Traditionally, ICRP and UNSCEAR provide the description of separate organ and system reactions to IR. However, in practice under long-term (months–years) low-dose-rate (less than 0.1 mGy/min) exposure of a person due to external exposure and/or radionuclide intake, not only organs and tissues but also the whole body could be affected. Tissue reactions within a unified organism are not independent from each other; they can superimpose on one another in time and mutually burden the course of each other, forming rather specific clinical syndrome of multiorgan radiation effects.

Although CRS manifestations are not specific, the sequence of their appearance under prolonged radiation exposure and their regress after the termination or considerable decrease in dose rate are characteristics of it, and that allowed Russian scientists AK Guskova, GD Baysogolov, NA Kurshakov, SA Kirillov, et al. to identify chronic radiation syndrome (in Russian literature, this syndrome acquired the name “chronic radiation sickness”) as an independent nosological form of radiation pathology.

NA Kurshakov in one of his first summarizing scientific papers, related to the issues of CRS, defined chronic radiation syndrome as pathological “process gradually developing as a result of repeated exposure to low but accumulating doses of external gamma- or X-rays, or due to repeated intake of radionuclides, and also in case of their single intake if they have a long-term half-life period and low clearance rate, as the influence of alpha- and beta-emitting radionuclides on the organism depends on their decay time and clearance rate” (Kurshakov 1956).

Utterly important characteristics of CRS were provided in the publications of AK Guskova et al. (1954). Authors emphasize that CRS results from long-term repeated exposure to rather low doses and has a long-term intermittent course. On the basis of the persons with CRS follow-up, the authors made an important addition that the disease can manifest not only within the period of protracted exposure but also even some time after its termination. The authors identified certain periods in CRS course that consistently succeed and displace one another under protracted radiation exposure (Guskova et al. 1954). Later on, not only clinical manifestations arising during chronic radiation exposure but also those that appear after its termination were defined as CRS. The late effects period was also distinguished. It was shown that disease development and progression are determined mainly by dose rate dynamics in critical organs (red BM and nervous system). The authors demonstrated that in case of low-dose-rate exposure, CRS clinical manifestations developed after rather a long period of time (the latency period made up to 2–5 years and more), whereas high-dose-rate exposure led to more severe changes in critical systems that appeared after a short latency period or even without it (Kurshakov 1956).

The subsequent follow-up of the nuclear enterprises personnel made it possible to specify the conditions of CRS formation and to note that the disease can appear as a result of long-term contact with sources of external γ-exposure that leads to accumulation of doses exceeding maximum permissible levels or due to intake of radionuclides (mainly through respiratory tract, gastrointestinal tract, injured skin). By this time, the evidence was obtained that in 3–4 years of work under increased external radiation exposure to doses up to 70–100 R and more, an organism develops CRS symptoms (Kurshakov and Kirillov 1967).

Particularly, important conclusions concerning CRS pathogenesis were made already in the 1950s by AK Guskova. It was shown that under chronic exposure at rather low doses, the changes in the nervous system appear early enough and progress in the course of CRS. It was established that early cardiovascular and other internal organs CRS manifestations are mainly determined by the central nervous system regulation changes. Pathological changes in internal organs in later terms of CRS course in their turn have adverse impact on the central nervous system status (Guskova 1960).

It is important to note that the term “chronic radiation syndrome” does not imply the duration of a disease (acute radiation syndrome manifestations can also remain for a long period of time); it only characterizes the result of protracted (chronic) radiation exposure of man.

Earlier it was considered that CRS manifestations might also include the acute radiation syndrome (ARS) consequences. However, as tissue reaction mechanisms at ARS and CRS differ, then such association was recognized as incorrect (Kurshakov 1956). It is necessary to agree that isolated initial signs of tissue radiation damage cannot be considered CRS manifestation either. However, their diagnosis is of great importance as it provides evidence of early body reactions to IR and possibility of CRS formation in case of radiation exposure continuation.

Thus, in view of current radiobiological understanding, CRS can be defined as a clinical syndrome appearing in a person due to protracted exposure to IR at doses exceeding the threshold values for the development of tissue reactions in critical systems (hematopoietic and nervous systems) which is characterized by a specific set of various organ dysfunctions.

