EntranceRadiosensitivity of tissues and organs of the body. Radiosensitivity of tissues and organs of the body Radiation syndromes: the effect of ionizing radiation on the hematopoietic, digestive and central systems
Chapter 3.6. Radiosensitivity of organisms and tissues
3.6.1. Radiosensitivity to external irradiation
Mammals and humans have the greatest radiosensitivity to radiation compared to birds, fish, etc. the difference in radiosensitivity also manifests itself in the organs that make up the body as a single whole. Cells of the same organ also have unequal sensitivity and unequal ability to regenerate after radiation damage.
To quantitatively study the radiosensitivity of an organism, survival or mortality curves are used (Fig. 30).
Fig.30. Mortality curve for mammals.
For all mammal species, such a curve is always S-shaped. This is explained by the fact that when irradiated in the initial dose range, no death is observed (up to the so-called “minimum lethal dose” - this is 4 Gy), and starting from a certain dose (the “minimum absolutely lethal dose” - this is 9 Gy) everyone dies animals. Since all mortality is recorded in the interval between these doses, in this segment the curve rises steeply, approaching 100%.
Due to the different radiosensitivity of organs and tissues, it is not indifferent to the body whether the entire body or only part of it is irradiated, or whether the body receives general but uneven irradiation. General uniform irradiation causes the greatest radiobiological effect. In general, the radiosensitivity of organs depends not only on the radiosensitivity of the tissues that leave the organ, but also on its functions.
The degree of radiosensitivity of tissues is characterized by a number of characteristics. Organs based on functional and biochemical characteristics that determine the sorption index of tissues can be distributed according to radiosensitivity in descending order: cerebral hemispheres, cerebellum, pituitary gland, adrenal glands, thymus, lymph nodes, spinal cord, gastrointestinal tract, liver, spleen, lungs, kidneys, heart, skin and bone tissue.
3.6.2. Tissue radiosensitivity
To identify hidden radiation damage to slowly renewing tissues (bone, muscle, nervous), Strelin combined irradiation with subsequent mechanical trauma. It was possible to identify the conservatism of radiation damage, manifested in the loss or inhibition of the ability of irradiated tissue to post-traumatic regeneration. Experiments have made it possible to establish that ionizing radiation also affects slowly renewing tissues, so they turn out to be potentially functionally inferior. An important reason that determines the degree and likelihood of developing long-term consequences in these tissues is the size of single doses and the total duration of irradiation. This is associated with the manifestation of reparation characteristic of these tissues. The consequence of hidden damage that occurs in the cells of these tissues is various complications of radiation therapy: myelitis, cystitis, heart disease, kidney disease, liver disease, and the possible occurrence of malignant neoplasms. Under the influence of equivalent doses, the number of chromosomal aberrations in liver and bone marrow cells will be the same. Therefore, the concept of radiosensitivity is quite relative when applied to various organs and tissues.
Based on the morphological characteristics of developing post-radiation changes, organs are divided into three groups:
Organs sensitive to radiation ;
Organs moderately sensitive to radiation ;
Organs resistant to radiation (see Fig. 31).
Rice. 31. Radiosensitivity of organs and tissues.
Blood diseases. With general irradiation within the limits of semi-lethal and lethal doses, a typical hematopoietic syndrome develops, which is characterized by pancytopenia – a decrease in the number of formed elements in the blood as a result of aplasia of hematopoietic tissue. Simultaneously with quantitative changes, morphological and biochemical changes in cells are observed. The restoration of the picture occurs slowly, over several months.
The hematopoietic organs are the most radiosensitive among other systems; changes in the peripheral blood picture are a consequence of damage to the hematopoietic tissue. Disturbances in hematopoietic processes occur very early and subsequently develop in phases.
Lungs. The lungs are the most sensitive organ of the chest. Radiation pneumonitis is accompanied by loss of epithelial cells that line the airways and pulmonary alveoli, inflammation of the airways, pulmonary alveoli and blood vessels, leading to fibrosis. These effects can cause pulmonary failure, and even death, within several months after chest irradiation. Data obtained from radiation therapy show that the threshold doses causing acute pulmonary death are about 25 Gy of x-ray or gamma radiation, and after irradiation of the lungs with a dose of 50 Gy, death is 100%.
Gonads (sex glands). Due to the extremely high radiosensitivity of germ cells in the early stages of development, already at doses of 0.05-0.1 Gy, mass cell death occurs in most animals and humans, and after 2-4 Gy - sterility. Mature cells - sperm, on the contrary, are extremely resistant. Therefore, fertility is maintained until the supply of viable mature germ cells is depleted. But even after this, the onset of sterility is temporary, as spermatogenesis is gradually restored from the remaining spermatogonia.
Physiological regeneration in the genital organs of female mammals is manifested mainly not in the replacement of individual cells, but in cyclically repeating developmental processes regulated by the endocrine apparatus and covering entire cellular complexes. The most sensitive element of the ovary is the egg. Exposure of both ovaries to single acute doses of 1–2 Gy causes temporary infertility and cessation of menstruation for 1–3 years. Acute doses of about 4 Gy lead to infertility. Sterility in females occurs at lower doses than in males, but is usually irreversible. This is due to the fact that the formation of female germ cells ends even before birth and in adulthood the ovaries are not capable of active regeneration. Therefore, if irradiation causes the death of all potential eggs, then fertility is lost irreversibly. As a result of ovarian damage, secondary sexual characteristics also change.
The effect of radiation on vision. Two types of eye damage are known - inflammatory processes in the conjunctiva and sclera at doses close to those causing skin lesions, and cataracts at doses of 3-8 Gy and cataracts at doses of 3-10 Gy, and the dose depends on the type of animal. In humans, cataracts appear when exposed to a dose of 6 Gy. The most dangerous in this case are neutrons, with irradiation with which the incidence of diseases is 3–9 times higher than with gamma radiation. The causes of cataract formation are not fully understood. It is believed that the leading role in this case is played by the primary damage to the cells of the growth zone of the lens, and the impact of disruption of its nutrition is relatively less.
Digestive organs. All digestive organs show reactions to AI. According to the degree of radiosensitivity, they are distributed as follows: small intestine, salivary glands, stomach, rectum and colon, pancreas and liver. When large doses of radiation affect the entire body or only the abdominal area, rapid damage to the intestines occurs, resulting in the development of gastrointestinal syndrome. Moderate and higher doses cause pronounced changes in the intestinal wall. Big role A violation of the barrier-immune function of the intestine also plays a role, as a result of which microflora enters the body and causes toxicosis and sepsis. The average time of death is 7–10 days.
The salivary glands respond to radiation with shifts in secretion. The secretion of the gastric glands during general irradiation changes depending on the initial state. Intestinal functions change in waves: in the first days there is an increase, then a decrease, which continues until the development of recovery processes or until the death of the body. Changes in pancreatic function depend on the dose: small doses stimulate, and large doses depress. In the liver, metabolic processes change, bile formation is inhibited, hemorrhages and necrosis occur.
The cardiovascular system. In experiments on mice, it was found that the outer layer of the vascular wall is the most radiosensitive due to the high content of collagen, a connective tissue protein that is susceptible to degeneration, which ensures the performance of stabilizing and supporting functions. It is significant that 4–5 months after irradiation, some vessels were completely devoid of the outer membrane. Moreover, in the skin of mice, already at doses of 4–15 Gy, a subsequent decrease in vascular restoration was found.
A study of the heart revealed immediate and long-term changes in the myocardium after local irradiation with doses of 5–10 Gy. Data were also obtained on the significant radiosensitivity of the cell layer lining the inner lining of the heart and valve leaflets, which contributed to the formation of intraventricular thrombi six months after local irradiation of the heart area of mice with doses of about 20 Gy.
Endocrine glands. The cells of the endocrine glands are highly specialized and divide slowly. The sensitivity of the endocrine glands to a radiation stimulus is mainly an indirect reaction and is carried out in a reflex way through the nervous system. Therefore, it is assumed that the imbalance of hormones observed after general irradiation, especially of the thyroid gland, adrenal glands and gonads, may be a consequence of the reaction of the hypothalamic-pituitary system, the main purpose of which is the regulation of the autonomic functions of the body (activity internal organs, glands, vessels).
Excretory organs. It is believed that the kidneys are quite resistant to radiation, but it is their damage that is a limitation for irradiation of abdominal tumors during radiation therapy. In acute radiation sickness, hemorrhages of varying intensity, congestion and degenerative phenomena are observed. Irradiation of both kidneys with a dose greater than 30 Gy over 5 weeks can cause incurable chronic nephritis with a fatal outcome. The mechanism of damage is poorly understood, but it is known that it is radiation cystitis that leads to serious complications of radiation therapy.
Bones and tendons. During intensive growth, bone and cartilage are more radiosensitive. After its completion, irradiation leads to necrosis of areas of the bone - osteonecrosis - and the occurrence of spontaneous fractures in the irradiation zone. Another manifestation of radiation damage is delayed healing of fractures, and even the formation of false joints.
