characteristics. In Ukraine, as already noted in Table 9.8, the permissible equivalent dose rate for specialists is 0.02 Sv/year, and in individual cases may be 0.05 Sv/year, provided that the total dose over a 5-year period does not exceed 0.1 Sv/year. For the general population, the MPD is set at 0.01 Sv/year.

Under The Influence of elevated doses of ionizing radiation, the combination of symptoms manifesting as a morbid state is referred to as radiation injury syndromes. Three MAIN TYPES OF such syndromes are recognized: 1) Syndrome I — bone marrow, or hematopoietic syndrome — predominant damage to Blood-forming organs (develops during acute injury at doses of 1–10 Gy); 2) Syndrome II — gastrointestinal syndrome — predominant damage to the digestive tract, Stomach and intestinal epithelial Cells (dose of 10–20 Gy); 3) Syndrome III — neuroparalytic, or Central Nervous system syndrome — damage to The Nervous System (dose of 20 Gy and above). With The Development of the latter syndrome, a toxemic form is sometimes distinguished—secondary damage to the nervous system (dose of 20–80 Gy) associated with a sharp drop in vascular tone accompanied by pronounced hypotension. This form of radiation sickness is often referred to as the vascular form. When exposed to doses exceeding 80 Gy, a cerebral form develops—primary damage to the nervous system.

The development of radiation injury syndromes is based on damage to cells in specific tissues, organs, and systems. For instance, the Development of the bone marrow syndrome is primarily associated with damage to stem Cells of the hematopoietic systems located in the bone marrow, progenitor cells of Hematopoietic organs, and lymphoid cells. Maturing myeloid cells—namely, megakaryocytes, monocytes, and macrophages—are somewhat more resistant to ionizing radiation. In the case of the gastrointestinal syndrome, the primary cause of its development is radiation damage to the epithelial cells of the gastrointestinal tract, whereas for the central nervous system syndrome, it is damage to the cells of this system and the disruption of neural networks.

Cellular death is understood primarily as the loss of proliferative capacity. Surviving cells are considered to be those capable of colony formation. Thus, the issue concerns the reproductive death of cells. This form of radiation-induced Cell injury is the most widespread.

Another variant of reproductive death in the progeny of irradiated cells is the formation of so-called giant cells, which arise from the fusion of two adjacent, most frequently 'sister' cells. Such cells are capable of 2–3 divisions, after which they die.

The main cause of reproductive cell death is structural alterations in DNA in the form of chromosomal rearrangements (chromosome aberrations).

Another form of radiation-induced cell inactivation—interphase death—occurs before cells enter The process of mitotic division. For most somatic cells of adult animals and humans, interphase death is recorded only after irradiation with doses reaching tens and hundreds of grays. At lower doses, the reproductive form of death is observed, the cause of which is structural chromosomal damage.

An important consequence of irradiation is the alteration of cell heredity, the carriers of which are various cytoplasmic Organelles. In this case, the functional activity of the progeny of irradiated cells decreases. This is possibly one of the causes of delayed radiation effects. Nevertheless, the primary cause of reproductive cell death during irradiation is damage to their genetic apparatus.

The processes of radiation-induced cell death that lead to cellular depletion of radiosensitive tissues and organs are based on interphase and reproductive cell death involving Two Types of cellular thanatogenesis—apoptosis and necrosis. The greater part of radiation-induced death associated with the loss of cellular reproductive capacity is the result of the loss of Genetic information due to chromosome aberrations.

The core mechanism of cellular depletion caused by reproductive cell death is the failure or inefficiency of DNA Repair. Facilitating conditions to enhance the effectiveness of cell death can be one of the ways to mitigate radiation effects at both the tissue and organism levels.

Radiation injuries are classified into acute and chronic, which, in turn, can be generalized or localized. They occur when the body is exposed to high doses of any type of radiation, either externally or through the internal intake of radioactive substances. Acute injuries develop from short-term exposure to high doses, whereas chronic injuries result from prolonged radiation exposure. Generalized injuries occur when large volumes of the body are irradiated and are referred to as radiation sickness, while localized injuries (from localized exposure) are termed radiation injuries or radiation Burns, as their Clinical presentation resembles thermal burns.

Acute Radiation Sickness (ARS). ARS develops from external irradiation at a dose exceeding 1 Gy, received either instantaneously or over a short period (from 3 to 10 days), as well as from the internal intake of radionuclides that create an equivalent absorbed dose. This condition is characterized by a pronounced initial reaction, a latent period whose duration is inversely proportional to the severity of the disease, a peak phase accompanied by impaired function of various organs and systems, and a recovery period.

The incidence of fatalities in the dose range of 2–10 Gy increases from 5 to 100%. They are observed predominantly within 5–8 weeks.

Initial Reaction of ARS. The time of onset of initial reactions from the moment of exposure, their duration and severity, as well as the manifestation of symptoms, are of fundamental importance for predicting the course of ARS. The main symptoms of ARS include: 1) dyspeptic symptoms (nausea, vomiting, diarrhea); 2) general clinical symptoms (weakness, headache, altered motor activity, fever, impaired consciousness, etc.); 3) hematological symptoms (lymphocytopenia, neutrophilic leukocytosis); 4) local symptoms (damage to the skin, mucous membranes, etc.).

In mild ARS (radiation dose of 1–2.5 Gy), most affected individuals may experience nausea, vomiting, weakness, reduced concentration, and other symptoms During the first 24 hours. Gradually, these symptoms subside.

Symptoms of radiation injury become more pronounced in moderately severe ARS (dose of 2–4 Gy). They begin to manifest as early as 1.5–3 hours post-irradiation and intensify as the dose increases.