The main criteria of CRS diagnosis are:

Threshold doses sufficient for CRS formation are being actively discussed so far. Threshold values of cumulative and annual dose vary considerably even for the Mayak PA personnel, among whom CRS cases are thoroughly studied (Guskova 2001; Guskova et al. 2002). According to the data of AK Guskova, the last estimates of a threshold dose of relatively uniform total-body γ-exposure sufficient for CRS formation make up 0.7–1.0 Gy/year and cumulative dose 2.0–3.0 Gy for the whole exposure period of 2–3 years (Guskova 2007). The lower limit of a threshold dose for CRS formation due to external γ-exposure in Mayak PA personnel estimated by other researchers makes up 0.7 Gy at dose rate of about 5.8·10⁻⁴ mGy/min (Osovets et al. 2011).

Threshold dose values for the CRS formation in population are not estimated so far. It should be noted that ICRP defines a threshold value of annual dose of chronic radiation exposure for the inhibition of hematopoiesis as ≥0.4 Gy (ICRP 2007), which is below a threshold for neurologic changes. Proceeding from the CRS concept as multiorgan pathological process in whose pathogenesis hematopoietic and neurologic disturbances predominate, it is logical to assume that the threshold dose for the CRS formation has to be slightly higher and should approximately correspond to a threshold dose for the formation of postradiation neurologic dysfunctions. In this context, the results of threshold dose estimations for the neurologic dysfunctions in Mayak PA personnel present a great interest although they are ambiguous. According to certain data, the main neurologic manifestations of CRS (vegetative dysfunction, asthenia, microorganic disorders of the central nervous system (CNS)) developed at an annual dose of γ-exposure >1 Gy (Okladnikova et al. 1992). The other research states that the appearance of vegetative dysfunction and asthenic syndrome was noted at cumulative dose of total-body γ-exposure 2.5– 3.0 Gy and dose rate of 1.3–1.5 Gy/year, and organic changes in the nervous system were registered at cumulative doses >4.0 Gy and dose rates >2.0 Gy/year (Sumina and Azizova 1991).

Probably, threshold dose values for the appearance of early CRS manifestations, which are predominantly of functional nature, in population can be lower than in the personnel that consists mainly of young healthy males. It is obvious that the population which is much more heterogeneous in age, initial health status, and other factors that influence radiosensitivity includes a larger group of radiosensitive people than the personnel does and threshold dose values for the CRS formation in the population might be lower.

The time necessary for the syndrome formation (the latency period) as well as severity of CRS are generally determined by dose rate and exposure dose to critical organs and also by individual radiosensitivity. The period of CRS formation in the Mayak PA personnel made up from 1 to 10 years depending on exposure dose and dose rate. The shortest latency period (1–2 years) was noted at annual doses of the total-body γ-exposure >2.0 Gy. The higher the exposure dose to persons with CRS, the shorter was the latency period (Okladnikova 2001). The latency period in persons with CRS residing in the Techa riverside villages was longer and typically made up 5–8 years and that indirectly testifies to much lower exposure doses to population than to the Mayak PA personnel.

CRS is characterized by the impairment of a large number of organs and systems, but most prominent changes occur in hematopoietic, immune, nervous, digestive, cardiovascular, and endocrine systems. The longer duration and intermittent character of the disease course are the other characteristic features of the CRS. The health status of persons with CRS undergoes alternations when improvement and deterioration periods succeed and displace one another. Moreover, their duration and intensity are determined by dose rate and cumulative exposure dose to critical organ systems and also by specific features of an organism. For CRS, the combination of local tissue reactions of critical systems and general (regulatory) functional disturbances which develop earlier than structural tissue changes is rather typical. It is important to note that separate unstable symptoms of chronic radiation exposure which should be considered as independent tissue reactions precede syndrome formation. In case of the exposure termination, the latter quickly regress; hence, CRS does not develop.