Muscles. Muscle tissue is the most radioresistant tissue; its morphological changes occur with local irradiation of several hundred Gy. Almost no cellular renewal occurs in the muscles. Mild muscle atrophy was detected only at doses of about 60 Gy. With general irradiation, changes in muscles occur already in the early stages of radiation sickness. From a dose of 3–5 Gy during whole body irradiation, approximately half of all irradiated people die within one to two months due to damage to bone marrow cells. Local doses allowed for radiation therapy of tumors can be significantly higher.
Radiosensitivity is determined, as a rule, in relation to acute irradiation, moreover, a single one. Therefore, systems consisting of rapidly renewing cells are more radiosensitive.
If the irradiation is chronic, then rapidly renewing cells will not react strongly to this background, and for cells that are dividing little or not dividing at all, the dose they receive over a long period of time will correspond to the same dose during acute irradiation. It turns out on the contrary that in this case those organs and tissues that are considered more radiosensitive are more vulnerable. Of course, this happens at a certain dose rate. No one has conducted radiosensitivity studies in this case, so our assumption, although it is completely obvious, remains only an assumption.
Skin. The skin and its derivatives are very actively renewing systems and therefore, in general, the skin is more radiosensitive. Along with high sensitivity, epidermal cells are good at repairing sublethal damage. The maximum tolerated dose of hard X-ray radiation is about 1000 rad for a single external exposure. Radiation damage to the skin is a complex of tissue damage to the epidermis, dermis and subcutaneous layers. When irradiated with moderate doses (3-8 Gy), a characteristic reddening of the skin occurs - erythema, which usually disappears after 24-58 hours. The second phase occurs after 2–3 weeks. It is accompanied by loss of the superficial layers of the epidermis. The skin condition is close to the first degree of thermal burns, such as sunburn, and can last for several weeks, then goes away. Dark spots remain on the skin. When the skin is irradiated with a dose of 10 Gy, the second phase of erythema lasts about a week, then blisters and ulcerations appear, accompanied by the release of fluid. The condition of the skin is reminiscent of second-degree thermal burns; healing can last for weeks, followed by the formation of permanent scars. At a dose of about 50 Gy, the epidermis is destroyed, the dermis and subcutaneous layers are damaged. Radiation reactions appear earlier, healing of ulcers and other injuries can last for years and have relapses.
Hair follicle cells are quite radiosensitive, and irradiation with a dose of 4–5 Hg already affects hair growth. After irradiation with this dose, the hair begins to thin and falls out within 1–3 weeks. At a later stage, hair growth may resume. However, with irradiation at a dose of about 7 Gy, permanent hair loss occurs. At doses that cause epilation, permanent destruction of most sebaceous and pore glands occurs.
Embryo and fetus. The most serious consequences of radiation are death before or during childbirth, developmental delay, abnormalities of many tissues and organs of the body, and the occurrence of tumors in the first years of life.
During the period of organ formation, irradiation causes intrauterine death or death immediately after birth. LD 50 for intrauterine death in mice is 1–1.5 Gy during the period of early organ formation, and reaches 7 Gy by the embryonic period. Irradiation at the stage of organ formation leads to high mortality immediately after birth. In addition, exposure to a dose of 1 Gy or greater after implantation causes malformations in 100% of the offspring, resulting in death in infancy or adulthood. Abnormalities can develop in all major organs and tissues of the body. Although the LD 50 is thought to be higher during the embryonic period, some microscopic damage can be observed with a dose of 1 Gy.
Anomalies in the development of the human fetus caused by radiation can be experimentally reproduced by irradiating mouse and rat embryos at comparable stages of development. By comparing the stages of their embryonic structures in the two periods of pregnancy, it is possible to construct a corresponding curve correlating the equivalent ages of mouse and human embryos. True, the development rates of mouse and human embryos differ with age, especially after the 14th day, but the average reduction coefficient between them is approximately 13. Therefore, extrapolation of the results of irradiation of mouse embryos to the effects in a human fetus has a high degree of probability, which allows us to obtain information about the specific sensitivity to radiation of individual human organs. Taking into account the given coefficient, the period of greatest radiosensitivity of the human embryo is greatly extended in time. It probably begins at conception and ends approximately 38 days after implantation; During this period of development, the rudiments of all organs begin to form in the human embryo through rapid differentiation from primary cell types. Similar transformations in the human embryo occur in almost every tissue between the 18th and 38th days. Since the transition of any cell from the embryonic state to the mature state is the most radiosensitive period of its formation and life, all tissues at this time turn out to be highly radiosensitive. The mosaic nature of the embryo differentiation process and the associated change in the number of the most radiosensitive cells determine the degree of radiosensitivity of a particular system or organ and the probability of the appearance of a specific anomaly at each time point. Therefore, fractionated irradiation results in more severe damage because the exposure involves a variety of germ cell types and their different distribution, resulting in damage to a large number of organ primordia at critical stages of development. During this period, maximum damage can be caused by the smallest doses ionizing radiation, to obtain anomalies in a later period of embryonic development, exposure to large doses of radiation is required. Approximately 40 days after conception, gross deformities are difficult to cause, and after birth they are impossible. However, it should be remembered that at each period of development, the human embryo and fetus contain a certain number of neuroblasts, which are highly radiosensitive, as well as individual germ cells capable of accumulating the effects of radiation.
As shown by the results of studying the consequences of irradiation of pregnant women during the atomic bombing in the cities of Hiroshima and Nagasaki, the degree of manifestation of anomalies and their features were generally consistent with those expected. Thus, according to one examination of 30 women who were 2000 m from the epicenter of the explosion and had serious symptoms of radiation exposure, in approximately half of the cases intrauterine fetal mortality, death of newborns or infants was noted, and in four of the 16 surviving children mental retardation was observed. According to another observation, almost half (45%) of children born to mothers exposed to radiation during pregnancy 7-15 weeks had signs of mental retardation. In addition, microcephaly, growth retardation, mongolism and congenital heart defects were noted in the offspring of women exposed to radiation in the first half of pregnancy; the frequency and severity of abnormalities were higher in cases where the affected mothers were less than 2000 m from the epicenter of the explosion. But even in these cases, such severe neurological disorders were not observed as were obtained when mice were irradiated; This is probably due to the low survival rate of such children. These observations relate only to 6-8 year old children, and at this age many disorders that can only be detected in adolescence and later do not yet appear.
It should be borne in mind that irradiation of an embryo in small doses can cause such functional changes in the cell that cannot be detected by modern research methods, but which contribute to the development of the disease process many years after irradiation. Consequently, all long-term consequences of irradiation of an embryo can be expressed to a greater extent than with irradiation of an adult organism. For example, the incidence of leukemia in the offspring of mothers exposed to X-rays during pregnancy approximately doubles.
Irradiation of a human embryo in the period of the first two months leads to 100% damage, in the period from 3 to 5 months - to 64%, in the period from 6 to 10 months - to 23% damage to the embryos.
If we summarize the experimental data, we can conclude that during mammalian pregnancy, irradiation with a dose of 0.5 Gy leads to the death of embryos during implantation, developmental defects during the formation of organs, cell loss and tissue underdevelopment during the embryonic period. Moreover, some experiments have shown an increase in the number of defects at a dose of 0.1 Gy, so it is believed that there is no threshold dose below which radiation would have no effect on mammals. In foreign literature before 1986, for example, the following figures were given for humans: irradiation of an embryo or fetus with a dose of 0.05 Gy during the first three months of pregnancy can increase the susceptibility to cancer by 10 times. Evidence is also provided that intrauterine diagnostics using X-ray radiation in doses of 0.002-0.200 Gy can cause the development of tumors in children. There is no consensus among experts, but many national and international committees monitor occupational and clinical exposure of women.
The reasons and mechanisms that determine the natural radiosensitivity of biological objects have not yet been fully disclosed, but many aspects have been well studied. For example, factors influencing the radio resistance of plants according to the classification of D.M. Grodzinsky are divided into 3 groups. The first group includes factors determined by the phylogeny of the species that cannot be modified: the anatomical structure of plants, seed size, volume of cell nuclei and chromosomes, number of chromosomes and ploidy. The second group includes factors characterizing the functional state individual structures cells and physiological state of the genome: stage of ontogenesis, content of sulfhydryl groups (SH-groups), presence of antioxidants and macroergs, ability for post-radiation recovery. The third group of factors are environmental factors, such as weather and climatic conditions and conditions of mineral nutrition of plants. Radiobiological effects of plants and animals have a number of similar reactions, such as the presence of critical (most radiosensitive) cells, tissues and organs, the same types of chromosomal aberrations, loss of control over metabolism, the formation of somatic and genetic mutations, cell transformation, radiation carcinogenesis (organ tumors ).
The reactions of living organisms to nuclear radiation are very diverse and are determined by the parameters of the radiation and the characteristics of the organism. The body's attitude to ionizing radiation is characterized by radiosensitivity and radiostability (radioresistance). These two terms are interrelated and reflect the same phenomenon from different angles - if an organism has high radiosensitivity, then it is characterized by low radioresistance, and vice versa.