Vomiting is accompanied by a drop in blood pressure. Exposure to doses of about 4 Gy leads to flushing of the face and scleral hyperemia, which resolve within 2–3 days. Most symptoms of the initial reaction in moderate ARS disappear during the first 24 hours.

In severe ARS (dose of 4–6 Gy), the initial reaction appears 30 minutes to 1.5 hours after exposure and is more pronounced. It typically resolves within 1–2 days. Facial and scleral hyperemia disappears by days 4–5. Marked asthenia is observed prior to the development of agranulocytosis and associated infectious complications.

Initial reactions of very severe ARS (dose of 6–10 Gy) appear within 30 minutes. Intractable vomiting occurs, potentially accompanied by diarrhea and pronounced hyperemia. Blood changes also take place, presenting as an initial leukocytosis that lasts for about a day.

At higher doses, as previously noted, the intestinal form of ARS develops (dose of 10–20 Gy), where death occurs on days 8–16. The toxemic form of ARS manifests at doses of 20–80 Gy, resulting in death on days 4–8, while the cerebral form (dose exceeding 80 Gy) leads to death on days 2–3. Doses exceeding 150 Gy cause death during exposure—so-called "death under the beam." Doses of 250–300 Gy and above cause instant fatality.

Latent Period of ARS. Following the resolution of the initial reaction in the course of ARS, a period of apparent well-being begins, during which nausea and diarrhea subside, and initial leukocytosis, skin hyperemia, and scleral redness disappear.

In mild ARS, the latent period is typically absent, and Clinical symptoms of the disease do not manifest.

In moderate ARS, patients' general condition changes only slightly, though they find physical and intellectual work difficult and tire easily. Simultaneously, blood changes occur—fluctuations in the counts of lymphocytes, platelets, and reticulocytes.

In severely ill ARS patients, well-being improves for a few days after the initial reaction period ends, but significant blood changes take place—leukocyte and platelet counts drop drastically, and agranulocytosis develops, which defines the peak of the disease.

In very severe ARS, patients' well-being also improves for a few days, but a critical drop in peripheral blood elements, particularly platelets, is observed. The symptoms of the initial reaction are replaced by damage to the oral and gastrointestinal mucosa, as well as the skin.

During the latent period, epilation (from Lat. e(x)—out and pilus—Hair removal) is observed. It occurs As a result of doses of 2.5–3.0 Gy affecting scalp hair. With doses of about 6 Gy, pronounced epilation manifests on days 4–17, and with doses of 6–10 Gy, on days 8–9. HEAD irradiation at doses of 12–15 Gy leads to permanent hair loss. Doses of 10 Gy and above cause epilation of eyelashes and eyebrows.

Peak Period of ARS. A significant decrease in peripheral blood leukocyte counts over several days indicates the onset of the peak period. The development of agranulocytosis is primarily determined by a decrease in the number of granulocytes and platelets in the peripheral blood. As a result of doses around 2 Gy, agranulocytosis develops on days 30–33 post-irradiation and lasts for 7–8 days; at doses around 4 Gy, it develops on days 10–20, and at 6 Gy, on days 7–8.

The peak period of ARS is characterized by leukopenia, thrombocytopenia, and related infectious diseases. Pneumonia, esophagitis, intestinal ulcers, and Sepsis may develop. The onset of agranulocytosis is preceded by 1–3 days of bone marrow cellular depletion and aplasia. Bone marrow irradiation at doses exceeding 6 Gy leads to the destruction of almost all stem cells. In this case, bone marrow transplantation becomes the only hope for survival. However, at irradiation doses of about 10 Gy, lethal intestinal injuries develop, rendering bone marrow transplantation ineffective.

Irradiation of the abdomen with doses exceeding 5 Gy leads to enterocolitis and hepatitis. Doses of 2–4 Gy cause damage to the oral mucosa. The impact of higher doses, as already mentioned, also causes severe injury to the intestinal mucosa, including perforations, Peritonitis, and intussusception. If these phenomena are accompanied by agranulocytosis and thrombocytopenia, saving the patient's life becomes impossible.

Recovery Period. If the outcome of ARS is non-fatal, the recovery period ensues. Its consequences and duration depend on the severity of ARS, lasting anywhere from 2–4 months to 1–3 years.

Immediate recovery begins right after agranulocytosis resolves. Body Temperature drops, and well-being improves. Blood parameters normalize: leukocyte, platelet, and reticulocyte counts increase. Bone marrow regeneration also takes place—the number of cells undergoing mitotic division increases, with immature cells predominating over mature ones. The condition of the mucous membranes of the Oral Cavity, nasopharynx, and gastrointestinal tract also improves. Hair begins to regrow. At the same time, for a long time, The Cardiovascular system's response to physical exertion differs from the physiological norm. Shortness of breath, Muscle and heart pain, and delayed wound healing may still be observed.

Main principles of ARS Treatment. During the initial reaction period, therapeutic measures are primarily reduced to providing supportive care using antiemetic drugs. In cases of overexposure, a specialized medical examination is required. Critical milestones for moderate severity are days 12–20 post-irradiation; for severe severity, days 5–12; and for very severe severity, the first day or even hours.

Patients with moderate and severe forms of ARS during the peak period are prescribed broad-spectrum Antibiotics and symptomatic treatments aimed at normalizing the Functions of the cardiovascular and central nervous systems.

In very severe forms of ARS, decontamination of the mucous membranes and skin is also performed using non-absorbable antibiotics and antiseptics. Bone marrow transplantation is performed if necessary.

Radiation sickness caused by internal exposure. The Factors Determining the biological effects of radioactive substances entering the body include: the routes of entry; the Physical state and Chemical Structure of the substances, along with their solubility and absorption rate at the site of application; the total radionuclide activity, radiation type, and energy spectrum; the pattern of distribution and redistribution of radioactive substances within the body; their pathways of elimination, excretion rate, and half-life period; the relative sensitivity of tissues to ionizing radiation and radioisotopes as chemical elements; as well as the functional state of organs and systems.