Already, the initial stage of CRS is characterized by a set of multiorgan functional changes in hematopoietic, cardiovascular, digestive, and other systems caused by impairment of regulatory systems function (nervous, endocrine, and immune systems). Cytopenia in this period occurs due to functional changes of proliferation and maturation of BM cells (Muksinova and Mushkachyova 1990). Such initial signs of CRS as arterial hypotension, disturbance of motor and secretory functions of the organs of the gastrointestinal tract (GIT), and others are directly connected with changes in regulatory function of the central nervous and endocrine systems. It essentially distinguishes CRS from ARS, at the basis of which already at the early stages lies the cell death in critical organs (HSC, GT epithelium, etc.).

The main manifestations of CRS are dose-dependent inhibition of hematopoiesis and neurologic dysfunctions. The most typical changes in peripheral blood at whole body uniform exposure are moderate but persistent leukopenia induced by the decrease in the number of neutrophils (1.3–2.6·10⁹/l) and band shift in the leukogram. In certain patients, toxic granulation of neutrophils and single promyelocytes and myelocytes were registered in the peripheral blood. In some cases, absolute lymphopenia was noted. Tendency to monocytosis, moderate thrombocytopenia, and emergence of giant thrombocytes frequently occurred. Typically, erythrocyte count remained within the normal range. Moderate erythrocytosis with tendency to reticulocytopenia was observed less often (to 1 %). Macrocytosis was quite often registered (Sokolova et al. 1963).

In the BM in 30 % of the patients, decrease in quantity of myelokaryocytes (to 30.0–50.0·10⁹/l) and increase in reticular and plasma cells and monocytes were noted. The delayed granulocyte maturation at the stage of band neutrophils and younger cells and the accelerated maturation and increase in mitotic activity of erythrokaryocytes frequently occurred. Given that hematopoiesis from the functional point of view is a unified system, hematological changes in CRS should be considered not as isolated impairment of separate hematopoietic lineages but as an outcome of the system radiation response of hematopoiesis. In cases of severe CRS, all hematopoietic lineages are involved in pathological process, including lymphopoiesis and erythropoiesis (Sokolova et al. 1963).

Comparing frequency and intensity of various neurologic syndromes with cumulative exposure dose, three main sequential neurologic syndromes were identified: syndrome of vegetative dysfunction or impairment of neurovisceral regulation, asthenic syndrome, and syndrome of radiation encephalomyelosis-type organic lesion of the CNS (Guskova 1960). The earliest neurologic syndrome of CRS is vegetative dysfunction. Clinical manifestations of this syndrome are multiform and are expressed in neurovascular and neurovisceral regulation impairment; the hypothalamus function (diencephalic syndrome) is less often affected. Generally, vegetative dysfunction is combined with temporary decrease in leukocyte, neutrophil, and thrombocyte content in blood and is characteristic of mild CRS cases. If the exposure proceeds, then a more profound functional impairment of the nervous system, in particular asthenic syndrome, develops which correlates with more expressed and permanent manifestations of hematopoiesis inhibition and changes in internal organs inherent to CRS cases of medium severity. Asthenic syndrome as a manifestation of CNS functional failure is characterized by inhibition of vegetative nervous system activity, bioelectrical brain activity, and changes in the higher nervous activity. It is shown that exactly these two neurologic syndromes determine CRS clinical picture and are early indicators of functional reaction of the nervous system to radiation exposure at doses exceeding threshold values. The syndrome of organic nervous system lesion is late CRS manifestation and occurs only at total-body exposure dose >2.0–3.0 Gy. It is formed gradually as a result of prolonged neurovascular, metabolic, and trophic disturbances, direct damage of the most sensitive structures of the nervous system, and is expressed in diffused microorganic encephalomyelosis-type symptomatology (Guskova 1960; Glazunov et al. 1959).

Changes in GIT (first of all, in stomach) in CRS cases also develop in a certain sequence. At first, unstable secretory function impairment (acidity decrease or increase can be observed) and delay in evacuation function of the stomach occur. If the exposure proceeds, then the intensity of functional disorders increase, and organic changes characterized by secretory function inhibition with the development of histamine-resistant achlorhydria appear. In severe cases, persons with CRS show both persistent functional and marked organic changes. Inhibition of the stomach secretory function was observed in majority of persons with CRS (Kabasheva and Doshchenko 1971). Patients suffered from regurgitation, nausea, and diarrhea. The above-mentioned digestion disorders usually developed in 2–3 years, and sometimes 4–5 years after the appearance of the first CRS symptoms (Doshchenko 1960).