Radiosensitivity is the body’s ability to respond to small doses of radiation, which manifests itself through non-lethal radiobiological effects in the body. Radio resistance is the body's ability to tolerate high levels irradiation (lethal and semi-lethal doses). The lower the dose that causes non-lethal radiobiological effects, the higher the radiosensitivity of the body. The higher the dose that causes the death of the organism, the higher its radioresistance.
To characterize the radiosensitivity of plants, the following criteria are used: laboratory and field germination, root length of seedlings, plant height, number of formed organs, flowers and seeds, plant weight, number and weight of seeds on one plant, plant survival, as well as the yield of chromosomal aberrations in meta - and anaphase.
Radiosensitivity is assessed by lethal and semi-lethal doses. Lethal dose - LD 100 (or LD 100/30) is the minimum dose of radiation that causes death in 100% of exposed organisms within 30 days. Accordingly, it determines the semi-lethal dose LD 50 (or LD 50/30) - the minimum radiation dose that causes the death of 50% of irradiated organisms within 30 days. LD50 values in nature vary quite significantly, even within the same species.
Plants of the lily family have the highest radiosensitivity among plants. The most radioresistant plants belong to the cruciferous family (Table 2).
table 2
Radiosensitivity of seeds of some higher plants
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Currant Gooseberry Corn |
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Potato |
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Currently, there is information about the radiosensitivity of more than 2000 plants belonging to different families, genera and species. However, radiosensitivity has been assessed in seeds - the stage of plant ontogenesis in which it is in a state of deep forced dormancy and therefore has high resistance to ionizing radiation and all damaging factors.
When seeds germinate, their radiosensitivity increases 15-20 times, because germination is accompanied by active cell division, and dividing cells are more sensitive to radiation than cells in the dormant stage. Besides prerequisite The presence of water is essential for seed germination. High water content of objects during irradiation contributes to a much greater release of free radicals (H o and OH o), which increases radiation damage.
In the world of lower plants and organisms, microorganisms, fungi and lichens have the highest radio resistance. Some types of microorganisms can withstand irradiation at doses of 10 4 - 10 5 Gy. Among woody plants, conifers are less radioresistant. After the Chernobyl accident, in coniferous forests located within a 30-kilometer zone from the nuclear power plant, a wide range of morphological anomalies of vegetative and generative organs was observed, the frequency of occurrence and severity of which depended on the radiation dose.
In a certain dose range (5-20 Gy), nuclear radiation has a stimulating effect. Radiostimulation has been found in all biological objects, from single-celled organisms to plants and animals. The effect of radiation stimulation was first obtained on plants in 1898. Irradiation of seeds causes the activation of many metabolic processes: the synthesis of nucleic acids, proteins, hormones increases, the activity of some enzymes increases, the permeability of membranes changes, the supply of nutrients to plants increases, etc. One of the most important mechanisms of the general stimulating effect of radiation is the formation of nonspecific substances of quinoid nature, which A.M. Kuzin gave it the name trigger effectors. Quinones are formed from polyphenols as a result of radiation-chemical reactions of oxidation and activation of polyphenol oxidases. When irradiated with high doses, quinones appear in plant objects in high concentrations and have an inhibitory effect on their development. In low concentrations (10 -7 -10 -8 M) these substances act as stimulants. Penetrating into the cell nuclei, they bind to histones and thereby remove the nonspecific blockade of the genome by these proteins, i.e. derepression (activation) of a certain group of genes occurs. Enhanced synthesis of messenger RNA, proteins, enzymes, and phytohormones that induce metabolic processes begins. This in turn significantly shortens the phases of the cell cycle in the early stages of development. The stimulating effect of irradiation was found not only when irradiating seeds, but also when irradiating tubers, bulbs, cuttings, rhizomes, and tendrils. An increased level of trigger effectors causes derepression (translation into an active state) of the genome not only in the cells of the apical growth point, but also in the lateral buds, which leads to intensive growth and an increase in the number of lateral shoots. Thus, the formation of nonspecific trigger effectors of a quinoid nature is one of the most important mechanisms of the general stimulating effect of radiation. Irradiation of seeds of various crops with stimulating doses before sowing leads to an increase in yield by 10-25% and an improvement in its quality, i.e. to increase the content of protein, sugar, starch, vitamins, amino acids and other substances that are formed in plants various types in the process of evolution. Potato stimulation occurs when tubers are irradiated in doses of 0.5-5.0 Gy 2-6 days before planting, while the yield increases by 18-25% and the starch content increases by 15%. Gamma irradiation of grapevine cuttings or rootstock increases the yield of full-fledged grafts by 11-34%. In this case, intensive cell division is observed in the cambial layer at the site of fusion of the rootstock and the scion, which contributes to a more rapid fusion of the tissues of the scion with the rootstock. Irradiation can remove tissue incompatibility between the rootstock and the scion. Gamma stimulation is used for forcing green crops, to accelerate the development and flowering of bulbous and flowering plants, and for breeding rare and medicinal plants.
Radiostimulation in animals has been studied less than in plants. According to a number of scientists, the mechanism of the stimulating effect of small doses of ionizing radiation on the animal body at the molecular biological level cannot differ significantly from the mechanism of action on plants. The intensity of metabolic processes, acceleration of development, growth and increased productivity of animals are carried out through the activation of steroid hormones that control these processes. Under experimental conditions, radiostimulation has been studied in mice and rats. The radiostimulation effect manifests itself in doubling fertility and accelerating growth and body weight. Radiostimulation is studied in poultry farming, cattle breeding, pig farming and fur farming. A broad radiostimulation effect was detected when irradiating eggs, chickens and laying hens. When chicken eggs were irradiated before being placed in an incubator with a dose of 0.03-0.05 Gy, the intensity of growth and development of embryos increased, the hatchability and survival rate of chickens increased, and the egg production of chickens increased. A stimulating effect was detected during irradiation of broiler chickens (when irradiated with a dose of 0.25 Gy and 0.5 Gy, the weight of chickens increased by 12-15%) and laying hens (egg production when irradiated with a dose of 0.5 Gy increased by 10-18%). The mechanism of the stimulating effect on chicken egg production and meat productivity is associated with the emergence of trigger effectors (gonadotropin-releasing hormones), which act on the pituitary gland and stimulate the production of steroid sex hormones, which accelerates growth and development. Irradiation of fine-wool sheep lambs at one, two and three months of age with small doses led to an increase in live weight, survival rate, shearing, density and length of wool. When day-old piglets were irradiated with doses of 0.1-0.25 Gy, an increase in body weight of 10-15% was observed in the first three months of life. Irradiation of minks and silver foxes with the same doses increased the survival rate of offspring, their resistance to diseases, and improved the quality of fur and the length of the skin. Thus, radiostimulation is a general biological phenomenon inherent in many organisms.
Currently, ionizing radiation is widely used to obtain mutant forms of plants. Under the influence of ionizing radiation, chromosomal and gene (point) mutations occur. Chromosomal mutations cause death. Gene mutations are a source of mutant forms, both beneficial and harmful to plants. It is known that the entire set of properties that are characteristic of a particular biological species is programmed into DNA in the form of a sequential alternation of nucleotides, i.e. in the form of a genetic code. Irradiation of DNA causes oxidation of pyrimidine bases and decomposition of purine bases. During the process of reduplication on a damaged matrix, erroneous repair is possible, i.e. replacement of purine bases with pyrimidine bases and vice versa, which leads to disruption of the genetic code and the appearance of gene mutations. The yield of mutations increases with increasing dose, but at the same time the sterility of plants increases, growth and morphogenesis processes are suppressed. Doses are used at which the ability of plants to form full-fledged reproductive organs is preserved. Economically useful mutants that combine high productivity with other traits appear, as a rule, very rarely. Selection-valuable mutant forms of plants are distinguished by their nutrient content, early ripening, disease resistance, resistance to lodging, increased productivity and other characteristics. Mutant forms are used as a donor of a useful trait in plant breeding. In world breeding practice, the largest number of varieties involving radiation mutants have been obtained in barley (68), rice (64), wheat (31), peanuts (14) and beans (10).
Mammals are the most interesting species in the animal world. It is known that mammals (humans and animals) have the greatest sensitivity to radiation compared to birds, fish, amphibians, etc. (Table 3). The reasons for the different radiosensitivity of organisms are still unknown. However, the general trend is as follows: from the embryo to the mature state, the radiosensitivity of the body and its organs gradually decreases, stabilizes in middle age and decreases again in old age.
The difference in radiosensitivity also manifests itself in the organs that make up the body as a whole. Cells of the same organ have different radiosensitivity and ability to regenerate after radiation damage. Based on radiosensitivity, all organs and tissues can be divided into three groups.
Table 3
Radiosensitivity of living organisms
The first group, the most sensitive to radiation, includes the bone marrow, gonads, spleen, and lymphoid tissue. The stem cells of these tissues are completely killed by a radiation dose of 10 Gy. Morphologically recorded changes in them occur upon irradiation with a dose of 0.25 Gy.
The second group, more resistant to radiation, includes the digestive tract, liver, respiratory organs, excretory organs, organs of vision, and muscle tissue. The cells of these tissues can withstand radiation doses of up to 40 Gy.