Radioactive substances may enter the body through food, drinking Water, air, intact skin, or wounds, either in a single instance or repeatedly. In small amounts, incorporated radioisotopes do not cause detectable pathologies; in moderate amounts, they cause minor disorders; and in large amounts, they lead to the development of radiation sickness. The latter develops when radioactive substances enter the body in quantities exceeding the maximum permissible level by 6 to 10 times.

When highly resorbable radioisotopes, such as cesium, strontium, and others, enter the body, the course of radiation sickness is largely independent of the routes of entry and is primarily determined by their specific tissue affinity (tropism).

When poorly absorbed radioisotopes enter the organism, the clinical presentation is driven chiefly by the route of administration, with the entry sites being predominantly affected. For instance, oral ingestion of cesium, yttrium, lanthanum, uranium, and certain other radioisotopes with limited ability to pass from the intestinal lumen into the BLOOD AND LYMPH results in diffuse damage to the gastrointestinal tract, manifesting as ulcerating and necrotizing enterocolitis.

An important factor in the development of radiation sickness from incorporated radioisotopes is their distribution pattern within the body. For example, radioisotopes of cesium, rubidium, niobium, and polonium accumulate more or less evenly in soft tissues, predominantly causing muscle and splenic atrophy, damage to the Testes, and suppression of hematopoiesis. Uranium radioisotopes initially affect the digestive tract and subsequently the kidneys. Heterotropic radioisotopes, such as cesium, lanthanum, and gold, induce lesions in the gastrointestinal mucosa, as well as liver cirrhosis, endocrine gland tumors, and Bone tissue damage. Osteotropic radioisotopes—including strontium, barium, yttrium, radium, and plutonium—suppress bone marrow hematopoiesis and cause bone tissue damage.

Internal radiation exposure can result in mild, moderate, or severe radiation sickness. Depending on the specific effects of the incorporated radioisotopes, damage may involve either individual organs or entire systems (such as hematopoiesis, Digestion, excretion, Respiration, Vision, and reproduction, as previously noted).

Upon The entry of radioisotopes into the body, early deployment of Methods and agents aimed at reducing their absorption and accelerating their elimination is essential. This is achieved through the administration of sorbents, gastric lavage, laxatives, and enemas. Substituting radioisotopes with stable elements by consuming enriched preparations or food products at all stages of their metabolism helps accelerate their excretion. To support the optimal function of organs and systems most sensitive to incorporated agents, appropriate supportive therapy must be administered.

Infectious and hemorrhagic complications arise from the intake of large quantities of radioisotopes that deliver whole-body radiation doses exceeding 10 Gy over a few days. Under such exposure levels, the administration of antibiotics and symptomatic treatments is mandatory.

Chronic radiation sickness (CRS). This condition develops as a result of prolonged exposure of the organism to ionizing radiation at doses exceeding maximum permissible limits.

The Characteristic Features of CRS are: 1) damage to organs and systems, the severity and onset timing of which are determined by the cumulative dose, type, and intensity of radiation, as well as the physiological Structure and function of the affected organ; 2) a protracted and wave-like clinical course, since reparative and adaptive reactions develop concurrently with progressive tissue damage.

Two main developmental patterns of CRS are distinguished: 1) The Emergence of syndromes resulting from total external irradiation or the intake of isotopes that quickly and evenly distribute across all organs and tissues; 2) the predominant damage to specific organs and systems resulting from intensive irradiation by isotopes with a pronounced deposition selectivity, or from localized external radiation sources.

Under prolonged radiation exposure and following its cessation or intensity reduction, the following conventional periods are distinguished: 1) the formation stage, or CRS proper; 2) recovery; 3) long-term consequences.

The first period is defined by the timeframe during which the bulk of the cumulative radiation burden accumulates—namely, the duration of work under adverse conditions, extending into the immediate years (up to 1—3 years) following the cessation or sharp decrease in radiation intensity. It is during this period that the primary clinical syndrome of CRS, along with its characteristic manifestations, is formed.

Depending on the radiation dose and individual biological characteristics, the severity of clinical manifestations can vary. The severity of CRS can be mild, moderate, severe, or extremely severe. In essence, these represent phases in the evolution of a single pathological process. If high-dose irradiation continues, these phases succeed one another. Depending on the timing of radiation cessation (or its reduction to a permissible level) and The Nature of the changes developed by that point, the disease plateaus at a certain degree of severity and ceases to progress further.

The recovery period in CRS typically begins 1 to 3 years after the cessation of exposure or a sharp drop in its intensity (below 0.05 Gy/year). By this time, the primary cycle of destructive changes is generally complete, and earlier-initiated reparative processes clearly predominate. Chronic radiation sickness may culminate in: 1) complete recovery—clinical healing; 2) recovery with residual defects; 3) stabilization of previously observed changes; 4) deterioration of health accompanied by the development of various syndromes that are partly radiation-induced but polyetiological in origin (such as leukemia, anemia, or accelerated biological Aging).

CRS presents with varying degrees of severity that correspond to specific ranges of cumulative doses and prolonged exposure intensities. For disease caused by uniform total-body irradiation, the severity criteria include: 1) the extent of the pathological process within the body, i.e., involvement of organs and systems with varying radiosensitivity; 2) The Nature and depth of changes (whether functional or anatomical structural alterations);

3) the recurrence rate of pathological manifestations and the completeness of recovery following the cessation or significant reduction of radiation exposure (to the maximum permissible level) and the administration of treatment.