The progression at all stages of CRS is to a great extent determined by vascular disorders. At the onset of a disease, they are limited to temporary disorders of peripheral blood circulation. Later, there appear more permanent changes in blood circulation in various sites of the vasculature. In case of lethal outcomes, pathological shifts in nervous system are caused by the development of severe cerebrovascular accidents with hemorrhages into brain matter and meninges. In parallel with direct radiation damage, vascular disorders aggravate neurotrophic tissue changes and determine development of the main neurologic syndromes of CRS (Guskova et al. 1954; Guskova 1960).

Follow-up of the persons with CRS allowed to establish both general patterns of pathological process development associated with various types of IR and characteristic features. Peculiarities of clinical picture of certain CRS manifestations (polymorphism of symptoms, depth and predominant level of impairment of different organs and systems function, a combination of various syndromes), and also a different ratio of neurologic, hematological, and visceral disorders, were determined by organ doses, their distribution in time and throughout the organism (Guskova 1960; Baysogolov and Springish 1960, Baysogolov 1961). A variety of clinical forms on the one hand and the established pathogenesis of the CRS on the other presupposed the necessity to develop a classification of the disease.

The first classification of CRS was suggested by GD Baysogolov in 1950, and in the subsequent years, it was modified (Baysogolov 1961; Guskova and Baysogolov 1971). According to the severity of the CRS course, three degrees are usually distinguished (I, II, and III degree). Severity of CRS as a result of total external γ-exposure correlates with the value of cumulative dose and annual exposure dose. In assessment of CRS course severity, one takes into account prevalence of pathological manifestations, their intensity, and also their reversibility in case of exposure termination or under the influence of medical assistance. Thus, severity of a syndrome is determined by:

Sometimes, the IV degree of CRS severity is distinguished, which is characterized by BM aplasia and infectious and septic complications with a hemorrhagic syndrome, and could have lethal outcome. Thus, the assessment of CRS severity is determined on the basis of the analysis of all CRS manifestations with due account for dynamics of organ exposure dose formation.

According to GD Baysogolov, it is hematological changes that influence the degree of CRS severity. It is shown that intensity of changes in the BM markedly correlates with the total CRS severity and depth of changes in peripheral blood cellular composition. Thus, in persons with CRS of mild severity, the amount of myelokaryocytes was within limits of 90.0–120.0·10⁹/l; the number of megakaryocytes, leukoerythroblastic ratio, and also neutrophil maturation index usually were within normal range. At the same time in severe CRS cases, absolute number of myelokaryocytes did not exceed 60.0·10⁹/l, megakaryocyte content decreased sharply or there were no megakaryocytes at all, and leukoerythroblastic ratios and neutrophil maturation index were going down. Decrease in neutrophil maturation index was caused by sharp reduction in the number of young granulocytes (Baysogolov 1961).

All researchers note low intensity, dynamic character, and reversibility of organ and system changes at initial stage of CRS (mild or I degree). Medium severity CRS cases (the II degree) are characterized more by expressed permanent changes in a number of organs and systems (hematopoietic, nervous, immune, etc.) and by the presence of relationship between objective data and subjective manifestations of a syndrome. Severe or III degree (some authors also distinguish most severe or IV degree) CRS cases are characterized by profound hypo- or aplastic-type inhibition of hematopoiesis with signs of organic disorders of the central nervous system (CNS) and irreversible dystrophic changes in visceral organs.

It is important to note that the division of CRS according to the degree of severity is rather relative as the intensity of different tissue reactions in patients can differ immensely and tissue reactions do not always correlate with each other. Moreover, poorly expressed clinical signs of CRS can have irreversible character and vice versa. It is also necessary to consider exceptional dynamism (progression if the radiation exposure continues, and regress in case of radiation exposure termination and medical treatment) of CRS pathological manifestation. With spreading of the process and intensification of symptoms, the CRS severity increases (Kurshakov 1956).

Long-term follow-up of the persons with CRS made it possible to identify provisionally the following stages: syndrome formation, recovery, and late effects (Guskova and Baysogolov 1971

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