The third group includes nervous tissue, skin, cartilage and bone tissue, which can withstand radiation doses of up to 80 - 100 Gy.
The most radiosensitive organs and systems are called critical. Their defeat is associated with the death of the body within a certain period of time after irradiation. Cells of critical organs have a short life cycle and high rates renewal (tens and hundreds of thousands of cells die and form again in one minute). The hematopoietic system and gastrointestinal tract have a higher renewal rate. The central nervous system consists of highly differentiated cells that do not recover after dying.
Hematopoietic organs include bone marrow, lymphatic tissue, spleen, thymus gland. Disruption of the hematopoietic processes in these organs occurs very early - directly during radiation exposure, and the further development and manifestation of the disorders are of a phase nature, which is associated with different radiosensitivity of the cells and with the recovery processes in the cells.
The most highly radiosensitive organ is the bone marrow; during general irradiation it is affected first. When animals are externally irradiated with LD doses of 50/30 or higher, cell mitosis stops, degenerative forms of some types of cells appear, and the number of red blood cells in the blood decreases. Early changes in the bone marrow during external irradiation also include a decrease in immature forms of the red and white fraction, platelets and an increase in granulocytes. It has been established that the bone marrow has a fairly high ability to regenerate (i.e., to restore), which at moderate lethal doses occurs in 4-7 days, and by the end of the 4th week the bone marrow picture or blood structure becomes close to normal. With lethal and superlethal doses of radiation, normal cell content is not restored and bone marrow aplasia occurs.
Radiation exposure to lymphatic tissue leads to early destruction of lymphoblasts and lymphocytes in the tissue itself and lymphocytes in the peripheral blood. Semi-lethal and lethal doses of radiation cause tissue structure disorders, various changes in lymph nodes and other lymphoid formations.
Irradiation of the spleen with a semi-lethal dose leads to the cessation of mitosis and the death of some lymphocytes. As a result of the destruction of cellular elements, the organ decreases in size and weight.
The cells of the thymus gland - thymocytes (lymphocytes) - almost all die within the first day. Restoration of cells to the original level occurs due to single undamaged cells.
A characteristic reaction of the body to radiation exposure is a change in the number of leukocytes: in the first minutes and hours there is a slight decrease; after 6-8 hours - an increase of 10-15% from the initial level; after 24 hours - a sharp decrease from the initial level. The degree and phase of changes in the number of leukocytes are directly dependent on the dose, as well as on the type of animal. The time required for the leukocyte count to return to normal is 2-3 months.
Irradiation of animals with semi-lethal doses leads to changes in the number of red blood cells. On the first day, the number of cells and hemoglobin content in the blood increase by 10-15%, then on the 15-20th day the content decreases by 2-3 or more times the norm. In parallel with quantitative disturbances, morphological and biochemical disturbances occur: an increase in cell size, pyknosis of nuclei and vacuolization of the cytoplasm, as well as the formation of binucleate cells and cells of abnormal shapes. Red blood cells are restored to normal numbers in 2-5 months.
In terms of radiosensitivity, platelets occupy an intermediate position between leukocytes and erythrocytes. Irradiation with a dose of LD 50 leads to a sharp decrease in the number of platelets on the first day. Cells appear with various anomalies: binucleate, with disproportionate sizes of the nucleus and cytoplasm. Processes such as prothrombin absorption, blood clotting, plasma recalcification and others are disrupted in the body. Platelet recovery is observed 35-45 days after irradiation.
The most radiosensitive blood cells are lymphocytes. A registered decrease in the content of lymphocytes is observed upon irradiation with a dose of 0.6 Gy. When irradiated with a dose of LD 50/30, the greatest decrease is observed after 1-3 days. This period is characterized by morphological changes in cells, a violation of the ratio of small forms, the appearance of binucleate cells, granularity and vacuolization of the nucleus and protoplasm, and changes in enzyme activity. The phasic changes characteristic of leukocytes are absent in lymphocytes.
Along with significant changes in the structure of the blood and hematopoietic organs, structural changes in the walls of blood vessels, especially capillaries, are noted. This is accompanied by various hemorrhages (point and diffuse) and bleeding (external and internal).
All digestive organs exhibit functional and morphological reactions to irradiation. According to the degree of radiosensitivity, they are distributed as follows: small intestine, salivary glands, stomach, rectum and colon, pancreas, liver. The greatest sensitivity is in the glandular epithelium and villous epithelium. Irradiation leads to the cessation of cell division and cell death, to the denudation of villi and crypt cells, which is accompanied by the release of blood plasma into the intestine, and also leads to a decrease in the barrier-immune function of the intestinal wall, as a result of which intestinal microflora enters the body and causes toxicosis and bacteremia. Radiation damage manifests itself through nausea, vomiting, and diarrhea. Large doses of radiation exposure inhibit the secretion of the gastric glands, which leads to morphological changes - hemorrhages, catarrhs, ulcers, cicatricial stenoses, fistulas. The functional state of the gastrointestinal tract is normalized over different periods, up to several months.
The gonads of mammals react to irradiation in basically the same way. The main species difference is the magnitude of the damaging dose, which is closely related to the species' radiosensitivity of organisms. When radiation affects the gonads, the generative function is more damaged and their hormonal activity is less disrupted. The degree of post-radiation changes in the gonads depends mainly on the dose and method of irradiation. The germ cells of the testes, according to radiosensitivity, are arranged in the following descending order: spermiogonia, spermiocytes, spermids, mature sperm. Histological examination reveals numerous hemorrhages in the parenchyma of the gland, in the lumens of the seminiferous tubules - an accumulation of necrotic cells, single altered spermiogonia and spermiocytes. Spermatogenesis is restored due to surviving spermiogonia after a few months, but a large number of defective sperm are noted, and sclerotic processes develop in the parenchyma of the testes. In young immature animals, the testes and ovaries are more sensitive to radiation than in mature animals. According to the degree of decrease in radiosensitivity, cells of a functioning ovary are located in the following order: oocytes of the second order in mature follicles, oocytes of the first order, mature eggs, epithelium of secondary and primary follicles, corpus luteum, integumentary epithelium. Radiation damage to the ovaries is the same in all animals: first, the most radiosensitive cells are damaged and die, destruction of the epithelium occurs, fibrous growth of the connective tissue of the ovary, disruption of reproductive cycles, and hormonal abnormalities. Restoration of ovarian function is very slow. The radiosensitivity of mammalian oocytes is determined by the morphology of the diplotene stage, i.e. configuration of chromosomes in the nucleus. Oocytes with a diffuse arrangement of chromosomes are more radiosensitive (mouse, hamster oocytes) than oocytes with a compact arrangement (dog, human oocytes).
Thus, external irradiation of plants and mammals leads to the formation of various radiation effects in them.
Radiation syndromes.
Not only different individuals of the same species are characterized by unequal radiosensitivity, but different cells, tissues, organs, and organ systems of the same organism. The patterns of biological effect (damage) during irradiation are determined by two groups of factors. Firstly, the magnitude of the equivalent dose absorbed by the body and its distribution in space and time, Secondly radiosensitivity of tissues, organs and organ systems that are essential for the functioning of the body. The combination of these factors determines the specificity and time of manifestation of the effects of radiation.
The picture of damage to mammals by ionizing radiation, including humans, has been most fully studied. As already noted, ionizing radiation is a specific, unparalleled physical effect on living systems. First of all, the specificity of this irradiation is determined by the high penetrating ability of most types of ionizing radiation. Thus, as a result of total irradiation of the body with X-ray, g-, b-, bremsstrahlung, neutron, and proton radiation, not a single part of the body remains unirradiated. Only in the case of a-irradiation can the body receive local irradiation.
In most cases, when animals and humans are irradiated, changes occur in the body, which are usually called by the general term – radiation sickness. Radiation sickness in humans and other mammals is understood as a certain complex of manifestations of the damaging effects of ionizing radiation on the body. The variety of radiation reactions of the body depends on the method of irradiation (general, local, external or internal from incorporated radionuclides), the temporary factor of irradiation (single, repeated, prolonged, chronic). The intensity of the effects of radiation also depends on the spatial factor, i.e. on the size of the irradiated surface and the distribution of the absorbed dose in a living organism. According to this factor, irradiation of the body can be total, local, uniform, or uneven. The most typical example of radiation damage to mammals and humans is acute radiation sickness (ARS). ARS manifests itself during a single total external irradiation at equivalent doses of more than 1 Sv. To understand the basic patterns of manifestations of radiation injury, it is necessary to introduce the concept of “critical organ”. The term “critical organ” in radiobiology refers to vital tissues, organs or organ systems whose structure and functions are disrupted when irradiated in a certain dose range, which causes disease or death of the body a certain time after irradiation. There is a strict relationship between the absorbed dose and the average life expectancy of an irradiated organism, determined by the different radiosensitivities of critical organs. Let us consider the dependence of the average life expectancy of an irradiated organism on the magnitude of the absorbed dose. Figure 1 presents data from experiments that determine this dependence when mice are irradiated with X-rays. As can be seen, an increase in the absorbed dose from 0 to 10 Gy leads to a decrease in the life expectancy of mice to several days. With a further increase in the radiation dose (10–100 Gy), the average life expectancy of animals does not change. Mice irradiated in this dose range live 1-5 days. A subsequent increase in the absorbed dose to 1000 Gy leads to a sharp reduction in the life expectancy of irradiated mice. In this dose range, this indicator decreases from several days to several minutes. Similar data on the dependence of life expectancy on the radiation dose were obtained in experiments with many animals. The specific nature of the dependence of life expectancy on the radiation dose shown in the figure is determined by the radiosensitivity of the main critical organs in mammals: red bone marrow, gastrointestinal tract, central nervous system. Irreversible damage to these critical organs causes the manifestation of the main clinical syndromes during irradiation of humans and mammals: bone marrow (hematopoietic), gastrointestinal, cerebral. From Figure 1 it is clear that in the dose range of 0–10 Gy, the death of mice is caused by damage to the hematopoietic system, in the range of 10–100 Gy by damage to the gastrointestinal tract. Rapid death of animals at doses of 100–1000 Gy occurs due to damage to the central nervous system.