Experience accumulated in radiation medicine indicates that CRS can occur in individuals who have undergone prolonged, continuous, or systematically repeated external exposure to low-dose ionizing radiation exceeding permissible limits. The condition can also be triggered by the continuous action of radioactive substances that entered the body via the respiratory tract, damaged skin, or digestive tract, and became firmly anchored in tissues for a more or less extended period (depending on their half-life and clearance rate). CRS may also develop as a result of combined internal and external exposure. Essentially an occupational disease, chronic radiation sickness can occasionally arise as a complication of therapeutic ionizing radiation use. Depending on its course and severity, CRS is categorized into several degrees. Each represents a specific stage in the development of the pathological process, although the grading of the disease remains somewhat conventional. CRS is a systemic condition characterized by a significant depression of immunological reactivity. The clinical picture of CRS predominantly encompasses Disorders of the nervous, hematopoietic, cardiovascular, and digestive systems, the kidneys, as well as disturbances in metabolic processes and endocrine functions.

A different clinical course is observed in radiation sickness caused by radionuclides with a pronounced organotropism or by localized external irradiation, where predominantly local damaging effects are noted.

Mild degree of CRS severity. This stage is primarily characterized by autonomic-visceral disorders, initial asthenic manifestations, and moderate changes in peripheral blood composition. Patients report a decline in well-being, increased fatigue, reduced physical and mental performance, Sleep disturbances, and heightened excitability. Concurrently, Digestive System disorders occur, such as intestinal and biliary dyskinesia, alongside dyspeptic symptoms.

Vegetovascular dystonia and internal organ dysfunction, coupled with developing initial asthenization, lead to astheno-vegetative syndrome. Over time, asthenic symptoms may become more pronounced, manifested by intensified headaches, periodic nausea and dizziness, memory decline, and progressive general weakness.

Moderate degree of CRS severity. This stage is characterized by the further progression and severity of astheno-vegetative disorders. Early signs of central nervous system damage may appear, including reflex alterations, vestibular and neurovascular regulatory disorders, and proximal tachycardia. Cardiovascular system dysfunctions also develop.

At this severity level, the hematopoietic system is particularly affected. The leukocyte count in peripheral blood drops, with leukopenia exhibiting a persistent character accompanied by neutropenia and lymphocytopenia. Protein, carbohydrate, and Cholesterol Metabolism disorders are observed in the blood.

Additional complications may include endocrine dysfunction, altered intestinal motility, initial cellular depletion of the bone marrow, development of toxic hepatitis, and an increased Susceptibility to infectious diseases.

Severe degree of CRS. This stage features profound and severe changes: marked organ dystrophy, suppression of hematopoiesis, loss of tissue regenerative capacity, and the onset of cutaneous and nasal bleeding. Bone marrow cell maturation is arrested. Severe dysfunctions of the nervous system are observed, including the development of encephalopathy. The digestive tract is affected, The Immune System is severely compromised, and symptoms such as hair loss (epilation) and nail brittleness appear. The patient's general condition deteriorates sharply.

Very severe chronic radiation sickness (CRS) is characterized by extreme exhaustion of the patient. Bone marrow hypoplasia or aplasia, hemorrhages, sepsis, ulceronecrotic lesions of the oral mucosa, nasopharynx, and digestive tract, nervous system disorders, as well as dystrophic and necrotic changes in tissues and organs are typically observed. With an increased duration of exposure and a higher cumulative dose, a fatal outcome occurs.

Nowadays, a severe degree of CRS is unlikely thanks to preventive and therapeutic measures. A fatal outcome may be caused by the failure of vital organs and systems. It is important to account for the intensification of the chronic damaging effects of ionizing radiation by other factors: toxic chemicals, electromagnetic non-ionizing radiation, smoking, alcohol abuse, malnutrition, poor living conditions, etc.

Treatment of patients with CRS. It can be effective only under the conditions of terminating re-irradiation, conducting a comprehensive diagnostic evaluation of the patient to determine the extent of systemic damage, and prescribing appropriate treatment. The management of mild and moderate forms of CRS necessarily involves general supportive measures and a high-calorie, vitamin-enriched therapeutic diet.

Asthenic conditions are treated with neurotropic agents. In cases of infectious complications, antibiotics are used. Symptomatic agents are employed to normalize the functioning of Internal Organs and the nervous system. Blood transfusions are sometimes advisable.

When treating patients with severe CRS, special attention is paid to anti-infective measures and the management of hemorrhagic syndrome. Combination therapy is prescribed using broad-spectrum antibiotics and antifungal drugs, as well as medications that reduce vascular wall permeability (Vitamins C, K, and P, calcium chloride, etc.). Symptomatic agents are used to normalize The activity of the cardiovascular, respiratory, digestive, endocrine, and nervous systems, stimulate the immune system, etc. Whole blood, plasma, red blood cell, leukocyte, and platelet concentrates are systematically transfused.

Reproductive function under the action of ionizing radiation. As noted earlier, the gonads belong to the organs most highly sensitive to ionizing radiation. It is believed that in humans, at an absorbed dose rate of 0.001 Gy/day over 1–2 years (reaching a cumulative dose of 1.0–2.25 Gy), alterations in sperm motility and degenerative-dystrophic Changes in the form of testicular atrophy already occur. Such noticeable changes are observed at a dose rate of 0.005–0.1 Gy/day—manifesting as a significant reduction in sperm count and testicular mass, which may still be followed by the gradual restoration of normal testicular function. Permanent male sterility can occur in individuals exposed to testicular irradiation (e.g., during radiotherapy) as a result of 30–40 Gy.

Unlike Spermatogenesis, all female ovarian oocytes are formed during the embryonic developmental period and thereafter merely mature. It is estimated that as a result of a dose rate of 0.01 Gy/day, only upon reaching a cumulative dose of 0.1 Gy does a decrease in the number of primary ovarian follicles occur, which does not noticeably progress further due to such a dose rate. Chronic exposure at 0.00001–0.0001 Gy/day with a total absorbed dose of about 0.4 Gy causes minor and relatively infrequent variations in the Menstrual cycle duration without adverse effects on the course of pregnancy, childbirth, or infant health.

Female sterility occurs under the influence of ionizing radiation at a dose of about 10 Gy and becomes permanent due to the destruction of all primary follicles.

The impact of ionizing radiation on the embryo and fetus. The radiosensitivity of the embryo and fetus is much higher than that of a postnatal or adult human organism. Therefore, radiation effects in them exhibit certain distinct features.

The INTRAUTERINE DEVELOPMENT OF a child takes place in 3 distinct periods: pre-implantation, Organogenesis, and the fetal period. Pre-implantation begins at the moment of egg Fertilization. Undergoing rapid division, the fertilized ovum simultaneously travels through the fallopian tube from the Ovary to the Uterus for 9 days, where it implants into the uterine mucosa on the 11th day post-fertilization.

An absorbed dose of radiation that is sufficiently high during this period proves fatal to the tiny embryo, which consists of only a few

cells. At lower levels of exposure, the damage is not as catastrophic, and the embryo retains the capacity for normal development.

Radiological studies indicate that during the pre-implantation period, the radiosensitivity of the embryo heavily depends on the duration of exposure (in days and hours). Changes in radiosensitivity are evidently driven by The Cell count the embryo has already attained at the moment of irradiation and the phase of the Cell Cycle these cells are in.

The highest radiosensitivity is observed immediately after sperm penetration into the egg. In experiments involving X-ray and y-irradiation, the death of 50% of sperms was observed at a dose of 0.15 Gy at the moment of penetration and only at 0.3 Gy after 4–6 hours. At this time, the process of chromosome duplication preceding the First Division begins in the fertilized egg. The second peak of radiosensitivity coincides with the time the embryo emerges from the blastocyst membrane immediately before implantation.

Following the implantation of the embryo into the uterine mucosa, organogenesis begins—a period that in humans lasts from the 9th day to the 6th week of post-conception life. During this period, embryonic Cell Differentiation and the formation of organs and body parts commence. The disruption of embryonic development during organogenesis is preceded by a chain of diverse reactions and events. Their type and duration depend on the dose magnitude and, particularly, on the developmental stage at the time of irradiation. The dominant type of radiation damage during the formation of future organs is represented by various teratogenic defects and malformations.

The most characteristic manifestations of radiation-induced teratogenic effects include alterations in the forming Skeleton. Various skeletal damages have been recorded within the dose range of 0.05–0.25 Gy on the 7th day post-conception.

During the organogenesis period, cell specialization is frequently accompanied by their migration. The central nervous system undergoes a particularly complex development, which accounts for its extreme sensitivity to radiation. Nervous system defects are induced by doses on the order of 0.1 Gy at the most sensitive developmental stages. Among the consequences of irradiation during Embryogenesis, Structural and functional disorders of the central nervous system rank first. A high percentage of microcephaly combined with mental retardation has been noted. The minimum dose causing such pathology in children exposed during the atomic bombings of Hiroshima and Nagasaki proved to be lower than 0.2 Gy. Brain dysfunction was recorded in them as a result of exposure to a dose of about 0.1 Gy.

Fetogenesis, The final stage of fetal development in humans, begins at the 7th week post-conception. This is the most thoroughly studied period of intrauterine development from a radioembryological perspective. It has been established that ionizing radiation at 4–11 weeks of gestation causes the formation of anomalies in various internal organs. Irradiation at 11–16 weeks induces microcephaly, persistent growth restriction of the fetus, and genital anomalies. As a result of ionizing radiation exposure at 16–20 weeks of gestation, moderate microcephaly and growth retardation are observed. Exposure after the 30th week of gestation is more likely to cause functional disorders rather than morphological ones.

Irradiation during intrauterine development carries a high probability of tumorigenesis. Among oncological diseases, Brain Tumors constitute a significant proportion. The consequence of exposing pregnant women to doses of 0.1–0.2 Gy was the birth of children with developmental defects (growth retardation, mental retardation).

An Analysis of the manifestation dynamics of specific malformations shows that in areas contaminated with radioisotopes as a result of the Chernobyl accident, the frequency of all malformations increases, especially cleft lip and palate, renal and ureteral duplication, polydactyly, and neural tube defects. Dominant Mutations play a major role in the Etiology of polydactyly. Araphias (both facial and neural tube defects) are predominantly multifactorial disorders, whereas THE CONTRIBUTION OF genetic factors to the occurrence of renal and ureteral duplication remains undetermined. In medical abortuses (miscarriages), no increase in aneuploidies (mono- or trisomies) is observed, nor is it possible to detect a direct teratogenic effect involving the death of organ rudiment cells as one of the radiobiological Reactions of the embryo.

Radiation-induced carcinogenesis. Numerous studies indicate that as a result of ionizing radiation exposure, the incidence of malignant tumors of various localizations increases in humans. Most malignant tumors arise from a single (initiating) cell that undergoes transformation. The initial stage of malignant cell transformation is the emergence of an oncogene mutation (tumor suppressor Gene). Oncogenes, which are responsible for executing the genetic program in the cell that shifts it into a malignantly altered state, pre-exist in the normal cellular genome. The execution of the oncogene program within the cell can be triggered by both external and internal organismal factors.

The process of developing radiation-induced cell damage shares a common stage with Damage caused by chemical carcinogens—post-Replication DNA repair. Errors in this process are considered universal sources of mutations. Furthermore, as a result of the Introduction/43.html">Action of Certain carcinogens, the targets of post-replication repair—overlapping gaps—turn out to be identical to those affected by ionizing radiation

These gaps are not removed by pre-replication repair and pass through the Replication fork.