Rice. 1. Dependence of the average life expectancy of mice on the absorbed dose during total single irradiation with X-rays.
The y-axis is the absorbed dose, Gy; x-axis - average life expectancy of irradiated individuals, days.
The stepwise nature of the curve, associated with disruption of the structure and functioning of critical organs, has been obtained for many animals, incl. and for monkeys. These experimental results can, with a certain degree of probability, be extrapolated to humans (Fig. 2). As can be seen, with radiation doses in the range of 4-10 Gy, the average human life expectancy does not exceed 40 days. The death of those irradiated at such doses occurs due to destabilization of hematopoietic processes (bone marrow, hematopoietic syndrome). At high doses (10–30 Gy), the death of irradiated animals occurs due to damage to the gastrointestinal tract (gastrointestinal syndrome) and the life expectancy of individuals does not exceed 10 days. At very high doses (>30 Gy), radiation death, human life expectancy ranges from several hours to 2 days and the lethal effect is caused by damage to the central nervous system (cerebral syndrome).
Rice. 2. Dependence of the average life expectancy of monkeys (humans) on the absorbed dose during total single irradiation with X-rays.
The ordinate axis is the absorbed dose, the abscissa axis is the average life expectancy of irradiated individuals.
The leading role of these critical organs in the death of irradiated animals, when irradiated in the appropriate dose range, has been shown in numerous experiments. Thus, if a section of the bone marrow is shielded during total irradiation or the bone marrow of non-irradiated animals is transplanted into fatally irradiated animals, the number of dead animals can be prevented or reduced at doses up to 10 Gy. Such experiments were carried out on various animals and they indicate that the death of individuals in this dose range is due precisely to damage to the hematopoietic system. The intestinal mechanism of death in the dose range of 10 - 30 Gy is evidenced by experiments with local irradiation of the excreted intestine. In this case, the death of animals occurs in the same time frame as with total irradiation with the same doses. When animals' heads are locally irradiated with doses greater than 100 Gy, their death occurs in the first days and hours after irradiation, accompanied by convulsions, which indicates damage to the central nervous system.
Thus, when animals and humans are irradiated, a clear dependence of the severity of radiation syndromes on the absorbed dose of radiation appears. The nature of this dependence is due to differences in the cellular renewal systems of the corresponding critical organs.
A stable state of dynamic equilibrium of any cell population in a living organism is maintained by a system of cellular renewal. The loss of any cell (due to death or migration) in the system is compensated by the appearance of new cells, which ensures the unchanged functions of this tissue or organ. Different types of cells are characterized by unequal life cycle durations, and accordingly, they also differ in renewal rates. In a living organism, hundreds of thousands of outdated cells die every minute and new cells appear in their place, which after a certain time will also die off, being replaced by another generation of cells. This stable state of dynamic equilibrium between cell death and the appearance of new cells is a necessary condition maintaining the vitality of the body. Any adult, normally functioning organism is in a state of strictly balanced cellular renewal, which takes place in most tissues and organs. Violation of this state, i.e. cellular homeostasis, leads to the death of the organism. Such processes, leading to disruption of cellular homeostasis, occur during the action of ionizing radiation on animal organisms. First of all, the death of mammals during irradiation occurs due to disruption of the functioning of two self-renewing cellular systems - hematopoietic and gastrointestinal. At very high doses of radiation, the death of animals occurs due to interphase death of cells of the central nervous system, which practically do not renew in adult animals.
Hematopoietic syndrome. Red bone marrow is a typical example of a cellular renewal system.
Red bone marrow is characterized by high radiosensitivity and therefore damage to the hematopoietic system to varying degrees is observed during irradiation even at relatively low doses. Using red bone marrow as an example, we will consider the general principles of the functioning of the cellular renewal system, which can be extrapolated to other self-renewing cell systems.
As is known, the main function of red bone marrow is the production of differentiated mature blood cells - erythrocytes, leukocytes, lymphocytes, platelets. The loss of any of these cells in the body is replaced by the formation of a new cell in the bone marrow. In the system of cellular renewal of mammals, several types of cells can be conventionally distinguished, differing in the degree of maturity and differentiation, the so-called cell pools(Fig. 3). The precursors of blood cells are young undifferentiated red bone marrow cells – stem(clonogenic) cells. These cells are able to constantly divide and provide new cells into the blood. After going through one or more divisions, the stem cell differentiates, matures and turns into some kind of functionally active cell. Division, differentiation, and maturation of various types of cells occur at such a rate as to maintain a certain amount of certain cellular elements in the peripheral blood. The rate of cell renewal can vary within certain limits, depending on the physiological state of the body. For example, the rate of blood cell renewal increases during inflammatory processes.
Fig.3. Schematic representation of the blood cell renewal system in the mammalian body
Under the influence of ionizing radiation, sharp disturbances in the dynamic balance between individual pools occur, which leads to severe functional disorders and, ultimately, can lead to the death of the organism. In this case, disruption of cellular homeostasis occurs due to a temporary delay in cell division, reproductive and interphase death of young undifferentiated cells, changes in the duration of cell maturation processes, and a decrease in the lifespan of mature cells. As a result of these processes, the first three pools begin to empty immediately in the coming hours after irradiation. The number of mature cells begins to decrease much later, when their natural loss ceases to be replenished due to the depletion of the corresponding pools. In accordance with the Bergonier-Tribondo rule, young, dividing cells are characterized by the highest radiosensitivity. It has been shown that at a dose of 6–7 Gy of electromagnetic ionizing radiation, only 2–3 stem cells out of every thousand red bone marrow cells retain proliferative activity. As a result of irradiation, the process of formation of new cells is suppressed and the pools of various cellular elements are depleted in accordance with their lifespan.
Depletion of the bone marrow begins immediately after irradiation and continues until a certain minimum, after which the number of cells begins to increase due to the regeneration of surviving cells. The relative number of surviving cells, the duration of depletion of cell pools, and the intensity of regeneration processes depend on the radiation dose. Figure 4 shows the dynamics of changes in surviving cells when mice were irradiated at D 37. As you can see, with this dose of radiation, only about 10% of stem cells remain in the body on days 6-8. 10 days after irradiation, the number of cells begins to increase due to the proliferation of surviving cells. On day 16, the number of stem cells is already 70% of the number of stem cells in a non-irradiated organism.
Fig.4. Change in the number of red bone marrow stem cells after irradiation of mice at a dose equal to D 37.
The nature of changes in the composition of cells in the peripheral blood of an irradiated organism is determined by the lifespan and radioresistance of mature blood cells. The number of the longest living blood cells - erythrocytes (lifetime more than 3 months) decreases very slowly (Fig. 5). The rate of decrease in the number of erythrocytes in peripheral blood is 1% per day of their total number (@ 25 × 10 7 cells). This rate of decrease in these cells is determined mainly by the natural loss of red blood cells from the blood, since these anucleate cells are characterized by relatively high radioresistance. A sharp decrease in the number of granulocytes and agronulocytes in the blood after irradiation is associated with the high radiosensitivity of these cells. With relatively small doses of radiation (3-4 Sv), not only young, poorly differentiated cells in the bone marrow, lymphoid tissue, and spleen die, but also mature leukocyte cells in the peripheral blood. As can be seen from the figure, 4-5 days after irradiation, only about 20% of the total number of leukocytes is detected in the blood. Lymphocytes have particularly low resistance to ionizing radiation, while neutrophils (granulocytes) are characterized by relatively high resistance. Relatively high stability is also characteristic of platelets. Experimental curves characterizing the renewal of platelets and neutrophils reflect the short life span of these cells.
Rice. 5. Change in the number of cellular elements of peripheral blood after irradiation of mice with X-ray radiation at a dose equal to D 37.
1- red blood cells; 2 – leukocytes; 3 – platelets; 4 – lymphocytes;
5 – neutrophils
The abscissa axis is the time after irradiation, the ordinate axis is the proportion of living cells.