As a rule, a considerable amount of time elapses between exposure and the development of tumors, due to the existence of a latent period. In humans, this period can last for over 30 years for certain malignancies. The manifestation timeframe for radiation-induced leukemia, which has the shortest latent period, is typically around 10 years.

Leukemias also belong to malignant diseases whose incidence is higher than that of other oncological disorders caused by ionizing radiation. This is due both to the oncogenic action of ionizing radiation and its direct impact on blood cell reproduction.

Experiments on rats have shown that a several-fold increase in the incidence of leukemia compared to the control group can occur following acute irradiation at a dose of 5–7 Gy, and at least 12–15 Gy under fractionated exposure. Notably, the higher the dose rate, the greater the likelihood of developing leukemia and other oncological diseases.

A specific feature of the oncogenic action of ionizing radiation is that total-body irradiation induces a significantly higher incidence of leukemia than local exposure (e.g., of the lymph nodes). Furthermore, acute total-body exposure to relatively high doses causes leukemia more frequently than fractionated and, even more so, chronic exposure.

It is estimated that prolonged irradiation of the human bone marrow increases the incidence of leukemia at doses of 5–35 Gy. For instance, among survivors of the atomic bombings of Hiroshima and Nagasaki exposed to doses of 10–14 Gy in 1960–1980, the annual incidence of leukemia per 1 million population was 563–1336 cases, whereas for those exposed to 0.3–2.0 Gy, it was 42–68 cases. It is worth noting that the spontaneous level of leukemia is 11 cases per 1 million population.

Leukemia is one of the most common radiation-induced cancers, but other malignancies also occur, particularly in tissues and organs with high cellular proliferative activity—such as the Ovaries, testes, Mammary Glands, and others. For example, in mice, the threshold dose that does not cause the development of testicular tumors can be considered 0.35 Gy for acute irradiation and 0.9 Gy for chronic irradiation.

It is believed that the threshold doses for the oncogenic effect of ionizing radiation in humans range within 0.5–5.0 Gy. However, as previously noted, the currently dominant concept is the linear no-threshold model of ionizing radiation action. This means that despite a sharp decrease in the frequency of radiation-induced oncogenesis as the dose decreases, there remains a very small, yet non-zero, probability of malignant tumor development even at doses lower than 0.5 Gy.

The Effect of ionizing radiation on lifespan. The most widespread hypothesis regarding the mechanisms of organismal aging attributes aging to the accumulation of DNA damage over time: single-strand and double-strand breaks, deletions, protein-DNA cross-links, etc. Ionizing radiation likewise induces similar DNA structural alterations within cells.

It should be noted that the state of the Endocrine System determines the duration of developmental cycles and the turnover of cell populations in the tissues of various organs, including those highly sensitive to ionizing radiation (hematopoietic tissues, mucosal epithelium, etc.).

There is also The phenomenon of radiation-induced apoptosis—the acceleration of genetically programmed cell death.

The effect of ionizing radiation on the lifespan of mice and rats has been studied relatively well, unlike that of humans. Specifically, it has been established in mice that following acute γ-irradiation, the expected lifespan is reduced by approximately 5.4% per 1 Gy of dose. This reduction in lifespan depends on the radiation dose—the higher the dose, the more pronounced the effect. There is also a dependence of this effect on the type of radiation. For instance, for neutrons, the effect is nearly 10 times greater than for γ-rays. Note that at equal doses, chronic exposure to ionizing radiation causes a smaller reduction in lifespan than fractionated exposure, and even less than acute exposure. Thus, at a dose rate of 0.1 Gy/week, the lifespan of mice is reduced by approximately 10%.

Calculations indicate that an absorbed dose of 0.001 Gy/day shortens human lifespan by 0.5–0.6%, but such changes cannot be detected against the Background fluctuations of this indicator, particularly due to the Influence of other adverse factors.

Prophylactic radioprotective agents. Substances capable of preventing or mitigating the severity of radiation-induced injuries when used prophylactically are called radioprotectors. In a broad sense, radioprotectors include Radioresistance stimulators and blockers of radionuclide uptake into tissues and organs (substances that protect against internal irradiation).

Substances that act directly as radioprotectors exhibit a protective effect upon prophylactic administration, which manifests as the preservation of the life of the irradiated organism or the mitigation of the severity of radiation injury, thereby prolonging performance capacity and lifespan. Unlike other radioprotective agents, the radioprotective effect is their primary pharmacological property. Radioprotectors are effective only under conditions of

prophylactic use; their action is manifested in the first minutes or hours after administration, under relatively short-term and acute irradiation.

Most often, the degree of radioprotection provided by radioprotectors is characterized by the dose reduction factor (DRF), which reflects the fold decrease in the degree of injury and is calculated as follows:

where DD_50/30 is the median lethal dose at which 50% of the irradiated organisms die within 30 days.

Since, as already mentioned, an increase in dose leads first to the hematopoietic syndrome, followed by the gastrointestinal and cerebral syndromes, it is advisable to classify radioprotectors into three groups according to their purpose: myeloprotectors, and cerebroprotectors.

The action of myeloprotectors is primarily aimed at protecting the hematopoietic organs, the damage to which determines the severity of radiation sickness resulting from doses of 1–10 Gy.

The DRF value for promising myeloprotectors can reach 1.5–1.7. The Mechanism of their action is primarily determined, depending on their structure, by their ability to inhibit nucleoprotein metabolism and mitotic division processes or to induce a state of Hypoxia. The latter leads to the development of the so-called oxygen effect. It is known that when ionizing radiation acts in the presence of oxygen, peroxide free radicals are formed, which enhance the impact of radiation. A decrease in oxygen content diminishes this effect.

Drugs that predominantly induce hypoxia include biologically active amines and their agonists—serotonin and other derivatives of indolylalkylamines (in particular, mexamine, adrenaline, mesaton, clonidine, epinephrine, etc.).

One of the effective hypoxia-inducing radioprotectors is indralin (an indralin agonist of alpha-adrenoreactive structures). Its action appears within 5–10 min and persists for 1 hour under short-term, high-dose exposure to ionizing radiation (γ-rays, electrons, protons, fast neutrons). The radioprotective effect of indralin is retained even when irradiated at doses exceeding the minimum lethal dose by 1.5–2 times.

Another, most numerous group of myeloprotectors, whose MECHANISM OF ACTION is realized at THE CELLULAR LEVEL, consists of sulfur-containing compounds, in particular mercaptoethylamine, its disulfide, cystamine, and other derivatives of these compounds (gamaphos, cystophos, etc.). Cyclic analogs of cystamine—thiazolines and thiazolidines—act longer than cystamine itself. This is because they are slowly cleaved in the organism upon conversion into the active form. One of the important radioprotectors containing an SH-group is Glutathione. It is present in Blood Cells in large quantities and ensures a high level of organism resistance to ionizing radiation.

Sulfur-containing radioprotectors are administered orally, and therefore a time of 40–50 min after intake is required for their accumulation in radiosensitive organs. Their radioprotective effect lasts 3–4 hours, after which the administration of the radioprotector can be repeated if necessary. They are relatively effective compounds; their DRF is typically 1.3–1.4, and for cystamine, 1.5.

The radioprotective properties of sulfur-containing compounds are determined mainly by the presence in their structure of a free and easily releasable SH-group. Due to this, they act as reducing agents capable of scavenging free radicals generated by irradiation. In addition, sulfur-containing radioprotectors possess a pronounced chelating ability for divalent metals, which are catalysts of oxidative processes. These compounds are also capable of inducing a hypoxic effect through The oxidation of sulfhydryl compounds. Another important property of sulfur-containing radioprotectors is their ability to temporarily inhibit the mitotic activity of cells in radiosensitive tissues, particularly hematopoietic ones, by influencing DNA Synthesis AND mitosis. This makes it possible to arrest the cell cycle in a radioresistant state.

Under the action of ionizing radiation at doses of 10–20 Gy, as previously noted, radiation sickness develops, in the clinical picture of which intestinal tract damage predominates, caused by the development of specific radiation-induced enteritis.

Currently, there are no effective pharmacological agents for protection against this type of radiation injury, although experimental data indicate the potential for developing enteroprotectors. Specifically, it has been demonstrated that the myeloprotectors cystamine and gammaphos exert a certain protective effect on the proliferation of intestinal mucosal enterocytes. Certain derivatives of thiazole, triazole, thiadiazine, and heteroalkane increase the radioresistance of intestinal epithelial stem cells, thereby extending the lifespan of irradiated animals by 4 to 5 times and causing the intestinal form of radiation sickness to «shift» toward the bone marrow syndrome. A similar effect on enterocyte stem cells is exerted by certain Prostaglandins and their analogues. The mechanism of their radioprotective action is associated with a reduction in oxygen consumption by intestinal epithelial cells.

The dominant lesion of the central nervous system, as noted previously, occurs as a result of ionizing radiation doses exceeding 80 Gy, leading to the cerebral form of acute radiation sickness. It is characterized by extremely severe cerebrovascular disorders—loss of consciousness, disorientation, ataxia, convulsions, respiratory failure, a sharp drop in blood pressure, and other complications. Death occurs within the first 3 days, or within hours when exposed to doses of 150 Gy and above. According to current concepts, the leading role in the development of central nervous system disorders is played by an extremely intensive depletion of NADH and ATP levels, which leads to deenergetization and neuronal death. The prophylactic administration of pharmacological agents that prevent the depletion of energy-rich compounds (certain metal-containing complexes, glutamatergic blockers, amides, aromatic carboxylic acids, etc.), as well as direct administration of NADH, Flavoproteins, and ATP, either individually or in combination, helps to extend animal lifespan by 8–10 times when exposed to doses of 100–150 Gy. In this case, the cause of animal death is not central nervous system failure, but rather the intestinal manifestations of radiation injury. Cerebroprotectants exhibit a protective effect ranging from 6 hours to 1 day after their administration into the body.

Radioresistance Stimulators. This group includes agents that enhance radioresistance across a broad range of doses—from «low» doses to those causing hematopoietic syndromes. They possess a wide spectrum of pharmacological properties, among which radiation protection is frequently not the primary one. Furthermore, they exhibit a radioprotective effect under conditions of both acute and protracted irradiation, and are effective when used both prophylactically and therapeutically.

For the action of radioresistance stimulators to manifest, a relatively prolonged intake into the body is required (typically 8–24 hours), yet the state of radioresistance can persist from several days to 1–2 weeks.

Among such agents, two main categories are distinguished: 1) those with sufficiently pronounced radioprotective properties capable of exerting an effect upon irradiation at doses that induce radiation sickness; and 2) those with relatively low radioprotective activity, yet capable of mitigating the adverse consequences (including delayed effects) of irradiation at doses that do not cause clinical pathologies.

The first group includes immunomodulators, hormonal preparations with estrogenic activity, and others.

Among immunomodulators with radioprotective activity, there are both microbial preparations (various Vaccines) and their extracts and fractions (Polysaccharides), as well as lipopolysaccharides derived from Bacteria and Fungi. Such effects are exhibited, for example, by Escherichia coli vaccines, typhoid vaccine, a series of antiviral vaccines, prodigiosan, pyrogenal, heparin, levan, and others. Promising radioresistance stimulators include Cytokinins—Polypeptides that regulate cell growth and differentiation; they possess specific hemato- and immunoregulatory properties, along with The ability to modify bone marrow repair processes upon irradiation. A pronounced radioprotective effect is also demonstrated by interleukins (lymphokines, monokines, etc.) and Thymus Hormones (thymalin, thymogen, T-activin). It should be noted that the radioprotective action of immunomodulators persists for several days after administration, and their repeated administration enhances their radioprotective efficacy.