Thus, the main reason for the depletion of the pool of mature blood cells that occurs in the early stages after irradiation is the sharp inhibition of cell division processes in the red bone marrow, spleen, and the death of a certain part of radiosensitive cells in the peripheral blood.
At radiation doses of up to 10 Gy, the death of mice occurs within 6–25 days. Most animals die 10-12 days after irradiation due to pathological processes caused thrombocytopenia, granulopenia, agronulopenia. The main causes of death of animals are infectious and hemorrhagic processes (see radiation sickness). Animals that survive this period have a greater chance of survival, because... after this period, the functional blood pool begins to fill up due to the division of surviving cells.
Gastrointestinal syndrome
The cause of death in mammals and humans when exposed to doses exceeding 10 Sv is damage to the gastrointestinal tract. The most radiosensitive organ in the gastrointestinal tract is the small intestine. After irradiation, devastation of the cells of the villi and intestinal crypts is observed. The processes occurring in this case are similar to the processes discussed above for blood cells and red bone marrow, however, with other quantitative characteristics. The degenerative and regenerative phases of intestinal tract cells are shorter than those of blood cells and red bone marrow. Gastrointestinal stem cells differentiate and mature much faster than blood cells. So, if the average maturation time for different types of blood cells is 3–8 days, then for cells of the gastrointestinal tract it is only 42–55 hours. Moreover, intestinal stem cells are more resistant to radiation than red bone marrow stem cells. The average lethal doses for the first group of cells are D 37 = 4-6 Gy, for the second group - D 37 = 1 Gy. Interphase cell death immediately after irradiation also plays a significant role in radiation damage to the intestinal epithelium. Therefore, the emptying of intestinal cells occurs very quickly; in mice, for example, the crypts of the small intestine are empty in 1–2 days, and the villi in 3–4 days. During this period, the death of most animals is observed with pronounced manifestations of gastrointestinal syndrome. When irradiated in lower doses that cause hematopoietic syndrome, intensive restoration of intestinal cells occurs, which completely ends by 5-6 days after irradiation.
Thus, the death of animals at doses that cause gastrointestinal syndrome is determined primarily by the devastation of the intestinal villi and crypts. This leads to disruption of the functioning of the digestive and excretory systems and imbalance of fluids in the body. All these processes are accompanied by damage to blood vessels, hemorrhages and the development of infectious processes. It is almost impossible to determine which of these processes makes the most significant contribution to the death of an animal. Experiments with irradiation of animals under sterile conditions indicate the important role of infectious processes in the death of animals.
Cerebral syndrome
The effect of ionizing radiation on the cells of the central nervous system is fundamentally different from their effect on the cells of the red bone marrow and intestines. When irradiating the central nervous system, there are practically no losses due to reproductive cell death. As is known, nervous tissue mainly consists of highly differentiated cells that are not capable of division. Accordingly, nerve cells are also characterized by high radioresistance. Interphase neuronal death occurs at very high doses of radiation, on the order of several hundred Grays. Moreover, it is unknown whether the cause of death is direct damage to nerve cells due to irradiation, or whether cell death is mediated by damage to other systems, primarily the blood supplying vessels.
Thus, in the radiobiology of humans and animals, there are three main critical organs (systems) responsible for the death of the organism during a single total irradiation. However, with other methods and conditions of irradiation, any organ or tissue that has absorbed a certain dose of ionizing radiation can become a critical organ. From this perspective, let us consider the radiosensitivity of the main human organs.
Radiosensitivity of individual tissues and human organs
Skin covering . Skin cells are actively renewed and therefore human integumentary tissues are very sensitive to the effects of radiation. However, the high proliferating activity of skin stem cells ensures their high regenerative ability and, accordingly, epidermal cells restore sublethal damage well. Thus, the D q value for these cells is about 5 Gy, while for hematopoietic cells it is only 0.5 Gy. With a single exposure to X-ray radiation, human skin tolerates doses of up to 10 Gy without visible symptoms of damage. At higher radiation doses, visible damage occurs - dermatitis and ulcerative skin lesions.
Organs of vision. Irradiation of the visual organs of mammals with relatively low doses (up to 3 Gy) leads to the occurrence of inflammatory processes in the sclera and conjunctiva. Higher doses (3-10 Gy) cause cataractogenic processes. Cataracts (clouding of the lens of the eye) in humans occur at doses greater than 6 Gy. Particularly dangerous in this regard is neutron irradiation, the effectiveness of which is several times higher than that of x-rays and gamma radiation. Clouding of the lens of the eye during irradiation is the primary diagnostic sign for determining the absorbed dose. The reasons for the formation of cataracts during irradiation are not fully understood.
Digestive system . As noted above, the most radiosensitive organ of this system is the small intestine. Damage to the cells of the small intestine primarily causes the manifestation of gastrointestinal syndrome. Other organs digestive system In descending order of radiosensitivity, they are located in the following order: oral cavity, tongue, esophagus, stomach, rectum and colon, pancreas, liver. As you can see, the most stable organ of the digestive system is the liver. Thus, with a single local irradiation of the liver of rats in doses of up to 15 Gy, no morphological changes can be detected in the cells. According to a number of researchers, the D0 value for rat liver cells is about 90 Gy.
The cardiovascular system . The effect of ionizing radiation on the cardiovascular system has been little studied. It has been shown that morphological changes in the myocardium are detected with a single X-ray irradiation in doses of 5 - 10 Gy. At doses of 15-20 Gy, blood clots form in the vessels of the heart. Blood vessels are more radiosensitive than cardiac muscle tissue. Even at relatively low doses electromagnetic radiation observed skin erythema, due to damage to blood vessels. It has been shown that skin blood vessels at doses of 4-10 Gy lose their ability to form capillaries. The high radiosensitivity of blood vessels is caused by damage to the outer layer of the vascular wall due to changes in the structure of the collagen protein.
Respiratory system. Lungs of adult mammals, incl. and humans - a stable organ with low cell proliferative activity. Therefore, this organ is relatively radioresistant. Thus, with local irradiation of the chest in relatively high doses (10-20 Gy), mice die after 100-150 days from pulmonary pneumonitis. LD 50/160 for mice with a single total irradiation was 13 Gy; with 20-fold fractionated irradiation, this figure increases to 45 Gy. Morphological changes in lung tissue when irradiated at a dose of 20 Gy are detected 3 months after irradiation. The duration of manifestation of radiation damage is determined by weak cellular renewal in the lung tissues.
Endocrine system. The endocrine glands consist of functional, highly differentiated cells, and accordingly, they are characterized by high radioresistance. At the same time, the ability for physiological regeneration of these cells is very low. With total irradiation of the body, imbalances of hormones are recorded, first of all, the content of hormones of the thyroid gland, adrenal glands and gonads changes. However, it is impossible to determine whether these changes are the result of direct damage to the endocrine glands or indirectly reflect the effects of radiation on other organ systems and on the entire body as a whole.
Central nervous system. Cells of the nervous system are characterized by high resistance to radiation. Nervous system reactions to radiation occur at very high doses. Thus, neurological symptoms in rats are observed 4-5 days after irradiation of the brain with a proton beam (beam diameter 3 mm) with an energy of 200 MeV at a dose of 200 Gy. At lower doses (10 -150 Gy), degenerative morphological changes develop over a longer period of time. When the diameter of the proton beam increases to 5 mm, morphological changes in brain tissue are more pronounced and appear faster. Experimental facts indicate an indirect mechanism of radiation damage to the nervous system, which is caused, first of all, by disruption of the blood supply to the tissue due to damage to blood vessels. It should be noted that functional changes in the central nervous system, for example, changes in conditioned reflexes, develop already at doses of 0.1 - 1 Gy, but they do not determine the final outcome of radiation damage to the body.
Excretory organs. The amount of experimental data on the effect of ionizing radiation on the excretory organs is very small. The most studied in this regard are the kidneys, which are classified as radioresistant organs. Experiments on various animals have shown that morphological and functional changes in them appear only at doses of more than 20 Gy. Experiments by T. Phillips on mice showed that with local irradiation in the kidney area, LD 50/180 was 24 Gy. After 16 months, this figure dropped to 13 Gy. At the same time, degenerative changes are detected in the tubules and glomeruli, leading to renal failure. Therefore, during radiation therapy of abdominal tumors, kidney damage is a limiting factor. According to some reports, irradiation of both kidneys for 5 weeks at doses above 30 Gy can cause irreversible chronic nephritis, leading to death.
Reproductive organs. Stem cells from which male gametes (spermatozoa) are formed in mammals are characterized by extremely high radiosensitivity. As a result, in most mammals and humans, already at doses of 0.5-1 Gy, cellular devastation of the testes occurs. With an absorbed dose of 2-4 Gy, the male body becomes completely sterile. However, mature sperm are characterized by very high levels of radioresistance. Experiments on mice and rats have shown that even with irradiation at doses of 1000 Gy, the structure and motility of sperm do not change and, accordingly, they retain the ability to fertilize an egg. The sterility of males that occurs after irradiation with relatively low doses is temporary and is eliminated as spermatogenesis is restored due to the proliferation of surviving viable spermatogonia.