Estrogens in the Initial Stages of action suppress the proliferative activity of bone marrow cells, which reduces their damage by ionizing radiation. Subsequently, processes of PROTEIN AND NUCLEIC acid synthesis stimulation come to the forefront, ensuring the recovery of hematopoiesis. Among such agents, diethylstilbestrol has been the most thoroughly studied, with a dose reduction factor (DRF) of 1.15–1.2.

Radioprotective effects are also exhibited by A number of polynucleotides and NUCLEOTIDES (polyribon, rhodopsin, phosphaden, etc.). Pronounced radioprotective properties are characteristic of desoxynat preparations (the sodium salt of DNA obtained from sturgeon milt), salts of orotic acid (a precursor of pyrimidine nucleotides), and the purine nucleoside riboxin.

The long-term impact of ionizing radiation at relatively low doses combined with psycho-emotional stress (as occurred during the cleanup of the Chornobyl disaster), exposure to chemical substances, hypoxia, and other factors can be accompanied by adverse asthenonegative, psychosomatic, and immunological disorders that diminish the general (nonspecific) resistance of organisms. For the prophylaxis of such disorders, vitamin preparations, vitamin-amino acid complexes, enzyme Cofactors, plant-derived adaptogens, apiculture and mariculture products, dietary supplements, and antioxidants are utilized.

These substances are capable of modulating the processes of protein, nucleic acid, carbohydrate, and Lipid Biosynthesis, as well as Energy Metabolism, which promotes the normalization of hematopoiesis and immunological reactivity, and mitigates the biochemical and physiological manifestations of stress responses. All of this enhances the organism's adaptogenic properties against extreme factors, including ionizing radiation.

Substances with such activity include vitamins and vitamin-amino acid complexes—tetrafolevit, amitetravit, amivit; adaptogen preparations based on

ginseng, eleutherococcus, Schisandra chinensis, leuzea, Rhodiola rosea (golden ROOT), etc.; and dietary supplements with adaptogenic properties—autolysate, fermetolysate, amivis, sodium succinate, and sodium malate, among others.

Bioantioxidants are capable of inactivating radiotoxins (products of Lipid Peroxidation, Phenolic Compounds, etc.), which exert an inhibitory effect on Cell Division processes and induce mutagenic and carcinogenic effects. Among bioantioxidants widely used for prophylaxis are $eta$-carotene, anthocyanins, mussel hydrolysate MIP-K, and others.

Antimutagenic properties are exhibited by the radioprotectors cystamine and gammaphos at doses lower than their radioprotective levels based on the survival criterion. Riboxin exhibits a similar effect.

Dietary supplements enriched with selenium, antioxidant vitamins, glutapyrone, difluoromethylornithine, and other BIOLOGICALLY ACTIVE SUBSTANCES reduce the incidence of leukemias and other radiation-induced delayed effects.

The risk of genetic consequences resulting from ionizing radiation exposure is significantly mitigated by Melanins—complex structures formed through the polymerization and oxidation of dihydroxyphenyl compounds. Proteinase inhibitors also exhibit antimutagenic and anticarcinogenic properties under conditions of prolonged ionizing radiation exposure.

Indenes containing five- and six-membered rings and nitrogen groups demonstrate donor-acceptor capacity to form intermolecular hydrogen and ionic bonds. Indene compounds (F-1, F-37, OA-1, etc.) facilitate The transfer of excess energy from irradiated DNA to themselves, thereby reducing the mutagenic effect of protracted irradiation.

Blockers of Radioisotope Uptake into the Body. To prevent and reduce the accumulation of radioisotopes in the body, adsorbents, ion-exchange preparations, non-radioactive (stable) isotope accumulation blockers, and isotope excretion accelerators are employed.

An effective prophylactic measure against incorporated radioisotopes of iodine in The Thyroid Gland involves preparations containing non-radioactive iodine—potassium iodide, hydroalcoholic iodine tincture, and Lugol's solution. The optimal protective dose of potassium iodide is 0.25 g (1 tablet) taken with tea, fruit jelly (kisel), or water daily for 7–10 days; for iodine tincture or Lugol's solution, the dose is 3–5 drops per Glass of milk or water 3 times a day. It is also advisable to apply iodine tincture to the skin in a grid pattern and to incorporate foods with a high content of non-radioactive iodine into the diet.

To prevent the absorption of radioactive substances from the digestive tract into the blood and lymph, as well as their accumulation in internal organs, adsorbents capable of binding specific radioisotopes are utilized. For instance, in the event of strontium isotopes entering the gastrointestinal tract, it is advisable to use barium sulfate, polysurmin, oxidized Cellulose, calcium alginate individually or in combination with hyaluronic acid, etc., as adsorbents. To prevent the absorption of cesium isotopes, potassium hexacyanoferrate (ferrocyanide), orthosiphon, bentonite clay, vermiculite (hydromica), Prussian blue, and carboxylase can be employed. Petacin adsorbs plutonium isotopes. Melanin not only exhibits antioxidant properties and acts as an antimutagen, but also binds isotopes of lead, lanthanum, zinc, chromium, copper, and mercury. Ion-exchange preparations (such as zeolite) bind yttrium, transuranic elements, and lanthanides. To accelerate The excretion of polonium, cobalt, copper, and mercury isotopes from the body, penicillamine and unithiol are used. Consuming large amounts of water facilitates the elimination of tritium. In addition, there are numerous Other Compounds capable of protecting organisms from internal irradiation.