Sterility of female mammals occurs at higher doses than in males (in rats – 15-20 Gy) and, as a rule, it is irreversible. The irreversibility of sterilization is due to the fact that the formation of female germ cells in mammals ends early after birth. As is known, in an adult organism the ovaries are not capable of active regeneration. Therefore, if all potential eggs are killed during irradiation, then the body’s fertility is lost irreversibly.
Control questions and tasks.
1. Describe the experimental design to determine LD 50 values when irradiated with X-rays:
b) fruit flies (drosophyll)
c) yeast cells
d) tobacco mosaic virus
2. There is a pattern: the higher the species is in evolutionary terms, the higher the radiosensitivity of individuals of this species . This means that representatives of highly organized groups of living organisms are less radioresistant than individuals belonging to groups with a simpler organization. How do you explain this pattern?
3. Individuals of the same species of living organisms are characterized by unequal radioresistance. Express your thoughts to explain this fact.
4. How do you understand the term “human radiation sickness”? What factors determine the manifestation of radiation sickness?
5. During a radiation accident, several people received varying doses of ionizing radiation. The individual dose for each person is unknown. According to the readings of a stationary dosimeter, it is clear that the individual dose for different exposed people can range from 0.1 Sv to 5 Sv. How can one determine the value of this indicator for each irradiated person 1-2 days after irradiation?
6. Within 7-10 days after human irradiation, a sharp decrease in the number of leukocytes and lymphocytes in the peripheral blood occurs. At the same time, the number of red blood cells in the blood changes slightly. Give an explanation for these facts.
7. The most radiosensitive organ in mammals is the red bone marrow, the most radioresistant is the nervous tissue. Why?
8. What causes the manifestation:
a) gastrointestinal syndrome;
b) cerebral syndrome
9. List the main tissues and organs to increase their radiosensitivity, starting with the less radiosensitive.
10. What factors determine the radiosensitivity of tissues, organs, organ systems, organisms?
11. Mice were irradiated with gamma radiation at an absorbed dose rate of 1 Gy/min for one hour. In what time interval will most of the irradiated animals die?
Lecture 9 a. The effect of ionizing radiation on mammals and humans.
As noted, the radiosensitivity of mammals, incl. and humans, is determined primarily by the radiosensitivity of the red bone marrow, since it is the degeneration of the hematopoietic system during total irradiation that leads to the death of the body. Therefore, the quantitative criterion for radiosensitivity is the equivalent doses at which animals die due to the manifestation of bone marrow syndrome. Quantitative characteristics The radiosensitivity of animals can be obtained by constructing survival curves. To construct a survival curve, the exposure, absorbed, or equivalent dose of ionizing radiation is marked on the x-axis. The y-axis shows the number of dead animals within 30 days, expressed as a percentage. Survival curves for mammals are S-shaped. This shape of the survival curve is due to the fact that the death of individual individuals begins when a certain (minimum lethal) dose is reached. When a certain (absolutely lethal) dose is reached, all irradiated animals die (Fig. 1.). As can be seen from the figure, when irradiated with X-rays, the death of mice begins at an absorbed dose of 4 Gy. In the dose range of 4-6 Gy, the number of dead animals increases slightly.
Rice. 1. Survival curve of mice under total X-ray irradiation (each point is represented by average data for 20 animals).
The majority of individuals die when irradiated in the dose range of 6-8 Gy. As you can see, by constructing a survival curve, it is possible to estimate the doses that cause the death of a certain number of animals. The most commonly used values in practice are LD 30 and LD 50. The figure shows that there is a significant scatter in the survival rate of individual individuals when irradiated at the same doses. This fact indicates the variability of the trait of individual radiosensitivity in experimental animals. Significant differences in the individual sensitivity of animals are also evidenced by the presence of such criteria as LD 30, LD 50, i.e. certain doses of radiation lead to the death of 30.50% of irradiated individuals. It should be noted that individual differences in radioresistance are observed not only in representatives of the same species, but also in animals of the same pure line, where individuals are characterized by an identical genotype.
The survival (death) of mammals in the studied dose range is determined, first of all, by the number of intact stem cells responsible for the renewal of blood cells.
The radiosensitivity of animals also depends on gender and age differences of individuals. As a rule, female mammals are more resistant to radiation than males. In Fig. 2. shows data on changes in LD 50 values in mice throughout life. As can be seen, the radiosensitivity of animals in the first weeks after birth is high; as the mice grow and develop, it decreases. Adult sexually mature mice aged 40 - 70 weeks are the most radioresistant. Then the radioresistance of individuals decreases and by the end of life this indicator reaches the level of newborn animals.
Rice. 2. Changes in radiosensitivity of mice of the same strain depending on their age.
Thus, the degree of resistance of animals to ionizing radiation varies greatly within one species, and radiosensitivity is determined by many factors (age, gender, physiological state of the body at the time of and after irradiation). Absorption of radiation doses of up to 10 Gy by mammals causes the appearance of various symptoms of radiation sickness. The manifestations of symptoms of radiation sickness have been experimentally studied in representatives of various species of mammals (mice, rats, dogs, sheep, goats, horses, monkeys).
Human radiation sickness. Forms of manifestation of radiation sickness
Information about human radiation sickness appeared after 1945. Observations of the surviving residents of the cities of Hiroshima and Nagasaki made it possible to obtain the first data on the clinical manifestations of radiation damage to people. Subsequently, the manifestation of radiation sickness was described many times in people who received radiation exposure under various circumstances. Many cases of human illnesses after irradiation are associated with accidents at nuclear power plants, on nuclear submarines, during irradiation with medical purposes. When exposed to a certain dose range (1-6 Sv), a certain set of changes occurs in the body, which leads to illness and can cause the death of a person. This set of changes in the body, caused by the damaging effects of ionizing radiation, is called radiation sickness. Radiation sickness can manifest itself in many forms. The forms of manifestation of human disease depend on the following factors: on the type of ionizing radiation (electromagnetic or corpuscular with different quality factors), on the method of receiving irradiation (general or local, uniform or uneven, external or internal), on the duration of irradiation (single, multiple, prolonged , chronic). Taking into account the above factors, a certain set of clinical manifestations of radiation injury in humans can be conditionally attributed to one of the following three forms:
a) acute radiation sickness with relatively uniform exposure
b) acute radiation injuries due to uneven irradiation
c) chronic radiation sickness
Acute radiation sickness with relatively uniform exposure
According to the severity of the manifestation, acute radiation sickness is divided into 4 categories: mild, moderate, severe, extremely severe. In most cases, clinical manifestations of the disease are detected at absorbed doses of X-ray and g-radiation of more than 1 Gy (D eq > 1 Sv). At lower doses, clinical manifestations may be absent or disappear quickly. When predicting the severity of radiation sickness, one should focus on the following examples:
Cells have different structures and perform different functions (for example, nerve, muscle, bone, etc.). To understand the mechanisms, defining natural radiosensitivity organism (without which it is impossible to correctly assess the consequences of human irradiation), it is necessary to consistently consider the cellular and tissue aspects radiosensitivity, because cell- basic biological unit , in which the effect of energy absorbed during irradiation is realized, which subsequently leads to the development of radiation damage. Among the many manifestations of cell life, the most sensitive to ionizing radiation is its ability to divide. Cell death (or lethal effect) is understood as the loss of a cell's ability to proliferate, and cells that have retained the ability to reproduce indefinitely are considered to survive.
Depending on the connection lethal effect With the process of division, two main forms of radiation cell death are distinguished: interphase (before cell division or without it) and reproductive (after the first or several subsequent cycles of division). Most cells, including the cells of many mammals, are characterized by a reproductive form of radiation death, the main cause of which is structural damage to chromosomes that occurs during irradiation. They are detected using cytogenetic research methods at different stages of mitosis (usually in anaphase or metaphase) in the form of so-called chromosomal rearrangements, or aberrations. The death of such aberrant cells or their descendants occurs due to uneven division or partial loss of vital genetic material due to improper connection of broken chromosomes or the tearing off of their fragments. Determination of the proportion of cells with chromosomal aberrations is often used as a reliable quantitative indicator of radiosensitivity, because on the one hand, the number of such damaged cells clearly depends on the dose of ionizing radiation, and on the other, reflecting its lethal effect.
Groups of cells form tissues that make up organs and systems (digestive, nervous, circulatory systems, endocrine glands, etc.).
Tissue is not just a sum of cells, it is already a system that has its own functions. It has its own self-regulation system and it has been established that tissue cells that are actively dividing are more susceptible to radiation. Therefore, muscles, brain, and connective tissues in adult organisms are quite resistant to the effects of radiation. Bone marrow cells, germ cells, and cells of the intestinal mucosa are the most vulnerable. Since most cell division occurs in a growing body, the effects of radiation on a child’s body are especially dangerous. The effect of radiation on the fetus can lead to the birth of defective offspring, and the most dangerous period is the 8-15th week of pregnancy, when the laying of the organs of the future person occurs.
In an adult organism, the most vulnerable is the red bone marrow, which produces blood cells that do not divide themselves and quickly “wear out.” Therefore, the body needs constant renewal. Leukocytes (white blood cells) produced by red bone marrow perform the function of protecting the body from pathogens of infectious diseases that have entered it (immune defense). As a result of impaired maturation of bone marrow cells, the content of leukocytes in the blood sharply decreases, which leads to a decrease in the body's resistance to various infections. The cells of the gonads are very sensitive; we recall that if for the entire organism as a whole with a single uniform irradiation the risk coefficient is taken as one, then for the gonads (ovaries, testes) it is equal to 0.25, and for red bone marrow – 0.12. The ovaries of adult women contain big number irreplaceable eggs at different stages of development. Therefore, irradiation leading to actual or reproductive death of eggs can cause permanent infertility. Irradiation of men with a dose of 2.5 Gy causes sterility for two to three years, and after irradiation with a dose of 4-6 Gy, permanent sterility occurs. In women, the mammary glands also have high radiation sensitivity (the risk coefficient for a single uniform exposure is 0.15).
In the digestive system, with a one-time uniform irradiation, the most radiosensitive is the liver, then in descending order of radiosensitivity are the pancreas, intestines, stomach, esophagus, salivary glands, tongue, and oral cavity. Hair follicle cells also have relatively high radiosensitivity. After irradiation with a dose of 3-4 Gy, hair begins to thin and fall out within 1-3 weeks. Hair growth can then resume. However, when irradiated with a dose of about 7 Gy, complete hair loss occurs.
It should be noted that a significant portion of radionuclides enters the body with inhaled air, food and water. In this case, the organs of the respiratory and digestive systems, as well as those organs in which radionuclides that enter the body accumulate, receive the highest doses of internal radiation.
For example, thyroid cells are highly specialized and divide slowly. The radiation risk coefficient for the thyroid gland with one-time uniform external irradiation is small - 0.03. However, when radioisotopes of iodine enter the body, they accumulate in the thyroid gland in unlimited quantities, which sharply increases the effective equivalent dose of radiation to this organ. The thyroid gland is one of the organs of the endocrine system - the most important regulatory system of the body. When particles containing radionuclides are inhaled, the area of deposition in the respiratory tract and lungs, the time of retention at the sites of deposition, and the duration of residence in the elimination routes determine the effective tissue dose. Soluble radionuclides enter the blood and spread throughout the body. Most types of cells that make up the structure of the lungs are relatively resistant to short-term irradiation, however, the lungs, as an organ with a fine structure, are characterized by significant radiosensitivity at the tissue level. The absorption of radionuclides in the gastrointestinal tract largely depends on their inclusion in various compounds. For example, the absorption of organically bound plutonium from the gastrointestinal tract is 25 times greater than the absorption of plutonium nitrate. In this case, 90% of the incoming plutonium accumulates in the skeleton, which leads to significant internal irradiation of the red bone marrow.
When exposed to different doses of radiation, the following radiation effects can be observed:
somatic (non-stochastic). These are direct physical injuries to the body that occur shortly after exposure to radiation; somatic-stochastic effects. These are consequences that are detected in large groups of people in more distant periods after exposure;
genetic effects. They manifest themselves in the form of chromosomal aberrations and dominant gene mutations.
Most radiation injuries occur long after acute single or chronic exposure. They are the so-called long-term effects of radiation, in contrast to the immediate effects, which include acute radiation sickness and the accompanying symptom complex. These late effects are dose dependent; As the dose increases, the severity of the lesion increases. In addition to the above-mentioned effects, two more types may occur in the long-term period, which are called stochastic (i.e. probabilistic, random): somatic (bodily) effects - malignant tumors and genetic effects - congenital deformities and disorders transmitted by inheritance. Both of these types of stochastic effects are based on radiation-generated mutations and other disorders in cellular structures responsible for heredity: in the first case (somatic diseases) - cancer - in non-reproductive somatic cells of various organs and tissues, in the second (in germ cells of the ovaries and testes) – genetic changes.
The patterns of damage to the entire organism are determined by two factors:
1) radiosensitivity of tissues, organs and systems essential for the survival of the organism;
2) the magnitude of the absorbed radiation dose and its distribution in space and time.
Each individually and in combination with each other, these factors determine predominant type of radiation reactions(local or general), specificity and time of manifestation(immediately after irradiation, soon after irradiation or in the long term) and their significance for the body.
It should be borne in mind that when moving from an isolated cell to a tissue, to an organ and an organism, all phenomena become more complicated. This happens because not all cells are affected equally, and the tissue effect is not equal to the sum of the cellular effects: tissues, and especially organs and systems, cannot be considered as a simple collection of cells. Being part of a tissue, cells are largely dependent on each other and on environment. Mitotic activity, degree of differentiation, level and characteristics of metabolism, as well as other physiological parameters of individual cells are not indifferent to their immediate “neighbors”, and, consequently, to the entire population as a whole. It is well known, for example, that wound healing occurs due to a temporary acceleration of the reproduction of remaining cells, which ensures tissue growth and replacement of tissue losses caused by injury, after which the type of cell division is normalized.
In addition, other factors have a great influence on tissue radiosensitivity: the degree of blood supply, the size of the irradiated volume, etc. Thus, the radiosensitivity of a tissue cannot be considered only from the standpoint of its constituent cells without taking into account morphophysiological factors. For example, erythroblasts change their radiosensitivity depending on their location in the body - in the spleen or bone marrow. All this complicates the assessment of the radiosensitivity of tissues, organs and the whole organism, but does not negate the fundamental and leading importance of cytokinetic parameters that determine the type and severity of radiation reactions at all levels of biological organization.
The most typical example of radiation damage to the body of animals and humans is acute radiation sickness, which occurs after uniform total single external irradiation. In this case, all systems, organs, tissues and cells are simultaneously exposed to radiation in the same dose. The best understanding of the main manifestations of radiation damage to the body can be achieved by comparing them with the absorbed dose in “critical organs”.
Critical organs are understood as vital organs or systems that are the first to fail in the studied range of radiation doses, which causes the death of the organism within a certain period of time after irradiation.
Thus, There is a strict relationship between the amount of absorbed dose in the body and average life expectancy, determined by differences in the radiosensitivity of individual vital (critical) systems.
With general body irradiation, depending on the equivalent absorbed dose, one of the syndromes associated with critical systems may predominate: 1) bone marrow (hematopoietic), 2) gastrointestinal, 3) cerebral. They develop as a result of irreversible damage to the relevant critical systems of the body - the hematopoietic system, gastrointestinal tract or central nervous system.
Bone marrow (hematopoietic) syndrome is associated with damage to red bone marrow stem cells. This is fatal to the body. Mature blood cells do not divide, are characterized by specialized functions, wear out quickly, and therefore must be constantly replaced with new ones. Damage to the bone marrow leads to a decrease in the number of different types of cells in the blood. A reduction in the number of peripheral blood cells causes symptoms that precede the death of the body: a decrease in the amount of blood, bleeding, infection. A reduction in the number of erythrocytes (red blood cells), and, accordingly, a decrease in hemoglobin in the blood leads to anemia (anemia). A decrease in the number of platelets involved in the blood clotting process leads to bleeding, which increases anemia. A decrease in the number of leukocytes (white blood cells) leads to a decrease in the body's resistance to various diseases.
Gastrointestinal syndrome is associated with damage to the layer of cells lining the inner wall of the small intestine, which leads to the penetration of infection into the body from the intestines due to the intestinal flora and the occurrence of infectious diseases. The inner, absorptive surface of the intestine has villi directed into the intestinal lumen. At the base of these villi are rapidly dividing cells. Disruption of the renewal process of these cells leads to gastrointestinal syndrome, the symptoms of which are pain in the gastrointestinal tract, loss of appetite, nausea, vomiting, diarrhea, ulceration of the mucous membrane of the mouth and pharynx, lethargy, and inertia. All this occurs against the background of bone marrow syndrome.
Cerebral syndrome is associated with disorders of the central nervous system. In the central nervous system, unlike the bone marrow and intestines, the cells are quite resistant to the effects of radiation, since mature nervous tissue consists of highly specialized cells that are not replaced during life. Exposure to radiation leads to functional disorders at the tissue level. Signs of cerebral syndrome are headaches, complete indifference to everything around you, impaired consciousness (temporary loss of consciousness is possible), convulsions. These symptoms are associated with brain damage.
The state of stable dynamic equilibrium of any cell population in a living organism, necessary for normal life, is maintained by cell renewal systems; any loss of cells (due to their death or migration) in the system is quantitatively replenished by the emergence of new cells, which ensures the unchanged function. Cells of each type have their own characteristic life cycle duration and, accordingly, differ in the rate of renewal.
Thus, the adult body is constantly in a state of strictly balanced cellular self-renewal, occurring continuously in a number of its vital systems.
Every minute, tens and hundreds of thousands of “used” cellular elements die off in each of them, being replaced by new ones, obviously ready to “sacrifice” themselves after a strictly defined period - and so on until the end of the life of the organism. Such a stable equilibrium in systems of cellular self-renewal, which is a necessary condition for the reliability of maintaining the viability of the organism, is called cellular homeostasis